Tacrolimus capsules are indicated for the prophylaxis of organ rejection, in adult patients receiving allogeneic kidney transplant [see Clinical Studies (14.1)], liver transplant [see Clinical Studies (14.2)] or heart transplant [see Clinical Studies (14.3)] and pediatric patients receiving allogeneic liver transplant [see Clinical Studies (14.2)] in combination with other immunosuppressants.

Tacrolimus capsules should not be used without supervision by a physician with experience in immunosuppressive therapy.

Tacrolimus capsules are not interchangeable or substitutable for other tacrolimus extended-release products. This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product. Under- or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision [see Warnings and Precautions (5.3)].

Oral Formulation (Capsules)

If patients are able to initiate oral therapy, the recommended starting doses should be initiated. Tacrolimus capsules may be taken with or without food. However, since the presence of food affects the bioavailability of Tacrolimus, if taken with food, it should be taken consistently the same way each time [see Clinical Pharmacology (12.3)].

General Administration Instructions

Patients should not eat grapefruit or drink grapefruit juice in combination with Tacrolimus capsules [see Drug Interactions (7.2)].

Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated Tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Therapeutic drug monitoring (TDM) is recommended for all patients receiving Tacrolimus capsules [see Dosage and Administration (2.6)].

Capsules

If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated. The initial dose of tacrolimus capsules should be administered no sooner than 6 hours after transplantation in the liver, or heart transplant patients. In kidney transplant patients, the initial dose of tacrolimus capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered.

The initial oral tacrolimus capsule dosage recommendations for adult patients with kidney, liver, or heart transplants and whole blood trough concentration range are shown in Table 1. Perform therapeutic drug monitoring (TDM) to ensure that patients are within the ranges listed in Table 1.

Table 1. Summary of Initial Oral Tacrolimus Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults

<div class="scrollingtable"><table width="100%"> <col width="32%"/> <col width="36%"/> <col width="32%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top">1. African-American patients may require higher doses compared to Caucasians <span class="Italics">(see Table 2)</span></td> </tr> <tr> <td align="left" colspan="3" valign="top">2. In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL during month 1-3 and 5-12 ng/mL during month 4-12 <span class="Italics">[see Clinical Studies (14.1)].</span></td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top">3. Patients with cystic fibrosis may require higher doses due to lower bioavailability<span class="Italics"> [see Clinical Pharmacology (12.3)].</span></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Patient Population</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus Capsules<span class="Italics"><span class="Sup">1</span></span> Initial Oral Dosage</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Whole Blood Trough Concentration Range</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> Kidney Transplant<br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> With Azathioprine<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.2 mg/kg/day, divided in two doses, administered every 12 hours<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> Month 1-3: 7-20 ng/mL<br/> Month 4-12: 5-15 ng/mL<br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> With MMF/IL-2 receptor antagonist<span class="Italics"><span class="Sup">2</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.1 mg/kg/day, divided in two doses, administered every 12 hours<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> Month 1-12: 4-11 ng/mL<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> Liver Transplant<br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> With corticosteroids only<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hours<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> Month 1-12: 5-20 ng/mL<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> Heart Transplant<br/> </p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> With azathioprine or MMF<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.075 mg/kg/day, divided in two doses, administered every 12 hours<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> Month 1-3: 10-20 ng/mL<br/> Month ≥ 4: 5-15 ng/mL<br/> </p> </td> </tr> </tbody> </table></div>

Dosage should be titrated based on clinical assessments of rejection and tolerability. Tacrolimus capsule dosages lower than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

The data in kidney transplant patients indicate that the African-American patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2) [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].

Table 2. Comparative Dose and Trough Concentrations Based on Race

<div class="scrollingtable"><table width="100%"> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Time After</span> <br/> <span class="Bold"> Transplant</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> Caucasian</span> <br/> <span class="Bold"> N=114</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> African-American</span> <br/> <span class="Bold"> N=56</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Dose</span> <br/> <span class="Bold"> (mg/kg)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Trough</span> <br/> <span class="Bold"> Concentrations</span> <br/> <span class="Bold"> (ng/mL)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Dose</span> <br/> <span class="Bold"> (mg/kg)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Trough</span> <br/> <span class="Bold"> Concentrations</span> <br/> <span class="Bold"> (ng/mL)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 7<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.18<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12.0<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.23<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 10.9<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Month 1<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.17<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12.8<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.26<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12.9<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Month 6<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.14<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11.8<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.24<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11.5<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Month 12<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.13<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 10.1<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.19<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11.0<br/> </p> </td> </tr> </tbody> </table></div>

Intravenous Injection

Tacrolimus injection should be used only as a continuous intravenous infusion and should be discontinued as soon as the patient can tolerate oral administration. The first dose of tacrolimus capsules should be given 8-12 hours after discontinuing the intravenous infusion.

The recommended starting dose of tacrolimus injection is 0.03-0.05 mg/kg/day in kidney and liver transplant, and 0.01 mg/kg/day in heart transplant given as a continuous intravenous infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

The whole blood trough concentration range described in Table 1 pertains to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous intravenous infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection. Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions (5.9)].

Oral formulation (capsules)

Pediatric patients, in general, need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole blood trough concentration range are shown in Table 3. Perform TDM to ensure that patients are within the ranges listed in Table 3.

Table 3. Summary of Initial Tacrolimus Capsule Dosage Recommendations and Whole Blood Trough Concentration Range in Children

<div class="scrollingtable"><table width="100%"> <col width="19%"/> <col width="51%"/> <col width="30%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">1. See <span class="Italics">Clinical Studies (14.2),</span> Liver Transplantation.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Patient Population</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Initial Tacrolimus Capsule Dosing</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Whole Blood Trough Concentration Range</span> <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pediatric liver transplant patients<span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 0.15 - 0.2 mg/kg/day capsules divided in two doses, administered every 12 hours<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Month 1-12: 5-20 ng/mL<br/> </p> </td> </tr> </tbody> </table></div>

For conversion of pediatric patients from tacrolimus for oral suspension to tacrolimus capsules or from tacrolimus capsules to tacrolimus for oral suspension, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration (2.6)].

Intravenous Injection

If a patient is unable to receive an oral formulation, the patient may be started on tacrolimus injection. For pediatric liver transplant patients, the intravenous dose is 0.03-0.05 mg/kg/day.

Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Due to its potential for nephrotoxicity, consider dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant, and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

In kidney transplant patients with post-operative oliguria, the initial dose of tacrolimus capsules should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh ≥ 10) may require lower doses of tacrolimus capsules. Close monitoring of blood concentrations is warranted.

The use of tacrolimus capsules in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. These patients should be monitored closely, and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments, and compliance. Whole blood trough concentration range can be found in Table 1.

Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week  post-transplantation.

The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.

Methods commonly used for the assay of tacrolimus include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore, assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer, they should be deep frozen at -20°C. One study showed drug recovery > 90% for samples stored at -20°C for 6 months, with reduced recovery observed after 6 months.

Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Tacrolimus capsules are contraindicated in patients with a hypersensitivity to tacrolimus. Tacrolimus injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions (6))].

Patients receiving immunosuppressants, including tacrolimus, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, examine patients for skin changes; exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor.

Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein-Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment.

Patients receiving immunosuppressants, including tacrolimus, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:

• Polyomavirus-associated nephropathy (PVAN), mostly due to BK virus infection

• JC virus-associated progressive multifocal leukoencephalopathy (PML)

• Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing CMV viremia and CMV disease.

Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions (6.1, 6.2)].

Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or overexposure to tacrolimus. Tacrolimus is not interchangeable or substitutable for tacrolimus extended-release products. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision. Instruct patients and caregivers to recognize the appearance of tacrolimus dosage forms [see Dosage Forms and Strengths (3)] and to confirm with the healthcare provider if a different product is dispensed.

Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, or heart transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using tacrolimus [see Adverse Reactions (6.1)].

Tacrolimus, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Nephrotoxicity was reported in clinical trials [see Adverse Reactions (6.1)].

Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration.

The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions (7.2)].

Tacrolimus may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions (6.1, 6.2)]. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of tacrolimus if neurotoxicity occurs.

Hyperkalemia has been reported with tacrolimus use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during tacrolimus therapy [see Adverse Reactions (6.1)]. Monitor serum potassium levels periodically during treatment.

Hypertension is a common adverse effect of tacrolimus therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions (5.7)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [see Drug Interactions (7.2)].

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take tacrolimus orally. Monitor patients for anaphylaxis when using the intravenous route of administration.

Tacrolimus is not recommended for use with sirolimus:

• The use of sirolimus with tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT), and is not recommended.

• The use of sirolimus (2 mg per day) with tacrolimus in heart transplant patients in a U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies (14.3)].

• The use of sirolimus with tacrolimus may increase the risk of thrombotic microangiopathy [see Warnings and Precautions (5.16)].

When co-administering tacrolimus with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions (7.2)].

Tacrolimus may prolong the QT/QTc interval and may cause Torsades de pointes. Avoid tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

When co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of  tacrolimus  with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions (7.2)].

Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered [see Adverse Reactions (6.2)].

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with tacrolimus.

The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with tacrolimus.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of tacrolimus should be considered [see Adverse Reactions (6.2)].

Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with tacrolimus. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA.

In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA.

When cannabidiol and tacrolimus are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of tacrolimus should be considered as needed when tacrolimus is co-administered with cannabidiol [see Dosage and Administration (2.2, 2.6) and Drug Interactions (7.3)].

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received Tacrolimus-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on Tacrolimus and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below.

The most common adverse reactions (≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:

Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

<div class="scrollingtable"><table width="100%"> <col width="39%"/> <col width="32%"/> <col width="30%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus/AZA</span> <br/> <span class="Bold"> (N = 205)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine/AZA</span> <br/> <span class="Bold"> (N = 207)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Nervous System</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Tremor<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 54%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 34%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Headache<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 44%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 38%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Insomnia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Paresthesia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Dizziness<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Gastrointestinal</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 44%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 41%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Nausea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 38%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 36%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Constipation<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 35%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 43%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 29%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Dyspepsia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 28%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 20%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Cardiovascular</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypertension<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 50%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 52%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Chest Pain<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 13%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Urogenital</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Creatinine Increased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 45%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 42%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Urinary Tract Infection<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 34%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 35%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Metabolic and Nutritional</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypophosphatemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 49%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 53%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypomagnesemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 34%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperlipemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 31%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 38%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperkalemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 31%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diabetes Mellitus <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 9%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypokalemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperglycemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Edema<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Hemic and Lymphatic</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Leukopenia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Miscellaneous</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Infection<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 45%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 49%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Peripheral Edema<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 36%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 48%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Asthenia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 34%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Abdominal Pain<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 33%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 31%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pain<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Fever<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 29%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 29%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Back Pain<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 20%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Respiratory System</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Dyspnea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Cough Increased<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Musculoskeletal</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Arthralgia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Skin</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Rash<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12%<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pruritus<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7%<br/> </p> </td> </tr> </tbody> </table></div>

Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n = 403), or one of two cyclosporine (CsA) regimens (Group A, n = 384 and Group B, n = 408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12-month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:

Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)

<div class="scrollingtable"><table width="100%"> <col width="25%"/> <col width="24%"/> <col width="26%"/> <col width="25%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus</span> <br/> <span class="Bold"> (Group C)</span> <br/> <span class="Bold"> (N = 403)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine</span> <br/> <span class="Bold"> (Group A)</span> <br/> <span class="Bold"> (N = 384)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine (Group B)</span> <br/> <span class="Bold"> (N = 408)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 13%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Urinary Tract Infection<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 28%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypertension<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 13%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 14%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Leukopenia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 13%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 10%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 10%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Edema Peripheral<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 13%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperlipidemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 10%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 13%<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab<br/> CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil<br/> </p> </td> </tr> </tbody> </table></div>

In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n = 212) or cyclosporine (n = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below:

Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)

<div class="scrollingtable"><table width="100%"> <col width="37%"/> <col width="31%"/> <col width="32%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus/MMF </span> <br/> <span class="Bold"> (N = 212)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine/MMF </span> <br/> <span class="Bold"> (N = 212)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Gastrointestinal Disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 44%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Nausea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 39%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 47%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Constipation<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 36%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 41%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Dyspepsia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Injury, Poisoning, and Procedural Complications</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Post-Procedural Pain<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 29%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 27%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Incision Site Complication<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 28%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Graft Dysfunction<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Metabolism and Nutrition Disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypomagnesemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 28%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypophosphatemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 28%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 21%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperkalemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperglycemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 21%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperlipidemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypokalemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Nervous System Disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Tremor<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 34%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 20%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Headache<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Blood and Lymphatic System Disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 28%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Leukopenia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Miscellaneous</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Edema Peripheral<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 35%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 46%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypertension<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 35%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Insomnia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 21%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Urinary Tract Infection<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Blood Creatinine Increased<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23%<br/> </p> </td> </tr> </tbody> </table></div>

Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection "Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies."

There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70); the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%), and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%), and Other (2%).

The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥ 15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation.

The most common adverse reactions (≥ 40%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials.

Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus

<div class="scrollingtable"><table width="100%"> <col width="24%"/> <col width="24%"/> <col width="20%"/> <col width="16%"/> <col width="16%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> U.S. TRIAL</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> EUROPEAN TRIAL</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus</span> <br/> <span class="Bold"> (N = 250)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine/ AZA</span> <br/> <span class="Bold"> (N = 250)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus</span> <br/> <span class="Bold"> (N = 264)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine/ AZA</span> <br/> <span class="Bold"> (N = 265)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold"> Nervous System</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Headache<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 64%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 60%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 37%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Insomnia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 64%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 68%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Tremor<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 56%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 46%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 48%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Paresthesia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 40%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold"> Gastrointestinal</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 72%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 47%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 37%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 27%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Nausea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 46%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 37%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 27%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> LFT Abnormal<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 36%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anorexia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 34%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 27%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 14%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Constipation<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 27%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 21%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold"> Cardiovascular</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypertension<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 47%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 56%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 38%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 43%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold"> Urogenital</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Kidney Function Abnormal<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 40%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 27%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 36%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Creatinine Increased<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 39%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> BUN Increased<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 9%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Oliguria<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Urinary Tract Infection<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 21%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold"> Metabolic and Nutritional</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypomagnesemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 48%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 45%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 9%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperglycemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 47%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 38%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 33%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperkalemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 45%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 13%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 9%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypokalemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 29%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 34%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 13%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold"> Hemic and Lymphatic</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 47%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 38%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Leukocytosis<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 8%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 8%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Thrombocytopenia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 20%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 14%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold"> Miscellaneous</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pain<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 63%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 57%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Abdominal Pain<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 59%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 54%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 29%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Asthenia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 52%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 48%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Fever<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 48%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 56%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Back Pain<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 29%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Ascites<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 27%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 22%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 8%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Peripheral Edema<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 14%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold"> Respiratory System</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pleural Effusion<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 36%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 35%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Dyspnea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 29%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 4%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Atelectasis<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 28%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 4%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold"> Skin and Appendages</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pruritus<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 36%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 20%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7%<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Rash<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 10%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 4%<br/> </p> </td> </tr> </tbody> </table></div>

Less frequently observed adverse reactions in liver transplantation patients are described under the subsection "Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies."

The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with tacrolimus (n = 157) or cyclosporine (n = 157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%).

The most common adverse reactions (≥ 15%) observed in tacrolimus-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.

Adverse reactions in heart transplant patients in the European trial are presented below:

Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

<div class="scrollingtable"><table width="100%"> <col width="37%"/> <col width="32%"/> <col width="31%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus/AZA</span> <br/> <span class="Bold"> (N = 157)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine/AZA</span> <br/> <span class="Bold"> (N = 157)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Cardiovascular System</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypertension<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 62%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 69%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pericardial Effusion<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 14%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Body as a Whole</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> CMV Infection<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Infection<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 21%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Metabolic and Nutritional Disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diabetes Mellitus<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperglycemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperlipemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 27%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Hemic and Lymphatic System</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anemia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 50%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 36%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Leukopenia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 48%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 39%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Urogenital System</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Kidney Function Abnormal<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 56%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 57%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Urinary Tract Infection<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Respiratory System</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Bronchitis<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 17%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Nervous System</span> <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Tremor<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6%<br/> </p> </td> </tr> </tbody> </table></div>

In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm.

In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and tacrolimus in combination with sirolimus (n=109), tacrolimus in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%).

Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with tacrolimus and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin < 10.0 g/dL) (65%), fasting blood glucose > 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs < 3000 cells/mcL (34%), serious bacterial infections (30%), magnesium < 1.2 mEq/L (24%), platelet count < 75,000 cells/mcL (19%), and other opportunistic infections (15%).

Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome.   Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection "Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies."

Kidney Transplantation

New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥ 126 mg/dL, HbA1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies (14.1)].

Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)

<div class="scrollingtable"><table width="100%"> <col width="32%"/> <col width="34%"/> <col width="34%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <br/> <span class="Bold"> Parameter</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> Treatment Group</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus/MMF</span> <br/> <span class="Bold"> (N = 212)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> NEORAL/MMF</span> <br/> <span class="Bold"> (N = 212)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> NODAT<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 112/150 (75%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 93/152 (61%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Fasting Plasma Glucose ≥ 126 mg/dL<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 96/150 (64%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 80/152 (53%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> HbA<span class="Sub">1C</span> ≥ 6%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 59/150 (39%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 28/152 (18%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Insulin Use ≥ 30 days<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 9/150 (6%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 4/152 (3%)<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Oral Hypoglycemic Use<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15/150 (10%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5/152 (3%)<br/> </p> </td> </tr> </tbody> </table></div>

In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of "use of insulin for 30 or more consecutive days with < 5-day gap" in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14. PTDM was reported in 20% of  tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 11). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12).

Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)

<div class="scrollingtable"><table width="100%"> <col width="52%"/> <col width="26%"/> <col width="22%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">1. Use of insulin for 30 or more consecutive days, with &lt; 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Status of PTDM<span class="Italics"><span class="Sup">1</span></span></span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus/AZA</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> CsA/AZA</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Patients without pre-transplant history of diabetes mellitus<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 151<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 151<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> New onset PTDM<span class="Italics"><span class="Sup">1</span></span> , 1<span class="Sup">st </span>Year<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30/151 (20%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6/151 (4%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">  </span> Still insulin-dependent at one year in those without prior history of diabetes<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25/151 (17%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5/151 (3%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> New onset PTDM<span class="Italics"><span class="Sup">1</span></span> post 1 year<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Patients with PTDM<span class="Italics"><span class="Sup">1</span></span> at 2 years<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16/151 (11%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5/151 (3%)<br/> </p> </td> </tr> </tbody> </table></div>

Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial

<div class="scrollingtable"><table width="100%"> <col width="34%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">1. Use of insulin for 30 or more consecutive days, with &lt; 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Patient Race</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> Patients Who Developed PTDM<span class="Italics"><span class="Sup">1</span></span></span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> African-American<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15/41 (37%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 3 (8%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hispanic <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5/17 (29%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1 (6%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Caucasian<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 10/82 (12%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1 (1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Other<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0/11 (0%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1 (10%)<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Total<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30/151 (20%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6 (4%)<br/> </p> </td> </tr> </tbody> </table></div>

Liver Transplantation

Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively (Table 13). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)].

Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients

<div class="scrollingtable"><table width="100%"> <col width="20%"/> <col width="22%"/> <col width="22%"/> <col width="18%"/> <col width="18%"/> <tfoot> <tr class="First"> <td align="left" colspan="5" valign="top">1. Use of insulin for 30 or more consecutive days, with &lt; 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. </td> </tr> <tr class="Last"> <td align="left" colspan="5" valign="top">2. Patients without pre-transplant history of diabetes mellitus.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold"> Status of PTDM<span class="Italics"><span class="Sup">1</span></span></span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> US Trial</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> European Trial</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Patients at risk<span class="Italics"><span class="Sup">2</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 239<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 236<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 239<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 249<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> New Onset PTDM<span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 42 (18%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30 (13%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26 (11%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12 (5%)<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Patients still on insulin at 1 year<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23 (10%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19 (8%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18 (8%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6 (2%)<br/> </p> </td> </tr> </tbody> </table></div>

Heart Transplantation

Insulin-dependent PTDM was reported in 13% and 22% of tacrolimus-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 14). Hyperglycemia defined as two fasting plasma glucose levels ≥ 126 mg/dL, was reported with the use of tacrolimus plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)].

Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients

<div class="scrollingtable"><table width="100%"> <col width="14%"/> <col width="20%"/> <col width="22%"/> <col width="22%"/> <col width="21%"/> <tfoot> <tr class="First"> <td align="left" colspan="5" valign="top">1. Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. </td> </tr> <tr> <td align="left" colspan="5" valign="top">2. Patients without pre-transplant history of diabetes mellitus.</td> </tr> <tr class="Last"> <td align="left" colspan="5" valign="top">3. 7-12 months for the U.S.trial.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold"> Status of PTDM<span class="Italics"><span class="Sup">1</span></span></span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> US Trial</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> European Trial</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus/MMF</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine/MMF</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus/AZA</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine/AZA</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Patients at risk<span class="Italics"><span class="Sup">2</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 75<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 83<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 132<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 138<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> New Onset PTDM<span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 10 (13%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6 (7%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 29 (22%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5(4%)<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Patients still on<br/> insulin at 1 year<span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7(9%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1(1%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24(18%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 4(3%)<br/> </p> </td> </tr> </tbody> </table></div>

Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies 

The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.

Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug.

Other reactions include:

When tacrolimus is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with tacrolimus co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.

Table 15 displays the effects of other drugs on Tacrolimus

Table 15. Effects of Other Drugs/Substances on Tacrolimus1

<div class="scrollingtable"><table width="100%"> <col width="35%"/> <col width="35%"/> <col width="29%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top">1. Tacrolimus dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures <span class="Italics">[see Clinical Pharmacology (12.3)],</span> literature reports of altered tacrolimus exposures, or the other drug's known CYP3A inhibitor/inducer status.</td> </tr> <tr> <td align="left" colspan="3" valign="top">2. High dose or double strength grapefruit juice is a <span class="Italics">strong</span> CYP3A inhibitor; low dose or single strength grapefruit juice is a <span class="Italics">moderate</span> CYP3A inhibitor.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top">3. Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting <span class="Italics">in vitro</span> CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate).</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Drug/Substance Class or Name</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Drug Interaction Effect</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Recommendations</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Grapefruit or grapefruit juice<span class="Italics"><span class="Sup">2</span></span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <span class="Italics">[see Warnings and Precautions (5.6, 5.11, 5.12)].</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Avoid grapefruit or grapefruit juice.<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Strong CYP3A Inducers<span class="Italics"><span class="Sup">3</span></span> : Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John's wort<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection <span class="Italics">[see Warnings and Precautions (5.11)]</span> .<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations <span class="Italics">[see Dosage and Administration (2.2, 2.6) and Clinical Pharmacology (12.3)]</span> .<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Strong CYP3A Inhibitors<span class="Italics"><span class="Sup">3</span></span> :<br/> Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, <span class="Italics">Schisandra sphenanthera</span> extracts<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose <span class="Italics">[see Warnings and Precautions (5.6, 5.11, 5.12)].</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Reduce tacrolimus dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations <span class="Italics">[see Dosage and Administration (2.2, 2.6) and Clinical Pharmacology (12.3)]</span> . <br/> Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary <span class="Italics">[see Warnings and Precautions (5.11)]. </span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <span class="Italics">[see Warnings and Precautions (5.6, 5.11, 5.12)].</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed <span class="Italics">[see Dosage and Administration (2.2, 2.6) and Clinical Pharmacology (12.3)]</span> . <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Other drugs, such as:<br/> Magnesium and aluminum hydroxide antacids<br/> Metoclopramide<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <span class="Italics">[see Warnings and Precautions (5.6, 5.11, 5.12)].</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed <span class="Italics">[see Dosage and Administration (2.2, 2.6) and Clinical Pharmacology (12.3)]</span> . <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> May decrease tacrolimus whole blood trough concentrations.<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed <span class="Italics">[see Dosage and Administration (2.2, 2.6)]</span> .<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Caspofungin<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> May decrease tacrolimus whole blood trough concentrations.<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed <span class="Italics">[see Dosage and Administration (2.2, 2.6)]</span> .<br/> </p> </td> </tr> </tbody> </table></div>

Direct Acting Antiviral (DAA) Therapy

The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of tacrolimus is warranted to ensure continued efficacy and safety [see Dosage and Administration (2.2, 2.6)].

The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. When cannabidiol and tacrolimus are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of tacrolimus should be considered as needed when tacrolimus is co-administered with cannabidiol [see Dosage and Administration (2.2, 2.6) and Warnings and Precautions (5.17)].

Risk Summary

Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress [see Human Data]. Advise pregnant women of the potential risk to the fetus.

Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses (0.5 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m2 basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data].

The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Risks during pregnancy are increased in organ transplant recipients.

The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death.

Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported.

Maternal Adverse Reactions

Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions (5.4)].

Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions (5.7, 5.8)].

Fetal/Neonatal Adverse Reactions

Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking tacrolimus.

Labor or Delivery

There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to tacrolimus.

Data

Human Data

There are no adequate and well controlled studies on the effects of tacrolimus in human pregnancy. Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus in utero have an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress.

TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 16. In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for renal and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.

Table 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus

<div class="scrollingtable"><table width="100%"> <col width="44%"/> <col width="28%"/> <col width="27%"/> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top">1. Includes multiple births and terminations.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top">2. Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Kidney</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Liver</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Pregnancy Outcomes<span class="Italics"><span class="Sup">1</span></span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> 462</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> 253</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Miscarriage</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24.5%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Live births</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> 331</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> 180</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      Pre-term delivery (&lt; 37 weeks)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 49%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 42%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      Low birth weight (&lt; 2500 g)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 42%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30%<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      Birth defects<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 8%<span class="Italics"><span class="Sup">2</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5%<br/> </p> </td> </tr> </tbody> </table></div>

Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients, and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients.

Animal Data

Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (2.6 to 6.9 times the recommended clinical dose range) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.

In a peri-/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects on parturition, and reduced pup viability at 3.2 mg/kg (2.6 to 6.9 times the recommended clinical dose range); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1.0 mg/kg (0.8 to 2.2 times the recommended clinical dose range).

Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation, produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (2.6 to 6.9 times the recommended clinical dose range).  Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 to 2.2 times the recommended clinical dose range) [see Nonclinical Toxicology (13.1)].

Risk Summary

Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies; exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for tacrolimus and any potential adverse effects on the breastfed child from tacrolimus or from the underlying maternal condition.

Contraception

Tacrolimus can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment with tacrolimus [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].

Infertility

Based on findings in animals, male and female fertility may be compromised by treatment with tacrolimus [see Nonclinical Toxicology (13.1)].

Safety and effectiveness have been established in pediatric liver transplant patients.

Liver Transplantation

Safety and efficacy in pediatric liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received tacrolimus, and supported by two pharmacokinetic and safety studies in 151 children who received tacrolimus. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)].

Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Clinical trials of tacrolimus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

The use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

African-American and Hispanic patients are at increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately [see Warnings and Precautions (5.4)].

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of tacrolimus [see Adverse Reactions (6.1, 6.2)], including tremors, abnormal renal function, hypertension, and peripheral edema; in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

{ "type": "p", "children": [], "text": "Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of tacrolimus [see Adverse Reactions (6.1, 6.2)], including tremors, abnormal renal function, hypertension, and peripheral edema; in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage. " }

Tacrolimus, previously known as FK506, is the active ingredient in Tacrolimus capsules. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S-[3R* [E(1S*,3S*,4S*)], 4S*,5R*,8S*, 9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]5,6,8,11,12,13,14,15,16, 17,18, 19,24, 25,26, 26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate.

{ "type": "p", "children": [], "text": "Tacrolimus, previously known as FK506, is the active ingredient in Tacrolimus capsules. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S-[3R* [E(1S*,3S*,4S*)], 4S*,5R*,8S*, 9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]5,6,8,11,12,13,14,15,16, 17,18, 19,24, 25,26, 26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate." }

The chemical structure of tacrolimus is:

{ "type": "p", "children": [], "text": "The chemical structure of tacrolimus is:" }

Tacrolimus has an empirical formula of C44H69NO12●H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

{ "type": "p", "children": [], "text": "Tacrolimus has an empirical formula of C44H69NO12●H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform." }

Tacrolimus is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, and magnesium stearate NF. The 0.5 mg capsule shell contains, FD & C Blue 1, FD & C Red 40, gelatin NF and titanium dioxide USP, the 1 mg capsule shell contains FD & C Blue 1, gelatin NF, iron oxide yellow and titanium dioxide USP, and the 5 mg capsule shell contains D & C Red 28, D & C Yellow 10, FD & C Blue 1, gelatin NF, and titanium dioxide USP.

{ "type": "p", "children": [], "text": "Tacrolimus is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, and magnesium stearate NF. The 0.5 mg capsule shell contains, FD & C Blue 1, FD & C Red 40, gelatin NF and titanium dioxide USP, the 1 mg capsule shell contains FD & C Blue 1, gelatin NF, iron oxide yellow and titanium dioxide USP, and the 5 mg capsule shell contains D & C Red 28, D & C Yellow 10, FD & C Blue 1, gelatin NF, and titanium dioxide USP." }

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB).

Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean ± S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 17).

Table 17. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients

<div class="scrollingtable"><table width="100%"> <col width="11%"/> <col width="10%"/> <col width="12%"/> <col width="11%"/> <col width="11%"/> <col width="12%"/> <col width="11%"/> <col width="12%"/> <col width="11%"/> <tfoot> <tr class="First"> <td align="left" colspan="9" valign="top">1. Not applicable</td> </tr> <tr> <td align="left" colspan="9" valign="top">2. AUC<span class="Sub">0-inf</span></td> </tr> <tr> <td align="left" colspan="9" valign="top">3. Not available</td> </tr> <tr> <td align="left" colspan="9" valign="top">4. AUC<span class="Sub">0-t</span></td> </tr> <tr> <td align="left" colspan="9" valign="top">5. Determined after the first dose</td> </tr> <tr> <td align="left" colspan="9" valign="top">6. Median [range] </td> </tr> <tr class="Last"> <td align="left" colspan="9" valign="top">7. AUC<span class="Sub">0-12</span></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <br/> <span class="Bold"> Population</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <br/> <span class="Bold"> N</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <br/> <span class="Bold"> Route (Dose)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="6" valign="top"> <p class="First"> <span class="Bold"> Parameters</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> C<span class="Sub">max</span> (ng/mL)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> T<span class="Sub">max</span> (hr)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> AUC</span> <br/> <span class="Bold"> (ng•hr/mL)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> t<span class="Sub">1/2</span> (hr)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> CL</span> <br/> <span class="Bold"> (L/hr/kg)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> V</span> <br/> <span class="Bold"> (L/kg)</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> <br/> <br/> Healthy Volunteers<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 8<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> IV (0.025 mg/kg/4 hr)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 652<span class="Italics"><span class="Sup">2</span></span>  ± 156<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 34.2 ± 7.7<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.040 ± 0.009<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1.91 ± 0.31<br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> 30<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> PO (5 mg) (capsules)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 28.8 ± 8.9<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1.5 ± 0.7<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 266<span class="Italics"><span class="Sup">2</span></span>  ± 95<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32.3 ± 8.8<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="3" valign="top"> <p class="First"> <br/> Kidney Transplant Patients<br/> </p> </td><td align="center" class="Botrule Rrule" rowspan="3" valign="top"> <p class="First"> <br/> <br/> <br/> 26<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> IV (0.02 mg/kg/12 hr)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 294<span class="Italics"><span class="Sup">2</span></span>  ± 262<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 18.8 ± 16.7<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.083 ± 0.050<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1.41 ± 0.66<br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> PO (0.2 mg/kg/day)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 19.2 ± 10.3<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 3.0<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 203<span class="Italics"><span class="Sup">2</span></span>  ± 42<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> PO (0.3 mg/kg/day)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24.2 ± 15.8<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1.5<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 288<span class="Italics"><span class="Sup">2</span></span>  ± 93<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> Liver Transplant Patients<br/> </p> </td><td align="center" class="Botrule Rrule" rowspan="2" valign="top"> <p class="First"> <br/> 17<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> IV (0.05 mg/kg/12 hr)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 3300<span class="Italics"><span class="Sup">2</span></span>  ± 2130<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11.7 ± 3.9<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.053 ± 0.017<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.85 ± .30<br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> PO (0.3 mg/kg/day)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 68.5 ± 30.0<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 2.3 ± 1.5<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 519<span class="Italics"><span class="Sup">2</span></span>  ± 179<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="3" valign="top"> <p class="First"> <br/> Heart<br/> Transplant Patients<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> IV (0.01 mg/kg/day as a continuous infusion)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 954<span class="Italics"><span class="Sup">4</span></span>  ± 334<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 23.6 ± 9.22<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.051 ± 0.015<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> PO (0.075 mg/kg/day)<span class="Italics"><span class="Sup">5</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 14.7 <span class="Underline">+ </span> 7.79<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 2.1<br/> [0.5-6.0]<span class="Italics"><span class="Sup">6</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 82.7<span class="Italics"><span class="Sup">7</span></span>  ± 63.2<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 14<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> PO (0.15 mg/kg/day)<span class="Italics"><span class="Sup">5</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 24.5 ± 13.7<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1.5<br/> [0.4-4.0]<span class="Italics"><span class="Sup">6</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 142<span class="Italics"><span class="Sup">7</span></span>  ± 116<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Italics"><span class="Sup">3</span></span> <br/> </p> </td> </tr> </tbody> </table></div>

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of the dosing regimen is necessary for optimal therapy [see Dosage and Administration (2.6)]. Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17 ± 10% in adult kidney transplant patients (N = 26), 22 ± 6% in adult liver transplant patients (N = 17), 23 ± 9% in adult heart transplant patients (N = 11) and 18 ± 5% in healthy volunteers (N = 16).

A single dose trial conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg.

In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94. In 25 heart transplant patients over a concentration range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.

If pediatric patients are converted between formulations, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.

Food Effects

The rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers.

The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean Cmax by 28% and 65%, respectively.

In healthy volunteers (N = 16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

In 11 liver transplant patients, tacrolimus administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 ± 18%) and Cmax (50 ± 19%), as compared to a fasted state.

Tacrolimus capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus [see Dosage and Administration (2.1)].

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S.trial, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Elimination

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A4 and CYP3A5). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

The mean clearance following IV administration of tacrolimus is 0.040, 0.083, 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

In a mass balance study of IV-administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1.0% and the elimination half-life based on radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015 L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7%, urinary elimination accounted for 2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5 hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of tacrolimus 0.172 ± 0.088 L/hr/kg.

Pediatric Patients

Tacrolimus capsules Pharmacokinetics in Pediatric Patients

Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and Cmax were 337 ± 167 ng·hr/mL and 48.4 ± 27.9 ng/mL, respectively. The absolute bioavailability was 31 ± 24%.

Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2 ± 2.4 years of age. Following IV infusion of a 0.06 mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2 ± 5.0 hours and 0.12 ± 0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and Cmax were 181 ± 65 ng·hr/mL and 30 ± 11 ng/mL, respectively. The absolute bioavailability was 19 ± 14%.

Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration (2.3)].

Renal and Hepatic Impaired Patients

The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19.

Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients

<div class="scrollingtable"><table width="100%"> <col width="19%"/> <col width="19%"/> <col width="18%"/> <col width="15%"/> <col width="15%"/> <col width="14%"/> <tfoot> <tr class="First"> <td align="left" colspan="6" valign="top">1. Corrected for bioavailability</td> </tr> <tr class="Last"> <td align="left" colspan="6" valign="top">2. 1 patient did not receive the PO dose</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Population (No. of Patients)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Dose</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> AUC<span class="Sub">0-t </span>(ng·hr/mL)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> t<span class="Sub">1/2</span></span> <br/> <span class="Bold"> (hr)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> V</span> <br/> <span class="Bold"> (L/kg)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Cl</span> <br/> <span class="Bold"> (L/hr/kg)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Renal Impairment<br/> (n = 12)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.02 mg/kg/4hr<br/> IV<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 393 ± 123<br/> (t = 60 hr)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26.3 ± 9.2<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1.07 ± 0.20<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.038 ± 0.014<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> Mild Hepatic<br/> Impairment<br/> (n = 6)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.02 mg/kg/4hr<br/> IV<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 367 ± 107<br/> (t = 72 hr)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 60.6 ± 43.8<br/> Range: 27.8 - 141<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 3.1 ± 1.6<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.042 ± 0.02<br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7.7 mg<br/> PO<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 488 ± 320<br/> (t = 72 hr)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 66.1 ± 44.8<br/> Range: 29.5 - 138<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 3.7 ± 4.7<span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.034 ± 0.019<span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Severe Hepatic<br/> Impairment<br/> (n = 6, IV) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.02 mg/kg/4hr<br/> IV (n = 2)<br/> <br/> 0.01 mg/kg/8hr<br/> IV (n = 4)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 762 ± 204<br/> (t = 120 hr)<br/> 289 ± 117<br/> (t = 144 hr)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 198 ± 158<br/> Range:81 -  436<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 3.9 ± 1.0<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.017 ± 0.013<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (n = 5, PO)<span class="Italics"><span class="Sup">2</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 8 mg PO<br/> (n = 1)<br/> 5 mg PO<br/> (n = 4)<br/> 4 mg PO<br/> (n = 1)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 658<br/> (t = 120 hr)<br/> 533 ± 156<br/> (t = 144 hr)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 119 ± 35<br/> Range: 85 - 178<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 3.1 ± 3.4<span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.016 ± 0.011<span class="Italics"><span class="Sup">1</span></span> <br/> </p> </td> </tr> </tbody> </table></div>

Patients with Renal Impairment

Tacrolimus pharmacokinetics, following a single IV administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 19) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)].

Patients with Cystic Fibrosis

Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration (2.2, 2.3)].

Racial or Ethnic Groups

The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of tacrolimus to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (±SD) tacrolimus Cmax in African-Americans (23.6 ± 12.1 ng/mL) was significantly lower than in Caucasians (40.2 ± 12.6 ng/mL) and the Latino-Americans (36.2 ± 15.8 ng/mL) (p < 0.01). Mean AUC0-inf tended to be lower in African-Americans (203 ± 115 ng·hr/mL) than Caucasians (344 ± 186 ng·hr/mL) and Latino-Americans (274 ± 150 ng·hr/mL). The mean (±SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was significantly lower than in Caucasians (19 ± 5.8%, p = 0.011). There was no significant difference in mean terminal T1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration (2.2)].

Male and Female Patients

A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences.

Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see Drug Interactions (7)].

Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Carcinogenesis

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions (5.1)].

A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.

The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system's ability to inhibit unrelated carcinogenesis.

Mutagenesis

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Impairment of Fertility

Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

Tacrolimus/Azathioprine (AZA)

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded.

There were 205 patients randomized to tacrolimus-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids, and azathioprine. Overall, 1-year patient and graft survivals were 96.1% and 89.6%, respectively.

Data from this trial of tacrolimus in conjunction with azathioprine indicate that during the first 3 months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year.

Tacrolimus/Mycophenolate Mofetil (MMF)

Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multicenter trial (Study 1), 1589 kidney transplant patients received tacrolimus (Group C, n = 401), sirolimus (Group D, n = 399), or one of two cyclosporine (CsA) regimens (Group A, n = 390 and Group B, n = 399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving tacrolimus/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the tacrolimus group exhibited higher estimated creatinine clearance rates (eCLcr) using the Cockcroft-Gault formula (Table 20) and experienced fewer efficacy failures, defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or loss to follow-up (Table 21) in comparison to each of the other three groups. Patients randomized to tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions (6.1)].

Table 20. Estimated Creatinine Clearance at 12 Months (Study 1)

<div class="scrollingtable"><table width="100%"> <col width="33%"/> <col width="9%"/> <col width="11%"/> <col width="9%"/> <col width="13%"/> <col width="25%"/> <tfoot> <tr class="First"> <td align="left" colspan="6" valign="top">1. All death/graft loss (n = 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n = 10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively).Weight was also imputed in the calculation of estimated GFR, if missing.</td> </tr> <tr class="Last"> <td align="left" colspan="6" valign="top">2. Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Group</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="5" valign="top"> <p class="First"> <span class="Bold"> eCL<span class="Sub">cr</span> [mL/min] at Month 12<span class="Italics"><span class="Sup">1</span></span></span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> N</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> MEAN</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> SD</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> MEDIAN</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Treatment Difference</span> <br/> <span class="Bold"> with Group C (99.2% Cl<span class="Italics"><span class="Sup">2</span></span> )</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (A) CsA/MMF/CS<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 390<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 56.5<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25.8<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 56.9<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> -8.6 (-13.7, -3.7)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (B) CsA/MMF/CS/Daclizumab<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 399<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 58.9<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25.6<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 60.9<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> -6.2 (-11.2, -1.2)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (C) Tac/MMF/CS/Daclizumab<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 401<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 65.1<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 27.4<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 66.2<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> -<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (D) Siro/MMF/CS/Daclizumab<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 399<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 56.2<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 27.4<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 57.3<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> -8.9 (-14.1, -3.9)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Total<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1589<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 59.2<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26.8<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 60.5<br/> </p> </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="6" valign="top"> <p class="First"> Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus  <br/> </p> </td> </tr> </tbody> </table></div>

Table 21. Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 1)

<div class="scrollingtable"><table width="100%"> <col width="31%"/> <col width="17%"/> <col width="17%"/> <col width="17%"/> <col width="18%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top">1. Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Group A</span> <br/> <span class="Bold"> N = 390</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Group B</span> <br/> <span class="Bold"> N = 399</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Group C</span> <br/> <span class="Bold"> N = 401</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Group D</span> <br/> <span class="Bold"> N = 399</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Overall Failure <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 141 (36.2%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 126 (31.6%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 82 (20.4%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 185 (46.4%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Components of efficacy failure<br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> BPAR <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 113 (29.0%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 106 (26.6%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 60 (15.0%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 152 (38.1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Graft loss excluding death <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 28 (7.2%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 20 (5.0%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12 (3.0%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 30 (7.5%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Mortality<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 13 (3.3%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7 (1.8%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11 (2.7%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 12 (3.0%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Lost to follow-up<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5 (1.3%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7 (1.8%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5 (1.3%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6 (1.5%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Treatment Difference of efficacy failure compared to Group C (99.2% CI<span class="Italics"><span class="Sup">1</span></span> )<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 15.8%<br/> (7.1%, 24.3%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 11.2%<br/> (2.7%, 19.5%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> -<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 26.0%<br/> (17.2%, 34.7%)<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> Key: Group A=CsA/MMF/CS, B=CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and   D = Siro/MMF/CS/Daclizumab<br/> </p> </td> </tr> </tbody> </table></div>

The protocol-specified target tacrolimus trough concentrations (Ctrough,Tac) were 3-7 ng/mL; however, the observed median Ctroughs,Tac approximated 7 ng/mL throughout the 12-month trial (Table 22). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant.

Table 22. Tacrolimus Whole Blood Trough Concentration Range (Study 1)

<div class="scrollingtable"><table width="100%"> <col width="25%"/> <col width="75%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top">1. 10 to 90<span class="Sup">th</span> Percentile: range of C<span class="Sub">trough</span>,<span class="Sub">Tac</span> that excludes lowest 10% and highest 10% of C<span class="Sub">trough,Tac</span></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Time</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Median (P10-P90<span class="Italics"><span class="Sup">1</span></span> ) tacrolimus whole blood trough concentrations range (ng/mL)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First"> Day 30 (N = 366)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6.9 (4.4 - 11.3)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First"> Day 90 (N = 351)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6.8 (4.1 - 10.7)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First"> Day 180 (N = 355)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6.5 (4.0 - 9.6)<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First"> Day 365 (N = 346)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6.5 (3.8 - 10.0)<br/> </p> </td> </tr> </tbody> </table></div>

The protocol-specified target cyclosporine trough concentrations (Ctrough,CsA) for Group B were 50-100 ng/mL; however, the observed median Ctroughs,CsA approximated 100 ng/mL throughout the 12-month trial. The protocol-specified target Ctroughs,CsA for Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median Ctroughs,CsA approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12.

While patients in all groups started MMF at 1 gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 23); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions.

Table 23. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)

<div class="scrollingtable"><table width="100%"> <col width="24%"/> <col width="24%"/> <col width="24%"/> <col width="28%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="4" valign="top">1. Percentage of patients for each time-averaged MMF dose range during various treatment periods.  Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold"> Time period (Days)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Time-averaged MMF dose (grams per day)<span class="Italics"><span class="Sup">1</span></span></span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">  Less than 2.0<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 2.0<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> Greater than 2.0<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-30 (N = 364)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 37%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 60%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 2%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-90 (N = 373)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 47%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 51%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 2%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-180 (N = 377)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 56%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 42%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 2%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-365 (N = 380)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 63%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 36%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1%<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First">      Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)<br/> </p> </td> </tr> </tbody> </table></div>

In a second randomized, open-label, multicenter trial (Study 2), 424 kidney transplant patients received tacrolimus (N = 212) or cyclosporine (N = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the tacrolimus/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving tacrolimus/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to over-immunosuppression (Table 24).

Table 24. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2)

<div class="scrollingtable"><table width="100%"> <col width="38%"/> <col width="24%"/> <col width="38%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">1. 95% confidence interval calculated using Fisher's Exact Test.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Tacrolimus/MMF </span> <br/> <span class="Bold"> (N = 212)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine/MMF </span> <br/> <span class="Bold"> (N = 212)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Overall Failure<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 32 (15.1%) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 36 (17.0%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Components of efficacy failure<br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> BPAR<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 16 (7.5%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 29 (13.7%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Graft loss excluding death<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6 (2.8%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 4 (1.9%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Mortality<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 9 (4.2%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 5 (2.4%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Lost to follow-up<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 4 (1.9%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1 (0.5%)<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Treatment Difference of efficacy failure compared to tacrolimus/MMF group (95% Cl<span class="Italics"><span class="Sup">1</span></span> )<br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1.9% (-5.2%, 9.0%)<br/> </p> </td> </tr> </tbody> </table></div>

The protocol-specified target tacrolimus whole blood trough concentrations (Ctrough,Tac) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median Ctroughs,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 25). Approximately 80% of patients maintained tacrolimus whole blood trough concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.

Table 25. Tacrolimus Whole Blood Trough Concentration Range (Study 2)

<div class="scrollingtable"><table width="100%"> <col width="23%"/> <col width="77%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top">1. 10 to 90<span class="Sup">th</span> Percentile:<span class="Sup">  </span>range of C<span class="Sub">trough</span>, <span class="Sub">Tac</span> that excludes lowest 10% and highest 10% of C<span class="Sub">trough</span>,<span class="Sub">Tac .</span></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Time</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Median (P10 - P90<span class="Italics"><span class="Sup">1</span></span> ) tacrolimus whole blood trough concentrations range (ng/mL)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 30 (N = 174)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 10.5 (6.3 - 16.8) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 60 (N = 179)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 9.2 (5.9 - 15.3)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 120 (N = 176)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 8.3 (4.6 - 13.3)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 180 (N = 171)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7.8 (5.5 - 13.2)<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 365 (N = 178)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7.1 (4.2 - 12.4)<br/> </p> </td> </tr> </tbody> </table></div>

The protocol-specified target cyclosporine whole blood concentrations (Ctrough,CsA) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median Ctroughs, CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12.

Patients in both groups started MMF at 1gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the tacrolimus/MMF group (Table 26) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the tacrolimus/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions (6.1)].

Table 26. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2)

<div class="scrollingtable"><table width="100%"> <col width="26%"/> <col width="24%"/> <col width="24%"/> <col width="25%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="4" valign="top">1. Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Time period (Days)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Time-averaged MMF dose (g/day)<span class="Italics"><span class="Sup">1</span></span></span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> Less than 2.0<br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> 2.0<br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> Greater than 2.0<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-30 (N = 212)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 25%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 69%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-90 (N = 212)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 41%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 53%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-180 (N = 212)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 52%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 41%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7%<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-365 (N = 212)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 62%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 34%<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 4%<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)<br/> </p> </td> </tr> </tbody> </table></div>

The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation.

In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed.

In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/ AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases.

One-year patient survival and graft survival in the tacrolimus-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall I-year patient survival (CsA/AZA and tacrolimus-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and tacrolimus-based treatment groups combined) was 81 % in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral tacrolimus dosing was 2 days.

Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients are often maintained at the low end of this target range.

Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9 .8 ng/mL to 19 .4 ng/mL.

Pediatric Liver Transplantation Using Tacrolimus Granules

The efficacy and safety of tacrolimus Granules plus corticosteroids were compared with a triple regimen of cyclosporine/corticosteroids/azathioprine in a randomized, open-label study, in de novo pediatric liver transplant patients. The study was conducted outside the United States and enrolled patients aged 16 years or younger. The distribution of pediatric patients by age was similar in both treatment groups, with a majority < 5 years. Patients were randomized to either tacrolimus for oral suspension 0.3 mg/kg/day (N = 91) or cyclosporine 10 mg/kg/day orally (N = 90) initiated 6 hours after completion of transplant surgery. Doses throughout the 1-year study period were adjusted to maintain whole blood trough levels within 5-20 ng/mL [see Dosage and Administration (2.3)]. Based on trough levels, doses of tacrolimus were adjusted to 0.17 mg/kg/day and 0.14 mg/kg/day by days 2 and 3, respectively. At 12 months, the incidence rate of BP AR, graft loss, death, or loss to follow-up was 52.7% in the tacrolimus group and 61.1 % in the cyclosporine group (Table 27).

Table 27. Key Efficacy Results at 12 Months in Pediatric Liver Transplant Recipients Receiving Tacrolimus Granules or Cyclosporine

<div class="scrollingtable"><table width="100%"> <col width="42%"/> <col width="26%"/> <col width="32%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">1. 95% confidence interval calculated using normal approximation.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> PROGRAF Granules </span> <br/> <span class="Bold"> (N </span> = <span class="Bold"> 91)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Cyclosporine</span> <br/> <span class="Bold"> (N </span> = <span class="Bold"> 90)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Overall Failure<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 48 (52.7%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 55 (61.1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> Components of efficacy failure<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> BPAR<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 40 (44.0%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 49 (54.4%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Graft loss<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7 (7.7%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 13 (14.4%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Graft loss excluding death<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1 (1.1%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6 (6.7%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Mortality<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 6 (6.6%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 7 (7.8%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Lost to follow-up<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 2 (2.2%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0<br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Treatment Difference of efficacy failure compared to cvclosporine <span class="Italics">(95% </span> Cr<span class="Sup">1</span>)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> -8.4% (-22.7%, 6.0%)<br/> </p> </td><td class="Botrule Rrule" valign="top"></td> </tr> </tbody> </table></div>

Two open-label, randomized, comparative trials evaluated the safety and efficacy of tacrolimus-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with tacrolimus or cyclosporine modified for 18 months. In a 3-arm trial conducted in the U.S., 331 patients received corticosteroids and tacrolimus plus sirolimus, tacrolimus plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year.

In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the tacrolimus plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32%  to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from 1 week to 3 months post-transplant, approximately 80% of patients maintained trough concentrations between 8 to 20 ng/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to18 ng/mL.

The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose tacrolimus; however, this regimen was associated with increased risk of wound-healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions (5.10)].

1. "OSHA Hazardous Drugs." OSHA.  http://www.osha.gov/SLTC/hazardousdrugs/index.html

{ "type": "p", "children": [], "text": "1. \"OSHA Hazardous Drugs.\" OSHA.  http://www.osha.gov/SLTC/hazardousdrugs/index.html" }

<div class="scrollingtable"><table width="100%"> <col width="55%"/> <col width="45%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Strength</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> 1 mg</span> <br/> (containing the<br/>  equivalent of 1 mg<br/>  anhydrous tacrolimus)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Shape/Colour</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Oblong/opaque green</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Imprint on capsule cap and body</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> "SAL" on the cap and "721" on the body</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Overbagged with 10 capsules per bag, NDC 55154-4168-0</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> NDC 55154-4168-0</span> </p> </td> </tr> </tbody> </table></div>

Note: Tacrolimus capsules, USP are not filled to maximum capsule capacity. Capsule contains labeled amount.

WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children.

Store and Dispense

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Tacrolimus can cause fetal harm. Tacrolimus capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Tacrolimus capsules. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures1.

Advise the patient or caregiver to:

Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Warnings and Precautions (5.1)].

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Warnings and Precautions (5.2)].

Inform patients that tacrolimus can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst, or hunger [see Warnings and Precautions (5.4)].

Inform patients that tacrolimus can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions (5.5)].

Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions (5.6)].

Inform patients that tacrolimus can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions (5.7)].  

Inform patients that tacrolimus can cause high blood pressure which may require treatment with antihypertensive therapy. Advise patients to monitor their blood pressure [see Warnings and Precautions (5.8)].

Inform patients that tacrolimus can cause blood clotting problems. The risk of this occurring increases when patients take tacrolimus and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria. [see Warnings and Precautions (5.16)]

Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription medicines and nonprescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice [see Drug Interactions (7)].

Inform women of childbearing potential that tacrolimus can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations (8.1, 8.2, 8.3)].

Based on animal studies, tacrolimus may affect fertility in males and females [see Nonclinical Toxicology (13.1)].

Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure).

Inform patients that tacrolimus can interfere with the usual response to immunizations and that they should avoid live vaccines. [see Warnings and Precautions (5.14)].

Rx only

Manufactured by:

Strides Pharma Science Limited

Bengaluru-562106, India

Distributed by:

Strides Pharma Inc.

East Brunswick, NJ 08816

Packaged and Distributed by:

MAJOR® PHARMACEUTICALS

Indianapolis, IN 46268 USA

Refer to package label for Distributor's NDC Number

Distributed By:

Cardinal Health

Dublin, OH 43017

L57838990525

Revised: 11/2023

PATIENT INFORMATION

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Tacrolimus (ta kroe′ li mus) Capsules, USP, for oral use

{ "type": "p", "children": [], "text": "\nTacrolimus (ta kroe′ li mus) Capsules, USP, for oral use\n" }

 Read this Patient Information before you start taking tacrolimus and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

{ "type": "p", "children": [], "text": " Read this Patient Information before you start taking tacrolimus and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. " }

What is the most important information I should know about tacrolimus?

{ "type": "p", "children": [], "text": "\nWhat is the most important information I should know about tacrolimus?\n" }

Tacrolimus can cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nTacrolimus can cause serious side effects, including:\n" }

{ "type": "", "children": [], "text": "" }

               o fever                                                                       o muscle aches

{ "type": "p", "children": [], "text": "               o fever                                                                       o muscle aches" }

               o sweats or chills                                                       o warm, red, or painful areas on your skin

{ "type": "p", "children": [], "text": "               o sweats or chills                                                       o warm, red, or painful areas on your skin" }

               o cough or flu-like symptoms

{ "type": "p", "children": [], "text": "               o cough or flu-like symptoms" }

What is tacrolimus?

{ "type": "p", "children": [], "text": "\nWhat is tacrolimus?\n" }

• Tacrolimus is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant.

{ "type": "p", "children": [], "text": "• Tacrolimus is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant." }

• Tacrolimus capsules is a type of tacrolimus immediate-release drugs and it is not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.

{ "type": "p", "children": [], "text": "• Tacrolimus capsules is a type of tacrolimus immediate-release drugs and it is not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you." }

Who should not take tacrolimus?

{ "type": "p", "children": [], "text": "\nWho should not take tacrolimus? \n" }

Do not take tacrolimus capsules if you:

{ "type": "p", "children": [], "text": "\nDo not take tacrolimus capsules if you:\n" }

•  are allergic to tacrolimus or any of the ingredients in tacrolimus capsules. See the end of this leaflet for a complete list of ingredients in tacrolimus capsules.

{ "type": "p", "children": [], "text": "•  are allergic to tacrolimus or any of the ingredients in tacrolimus capsules. See the end of this leaflet for a complete list of ingredients in tacrolimus capsules." }

What should I tell my healthcare provider before taking tacrolimus?

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Before taking tacrolimus, tell your healthcare provider about all of your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore taking tacrolimus, tell your healthcare provider about all of your medical conditions, including if you:\n" }

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o If you are able to become pregnant, you should use effective birth control before and during treatment with tacrolimus. Talk to your healthcare provider before starting treatment with tacrolimus about birth control methods that may be right for you.

{ "type": "p", "children": [], "text": "o If you are able to become pregnant, you should use effective birth control before and during treatment with tacrolimus. Talk to your healthcare provider before starting treatment with tacrolimus about birth control methods that may be right for you." }

o Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus. Talk to your healthcare provider before starting treatment with tacrolimus about birth control methods that may be right for you.

{ "type": "p", "children": [], "text": "o Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus. Talk to your healthcare provider before starting treatment with tacrolimus about birth control methods that may be right for you." }

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Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine, including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements.

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Especially tell your healthcare provider if you take:

{ "type": "p", "children": [], "text": "\nEspecially tell your healthcare provider if you take:\n" }

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Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above.

{ "type": "p", "children": [], "text": "Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. " }

Tacrolimus may affect the way other medicines work, and other medicines may affect how tacrolimus works.

{ "type": "p", "children": [], "text": "Tacrolimus may affect the way other medicines work, and other medicines may affect how tacrolimus works. " }

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine." }

How should I take tacrolimus capsules?

{ "type": "p", "children": [], "text": "\nHow should I take tacrolimus capsules?\n" }

{ "type": "", "children": [], "text": "" }

Tacrolimus capsules:

{ "type": "p", "children": [], "text": "\nTacrolimus capsules:\n" }

• Do not open or crush tacrolimus capsules.

{ "type": "p", "children": [], "text": "\n• Do not open or crush tacrolimus capsules." }

What should I avoid while taking tacrolimus capsules?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while taking tacrolimus capsules?\n" }

{ "type": "", "children": [], "text": "" }

What are the possible side effects of tacrolimus capsules?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of tacrolimus capsules?\n" }

Tacrolimus capsules may cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nTacrolimus capsules may cause serious side effects, including:\n" }

{ "type": "", "children": [], "text": "" }

                o frequent urination                        o drowsiness

{ "type": "p", "children": [], "text": "                o frequent urination                        o drowsiness" }

                o increased thirst or hunger            o loss of appetite

{ "type": "p", "children": [], "text": "                o increased thirst or hunger            o loss of appetite" }

                o blurred vision                              o fruity smell on your breath

{ "type": "p", "children": [], "text": "                o blurred vision                              o fruity smell on your breath" }

                o confusion                                    o nausea, vomiting, or stomach pain

{ "type": "p", "children": [], "text": "                o confusion                                    o nausea, vomiting, or stomach pain" }

{ "type": "", "children": [], "text": "" }

                       o           headache                               

{ "type": "p", "children": [], "text": "                       o           headache                                " }

                       o           confusion       

{ "type": "p", "children": [], "text": "                       o           confusion        " }

                       o           seizures           

{ "type": "p", "children": [], "text": "                       o           seizures            " }

                       o           changes in your vision

{ "type": "p", "children": [], "text": "                       o           changes in your vision" }

                       o           changes in behavior 

{ "type": "p", "children": [], "text": "                       o           changes in behavior  " }

                       o           coma

{ "type": "p", "children": [], "text": "                       o           coma" }

                       o           tremors

{ "type": "p", "children": [], "text": "                       o           tremors" }

                       o           numbness and tingling

{ "type": "p", "children": [], "text": "                       o           numbness and tingling" }

{ "type": "", "children": [], "text": "" }

                       o   shortness of breath                           o   feel lightheaded

{ "type": "p", "children": [], "text": "                       o   shortness of breath                           o   feel lightheaded " }

                       o   chest pain                                         o   feel faint

{ "type": "p", "children": [], "text": "                       o   chest pain                                         o   feel faint " }

{ "type": "", "children": [], "text": "" }

The most common side effects of tacrolimus capsules in people who have received a kidney, liver, or heart transplant are:

{ "type": "p", "children": [], "text": "\nThe most common side effects of tacrolimus capsules in people who have received a kidney, liver, or heart transplant are:\n" }

•    infections in general, including cytomegalovirus (cmv) infection  

{ "type": "p", "children": [], "text": "•    infections in general, including cytomegalovirus (cmv) infection   " }

•    tremors (shaking of the body)     

{ "type": "p", "children": [], "text": "•    tremors (shaking of the body)      " }

•    constipation                                   

{ "type": "p", "children": [], "text": "•    constipation                                    " }

•    diarrhea                            

{ "type": "p", "children": [], "text": "•    diarrhea                             " }

•    headache 

{ "type": "p", "children": [], "text": "•    headache  " }

•    stomach pain  

{ "type": "p", "children": [], "text": "•    stomach pain   " }

•    trouble sleeping          

{ "type": "p", "children": [], "text": "•    trouble sleeping          " }

•    nausea    

{ "type": "p", "children": [], "text": "•    nausea     " }

•    high blood sugar (diabetes)            

{ "type": "p", "children": [], "text": "•    high blood sugar (diabetes)             " }

•    low levels of magnesium in your blood 

{ "type": "p", "children": [], "text": "•    low levels of magnesium in your blood  " }

•    swelling of the hands, legs, ankles, or feet

{ "type": "p", "children": [], "text": "•    swelling of the hands, legs, ankles, or feet " }

•    weakness   

{ "type": "p", "children": [], "text": "•    weakness    " }

•    pain

{ "type": "p", "children": [], "text": "•    pain" }

•    high levels of fat in your blood

{ "type": "p", "children": [], "text": "•    high levels of fat in your blood" }

•    high levels of potassium in your blood

{ "type": "p", "children": [], "text": "•    high levels of potassium in your blood" }

•    low red blood cell count (anemia)

{ "type": "p", "children": [], "text": "•    low red blood cell count (anemia)" }

•    low white blood cell count  

{ "type": "p", "children": [], "text": "•    low white blood cell count   " }

•    fever

{ "type": "p", "children": [], "text": "•    fever " }

•    numbness or tingling in your hands and feet

{ "type": "p", "children": [], "text": "•    numbness or tingling in your hands and feet " }

•    inflammation of your airway (bronchitis)

{ "type": "p", "children": [], "text": "•    inflammation of your airway (bronchitis)" }

•    fluid around your heart

{ "type": "p", "children": [], "text": "•    fluid around your heart" }

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

{ "type": "p", "children": [], "text": "Tell your healthcare provider if you have any side effect that bothers you or that does not go away." }

These are not all the possible side effects of tacrolimus capsules. For more information, ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of tacrolimus capsules. For more information, ask your healthcare provider or pharmacist. " }

Call your doctor for medical advice about side effects. You may report side effects to  Strides Pharma Inc at 1-877-244-9825 or go to www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to  Strides Pharma Inc at 1-877-244-9825 or go to www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.\n" }

How should I store tacrolimus capsules?

{ "type": "p", "children": [], "text": "\nHow should I store tacrolimus capsules?\n" }

Store Tacrolimus capsules at room temperature between 68°F to 77°F (20°C to 25°C)

{ "type": "p", "children": [], "text": "Store Tacrolimus capsules at room temperature between 68°F to 77°F (20°C to 25°C)" }

Keep tacrolimus capsules and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep tacrolimus capsules and all medicines out of the reach of children.\n" }

General information about the safe and effective use of tacrolimus capsules. 

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of tacrolimus capsules. " }

•Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tacrolimus capsules for a condition for which it was not prescribed. Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about tacrolimus that is written for health professionals.

{ "type": "p", "children": [], "text": "•Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tacrolimus capsules for a condition for which it was not prescribed. Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about tacrolimus that is written for health professionals." }

• This Patient Information leaflet summarizes the most important information about Tacrolimus. If you would like more information, talk to your healthcare provider.

{ "type": "p", "children": [], "text": "• This Patient Information leaflet summarizes the most important information about Tacrolimus. If you would like more information, talk to your healthcare provider." }

What are the ingredients in tacrolimus capsules?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in tacrolimus capsules?\n" }

Active ingredient: tacrolimus, USP

{ "type": "p", "children": [], "text": "\nActive ingredient: tacrolimus, USP" }

Inactive ingredients: croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, and magnesium stearate NF. The 0.5 mg capsule shell contains, FD & C Blue 1, FD & C Red 40, gelatin NF and titanium dioxide USP, the 1 mg capsule shell contains FD & C Blue 1, gelatin NF, iron oxide yellow and titanium dioxide USP, and the 5 mg capsule shell contains D & C Red 28, D & C Yellow 10, FD & C Blue 1, gelatin NF, and titanium dioxide USP.

{ "type": "p", "children": [], "text": "\nInactive ingredients: croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, and magnesium stearate NF. The 0.5 mg capsule shell contains, FD & C Blue 1, FD & C Red 40, gelatin NF and titanium dioxide USP, the 1 mg capsule shell contains FD & C Blue 1, gelatin NF, iron oxide yellow and titanium dioxide USP, and the 5 mg capsule shell contains D & C Red 28, D & C Yellow 10, FD & C Blue 1, gelatin NF, and titanium dioxide USP." }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Strides Pharma Science Limited

{ "type": "p", "children": [], "text": "\nStrides Pharma Science Limited\n" }

Bengaluru - 562106, India

{ "type": "p", "children": [], "text": "Bengaluru - 562106, India" }

Distributed by:

{ "type": "p", "children": [], "text": "Distributed by:" }

Strides Pharma Inc.

{ "type": "p", "children": [], "text": "\nStrides Pharma Inc.\n" }

East Brunswick, NJ 08816

{ "type": "p", "children": [], "text": "East Brunswick, NJ 08816" }

Packaged and Distributed by:

{ "type": "p", "children": [], "text": "\nPackaged and Distributed by:\n" }

MAJOR® PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nMAJOR® PHARMACEUTICALS\n" }

Indianapolis, IN 46268 USA

{ "type": "p", "children": [], "text": "Indianapolis, IN 46268 USA" }

Refer to package label for Distributor's NDC Number

{ "type": "p", "children": [], "text": "Refer to package label for Distributor's NDC Number" }

Distributed By:

{ "type": "p", "children": [], "text": "\nDistributed By:\n" }

Cardinal Health

{ "type": "p", "children": [], "text": "\nCardinal Health \n" }

Dublin, OH 43017

{ "type": "p", "children": [], "text": "Dublin, OH 43017" }

L57838990525

{ "type": "p", "children": [], "text": "L57838990525" }

Revised: 11/2023

{ "type": "p", "children": [], "text": "\nRevised: 11/2023\n" }

Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

{ "type": "p", "children": [], "text": "Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information." }

This Patient Information has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration." }

NDC 55154-4168-0

{ "type": "p", "children": [], "text": "NDC 55154-4168-0" }

TACROLIMUS

{ "type": "p", "children": [], "text": "TACROLIMUS" }

CAPSULES, USP 1 mg

{ "type": "p", "children": [], "text": "CAPSULES, USP 1 mg" }

10 CAPSULES

{ "type": "p", "children": [], "text": "10 CAPSULES" }

PROGRAF® is indicated for the prophylaxis of organ rejection, in adult and pediatric patients receiving allogeneic kidney transplant [see Clinical Studies (14.1)], liver transplant [see Clinical Studies (14.2)], heart transplant [see Clinical Studies (14.3)], or lung transplant [see Clinical Studies (14.4)] in combination with other immunosuppressants.

PROGRAF should not be used without supervision by a physician with experience in immunosuppressive therapy.

PROGRAF capsules and PROGRAF Granules are not interchangeable or substitutable for other tacrolimus extended-release products. This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product. Under- or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended- release dosage forms must occur under physician supervision [see Warnings and Precautions (5.3)].

Intravenous Formulation - Administration Precautions due to Risk of Anaphylaxis

Intravenous use is recommended for patients who cannot tolerate oral formulations, and conversion from intravenous to oral PROGRAF is recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions that occurred with injectables containing castor oil derivatives [see Warnings and Precautions (5.9)].

Patients receiving PROGRAF injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen.

Oral Formulations (Capsules and Oral Suspension)

If patients are able to initiate oral therapy, the recommended starting doses should be initiated. PROGRAF Granules for oral suspension or PROGRAF capsules may be taken with or without food. However, since the presence of food affects the bioavailability of PROGRAF, if taken with food, it should be taken consistently the same way each time [see Clinical Pharmacology (12.3)].

General Administration Instructions

Patients should not eat grapefruit or drink grapefruit juice in combination with PROGRAF [see Drug Interactions (7.2)].

PROGRAF should not be used simultaneously with cyclosporine. PROGRAF or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated PROGRAF or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Therapeutic drug monitoring (TDM) is recommended for all patients receiving PROGRAF [see Dosage and Administration (2.6)].

Capsules

If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated. The initial dose of PROGRAF capsules should be administered no sooner than 6 hours after transplantation in the liver, heart, or lung transplant patients. In kidney transplant patients, the initial dose of PROGRAF capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered.

The initial oral PROGRAF capsule dosage recommendations for adult patients with kidney, liver, heart, or lung transplants and whole blood trough concentration range are shown in Table 1. Perform therapeutic drug monitoring (TDM) to ensure that patients are within the ranges listed in Table 1.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1. Summary of Initial Oral PROGRAF Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults</span> </caption> <col width="40%"/> <col width="34%"/> <col width="26%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>African-American patients may require higher doses compared to Caucasians <span class="Italics">(see <a href="#_Ref514770579">Table 2</a>).</span> </dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL. during month 1-3 and 5-12 ng/mL during month 4-12 <span class="Italics">[see <a href="#i4i_clinical_studies_id_a112f459-765b-47ee-a140-d1e984d31953">Clinical Studies</a> (<a href="#i4i_section_id_4f8fd71f-1184-4978-b27d-aa83dcee24dc">14.1</a>)].</span> </dd> <dt> <a href="#footnote-reference-5" name="footnote-5">‡</a> </dt> <dd>Patients with cystic fibrosis may require higher doses due to lower bioavailability <span class="Italics">[see <a href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</a> (<a href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</a>)].</span> </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Patient Population</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">PROGRAF Capsules</span><span class="Italics"><a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></span><span class="Bold"> Initial Oral Dosage</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Whole Blood Trough Concentration Range</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First">Kidney Transplant</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      With Azathioprine</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">0.2 mg/kg/day, divided in two doses, administered every 12 hours</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Month 1-3: 7-20 ng/mL</p> <p>Month 4-12: 5-15 ng/mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      With MMF/IL-2 receptor antagonist<span class="Italics"><a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a></span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">0.1 mg/kg/day, divided in two doses, administered every 12 hours</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Month 1-12: 4-11 ng/mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First">Liver Transplant</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      With corticosteroids only</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hours</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Month 1-12: 5-20 ng/mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First">Heart Transplant</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     With azathioprine or MMF</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">0.075 mg/kg/day, divided in two doses, administered every 12 hours</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Month 1-3: 10-20 ng/mL</p> <p>Month ≥ 4: 5-15 ng/mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First">Lung Transplant</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     With azathioprine or MMF</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.075 mg/kg/day<a class="Sup" href="#footnote-5" name="footnote-reference-5">‡</a>, divided in two doses, administered every 12 hours</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Month 1-3: 10-15 ng/mL</p> <p>Month 4-12: 8-12 ng/mL</p> </td> </tr> </tbody> </table></div>

Dosage should be titrated based on clinical assessments of rejection and tolerability. PROGRAF dosages lower than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

The data in kidney transplant patients indicate that the African-American patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2) [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2. Comparative Dose and Trough Concentrations Based on Race</span> </caption> <col width="17%"/> <col width="17%"/> <col width="22%"/> <col width="22%"/> <col width="22%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Time After Transplant</span> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Caucasian </span> </p> <p> <span class="Bold">N = 114</span> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">African-American</span> </p> <p> <span class="Bold">N = 56</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Dose</span> </p> <p> <span class="Bold">(mg/kg)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Trough Concentrations</span> </p> <p> <span class="Bold">(ng/mL)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Dose</span> </p> <p> <span class="Bold">(mg/kg)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Trough Concentrations (ng/mL)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Day 7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.18</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12.0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.23</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10.9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Month 1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.17</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12.8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.26</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12.9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Month 6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.14</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11.8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.24</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11.5</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Month 12</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.13</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10.1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.19</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11.0</p> </td> </tr> </tbody> </table></div>

In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly.

Intravenous Injection

PROGRAF injection should be used only as a continuous intravenous infusion and should be discontinued as soon as the patient can tolerate oral administration. The first dose of PROGRAF capsules should be given 8-12 hours after discontinuing the intravenous infusion.

The recommended starting dose of PROGRAF injection is 0.03-0.05 mg/kg/day in kidney or liver transplant, 0.01 mg/kg/day in heart transplant, and 0.01-0.03 mg/kg/day in lung transplant, given as a continuous intravenous infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

The whole blood trough concentration range described in Table 1 pertains to oral administration of PROGRAF only; while monitoring PROGRAF concentrations in patients receiving PROGRAF injection as a continuous intravenous infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as PROGRAF injection. Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions (5.9)].

Oral formulations (capsules or oral suspension)

Pediatric patients, in general, need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole blood trough concentration range are shown in Table 3. Perform TDM to ensure that patients are within the ranges listed in Table 3.

<div class="scrollingtable"><table width="100.58%"> <caption> <span>Table 3. Summary of Initial PROGRAF Capsule and PROGRAF Granules Dosage Recommendations and Whole Blood Trough Concentration Range in Children</span> </caption> <col width="33%"/> <col width="30%"/> <col width="37%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>See <span class="Italics"><a href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</a> (<a href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</a>)</span>, PROGRAF Granules Pharmacokinetics in Pediatric Patients.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">†</a> </dt> <dd>See <span class="Italics"><a href="#i4i_clinical_studies_id_a112f459-765b-47ee-a140-d1e984d31953">Clinical Studies</a> (<a href="#i4i_section_id_4107f1bb-96c3-4606-8556-e1e1ce583fb3">14.2</a>)</span>, Liver Transplantation.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">‡</a> </dt> <dd>Dose at 0.1 mg/kg/day if antibody induction treatment is administered.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">§</a> </dt> <dd>Patients with cystic fibrosis may require higher doses due to lower bioavailability <span class="Italics">[see <a href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</a> (<a href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</a>)].</span> </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Patient Population</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Initial PROGRAF Capsule and PROGRAF Granules Dosing</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Whole Blood Trough Concentration Range</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pediatric kidney transplant patients<span class="Italics"><a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">0.3 mg/kg/day capsules or oral suspension, divided in two doses, administered every 12 hours</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Month 1-12: 5-20 ng/mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pediatric liver transplant patients<span class="Italics"><a class="Sup" href="#footnote-7" name="footnote-reference-7">†</a></span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">0.15-0.2 mg/kg/day capsules or 0.2 mg/kg/day oral suspension, divided in two doses, administered every 12 hours</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Month 1-12: 5-20 ng/mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pediatric heart transplant patients<span class="Italics"><a class="Sup" href="#footnote-6">*</a></span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">0.3 mg/kg/day<span class="Italics"><a class="Sup" href="#footnote-8" name="footnote-reference-8">‡</a></span> capsules or oral suspension, divided in two doses, administered every 12 hours</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Month 1-12: 5-20 ng/mL</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Pediatric lung transplant patients</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.3 mg/kg/day<span class="Italics"><a class="Sup" href="#footnote-8">‡</a>,</span><a class="Sup" href="#footnote-9" name="footnote-reference-9">§</a> capsules or oral suspension, divided in two doses, administered every 12 hours</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Week 1-2: 10-20 ng/mL</p> <p>Week 2 to Month 12: 10-15 ng/mL</p> </td> </tr> </tbody> </table></div>

In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly.

For conversion of pediatric patients from PROGRAF Granules to PROGRAF capsules or from PROGRAF capsules to PROGRAF Granules, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration (2.6)].

Intravenous Injection

If a patient is unable to receive an oral formulation, the patient may be started on PROGRAF injection. For pediatric liver transplant patients, the intravenous dose is 0.03-0.05 mg/kg/day.

Due to its potential for nephrotoxicity, consider dosing PROGRAF at the lower end of the therapeutic dosing range in patients who have received a liver, heart, or lung transplant, and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

In kidney transplant patients with post-operative oliguria, the initial dose of PROGRAF should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh ≥ 10) may require lower doses of PROGRAF. Close monitoring of blood concentrations is warranted.

The use of PROGRAF in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. These patients should be monitored closely, and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments, and compliance. Whole blood trough concentration range can be found in Table 1.

Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.

The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.

Methods commonly used for the assay of tacrolimus include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore, assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer, they should be deep frozen at -20°C. One study showed drug recovery > 90% for samples stored at -20°C for 6 months, with reduced recovery observed after 6 months.

Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures1 [see How Supplied/ Storage and Handling (16.4)].

PROGRAF injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a polyvinyl chloride (PVC) container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Due to the chemical instability of tacrolimus in alkaline media, PROGRAF injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).

Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures1 [see How Supplied/ Storage and Handling (16.4)].

The required dose for PROGRAF Granules is calculated based on the weight of the patient. Use the minimum whole number of packets that corresponds to the required morning or evening dose. If the morning or evening dose is not covered by the whole number of packets, use one additional 0.2 mg packet to round up the dose. Do not use tubing, syringes and other equipment (cups) containing PVC to prepare or administer tacrolimus products. Do not sprinkle PROGRAF Granules on food. Prepare and administer PROGRAF Granules as follows:

   •    To prepare the dose, empty the entire contents of each PROGRAF Granules packet into a glass cup. Check for any remaining granules in the packet(s) and empty these into the cup.   •    Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the cup containing the PROGRAF Granules.   •    Mix and administer the entire contents of the cup. The granules will not completely dissolve. The suspension should be given immediately after preparation.   •    For younger patients, the suspension can be drawn up via a non-PVC oral syringe that will be dispensed with the prescription.   •    The cup or syringe should be rinsed with the same quantity of water (15 to 30 milliliters) and given to the patient to ensure all of the medication is taken.   •    The pharmacy must dispense with the Instructions for Use. Alert the patient to read the Instructions for Use.

PROGRAF is available in the following dosage forms and strengths:

{ "type": "p", "children": [], "text": "PROGRAF is available in the following dosage forms and strengths:" }

<div class="scrollingtable"><table width="100%"> <col width="19%"/> <col width="81%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Capsules</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Oblong, hard capsule for oral administration contains anhydrous tacrolimus USP as follows: </p> <p>   •    0.5 mg, light-yellow color, imprinted in red “0.5 mg” on the capsule cap and “<a name="id-823118709"></a><img alt="Letter f logo" src="/dailymed/image.cfm?name=image-01.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/>607” on capsule body</p> <p>   •    1 mg, white color, imprinted in red “1 mg” on the capsule cap and “<a name="id1908573719"></a><img alt="Letter f logo" src="/dailymed/image.cfm?name=image-02.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/>617” on capsule body</p> <p>   •    5 mg, grayish-red color, imprinted with white “5 mg” on the capsule cap and “<a name="id-2127991191"></a><img alt="Letter f logo" src="/dailymed/image.cfm?name=image-03.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/>657” on capsule body</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Injection</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">1 mL ampule for intravenous infusion contains anhydrous tacrolimus USP, 5 mg/mL </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">For Oral Suspension</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Unit-dose packets with white granules for oral suspension contains anhydrous tacrolimus USP:</p> <dl> <dt>•</dt> <dd>0.2 mg</dd> <dt>•</dt> <dd>1 mg</dd> </dl> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"19%\"/>\n<col width=\"81%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Capsules</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Oblong, hard capsule for oral administration contains anhydrous tacrolimus USP as follows: </p>\n<p>   •    0.5 mg, light-yellow color, imprinted in red “0.5 mg” on the capsule cap and “<a name=\"id-823118709\"></a><img alt=\"Letter f logo\" src=\"/dailymed/image.cfm?name=image-01.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/>607” on capsule body</p>\n<p>   •    1 mg, white color, imprinted in red “1 mg” on the capsule cap and “<a name=\"id1908573719\"></a><img alt=\"Letter f logo\" src=\"/dailymed/image.cfm?name=image-02.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/>617” on capsule body</p>\n<p>   •    5 mg, grayish-red color, imprinted with white “5 mg” on the capsule cap and “<a name=\"id-2127991191\"></a><img alt=\"Letter f logo\" src=\"/dailymed/image.cfm?name=image-03.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/>657” on capsule body</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Injection</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">1 mL ampule for intravenous infusion contains anhydrous tacrolimus USP, 5 mg/mL </p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">For Oral Suspension</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Unit-dose packets with white granules for oral suspension contains anhydrous tacrolimus USP:</p>\n<dl>\n<dt>•</dt>\n<dd>0.2 mg</dd>\n<dt>•</dt>\n<dd>1 mg</dd>\n</dl>\n</td>\n</tr>\n</tbody>\n</table></div>" }

PROGRAF is contraindicated in patients with a hypersensitivity to tacrolimus. PROGRAF injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "PROGRAF is contraindicated in patients with a hypersensitivity to tacrolimus. PROGRAF injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions (6)]." }

Patients receiving immunosuppressants, including PROGRAF, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, examine patients for skin changes; exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor.

Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein-Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment.

Patients receiving immunosuppressants, including PROGRAF, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:

Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions (6.1, 6.2)].

Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or overexposure to tacrolimus. PROGRAF is not interchangeable or substitutable for tacrolimus extended-release products. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision. Instruct patients and caregivers to recognize the appearance of PROGRAF dosage forms [see Dosage Forms and Strengths (3)] and to confirm with the healthcare provider if a different product is dispensed.

PROGRAF was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, heart, or lung transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using PROGRAF [see Adverse Reactions (6.1)].

PROGRAF, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Nephrotoxicity was reported in clinical trials [see Adverse Reactions (6.1)].

Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration.

The risk for nephrotoxicity may increase when PROGRAF is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions (7.2)].

PROGRAF may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions (6.1, 6.2)]. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of PROGRAF if neurotoxicity occurs.

Hyperkalemia has been reported with PROGRAF use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during PROGRAF therapy [see Adverse Reactions (6.1)]. Monitor serum potassium levels periodically during treatment.

Hypertension is a common adverse effect of PROGRAF therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions (5.7)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of PROGRAF [see Drug Interactions (7.2)].

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including PROGRAF, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. PROGRAF injection should be reserved for patients who are unable to take PROGRAF orally. Monitor patients for anaphylaxis when using the intravenous route of administration [see Dosage and Administration (2.1)].

PROGRAF is not recommended for use with sirolimus:

      •     The use of sirolimus with PROGRAF in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT), and is not recommended.

      •     The use of sirolimus (2 mg per day) with PROGRAF in heart transplant patients in a U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies (14.3)].

      •     The use of sirolimus with PROGRAF may increase the risk of thrombotic microangiopathy [see Warnings and Precautions (5.16)].

When co-administering PROGRAF with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of PROGRAF and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions (7.2)].

PROGRAF may prolong the QT/QTc interval and may cause Torsades de pointes. Avoid PROGRAF in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

When co-administering PROGRAF with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in PROGRAF dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of PROGRAF with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions (7.2)].

Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving PROGRAF therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of PROGRAF should be considered [see Adverse Reactions (6.2)].

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with PROGRAF.

The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with PROGRAF.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of PROGRAF should be considered [see Adverse Reactions (6.2)].

Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with PROGRAF. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA.

In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA.

When cannabidiol and PROGRAF are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of PROGRAF should be considered as needed when PROGRAF is co-administered with cannabidiol [see Dosage and Administration (2.2, 2.6) and Drug Interactions (7.3)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

Kidney Transplantation The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.

PROGRAF-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received PROGRAF-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on PROGRAF and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below.

The most common adverse reactions (≥ 30%) observed in PROGRAF-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with PROGRAF in conjunction with azathioprine are presented below:

<div class="scrollingtable"><table cellpadding="5.75pt" width="100%"> <caption> <span>Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF in Conjunction with Azathioprine (AZA)</span> </caption> <col width="53%"/> <col width="24%"/> <col width="23%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">PROGRAF/AZA</span> <br/> <span class="Bold">(N = 205)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Cyclosporine/AZA</span> <br/> <span class="Bold">(N = 207)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Nervous System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Tremor </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">54%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">34%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Headache</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">44%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">38%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Paresthesia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">23%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">44%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">41%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Nausea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">38%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">36%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Constipation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">35%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">43%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">23%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Dyspepsia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">28%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Cardiovascular</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hypertension </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">50%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">52%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Chest Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Urogenital</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Creatinine Increased </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">45%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">42%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Urinary Tract Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">34%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">35%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Metabolic and Nutritional</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hypophosphatemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">49%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">53%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hypomagnesemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">34%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hyperlipemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">31%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">38%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hyperkalemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">31%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Diabetes Mellitus</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hypokalemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hyperglycemia </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Edema</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Hemic and Lymphatic</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Anemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Leukopenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Miscellaneous</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">45%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">49%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Peripheral Edema</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">36%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">48%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Asthenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">34%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Abdominal Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">33%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">31%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Fever</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Back Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Respiratory System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Dyspnea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Cough Increased</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Arthralgia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Skin</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Rash</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Pruritus</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7%</p> </td> </tr> </tbody> </table></div>

Two trials were conducted for PROGRAF-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received PROGRAF (Group C, n = 403), or one of two cyclosporine (CsA) regimens (Group A, n = 384 and Group B, n = 408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12-month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with PROGRAF in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with PROGRAF in Conjunction with MMF (Study 1)</span> </caption> <col width="41%"/> <col width="20%"/> <col width="19%"/> <col width="19%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">PROGRAF</span> <br/> <span class="Bold">(Group C)</span> </p> <p> <span class="Bold">(N = 403)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Cyclosporine</span> <br/> <span class="Bold">(Group A)</span> </p> <p> <span class="Bold">(N = 384)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Cyclosporine</span> <br/> <span class="Bold">(Group B)</span> </p> <p> <span class="Bold">(N = 408)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Urinary Tract Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">28%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypertension </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">14%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Leukopenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Edema Peripheral</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperlipidemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab<br/> CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil</p> </td> </tr> </tbody> </table></div>

In the U.S. trial (Study 2) with PROGRAF-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received PROGRAF (n = 212) or cyclosporine (n = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with PROGRAF in conjunction with MMF in Study 2 are presented below:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF in Conjunction with MMF (Study 2)</span> </caption> <col width="54%"/> <col width="22%"/> <col width="24%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule Toprule" valign="top"><span class="Bold"> </span></th><th align="center" class="Lrule Rrule Toprule" valign="middle"><span class="Bold">PROGRAF/MMF</span></th><th align="center" class="Lrule Rrule Toprule" valign="middle"><span class="Bold">Cyclosporine/MMF</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> </span></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">(N = 212)</span></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">(N = 212)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td><td class="Botrule" valign="middle"></td><td class="Botrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">44%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">26%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Nausea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">39%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">47%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Constipation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">36%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">41%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">25%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Dyspepsia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">18%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">15%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Injury, Poisoning, and Procedural Complications</span> </p> </td><td class="Botrule" valign="middle"></td><td class="Botrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Post-Procedural Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">27%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Incision Site Complication</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">28%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">23%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Graft Dysfunction</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">18%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Metabolism and Nutrition Disorders</span> </p> </td><td class="Botrule" valign="middle"></td><td class="Botrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hypomagnesemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">28%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">22%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hypophosphatemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">28%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">21%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hyperkalemia </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">19%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hyperglycemia </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">21%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">15%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hyperlipidemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">18%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">25%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hypokalemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">16%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">18%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td><td class="Botrule" valign="middle"></td><td class="Botrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Tremor </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">34%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">20%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Headache</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">25%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Blood and Lymphatic System Disorders</span> </p> </td><td class="Botrule" valign="middle"></td><td class="Botrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Anemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">30%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">28%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Leukopenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">16%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">12%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Miscellaneous</span> </p> </td><td class="Botrule" valign="middle"></td><td class="Botrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Edema Peripheral</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">35%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">46%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Hypertension </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">32%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">35%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">30%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">21%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Urinary Tract Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">22%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Blood Creatinine Increased</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">23%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">23%</p> </td> </tr> </tbody> </table></div>

Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

Liver Transplantation

There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70); the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%), and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%), and Other (2%).

The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥ 15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation.

The most common adverse reactions (≥ 40%) observed in PROGRAF-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of PROGRAF and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving PROGRAF in the U.S. and European randomized trials.

<div class="scrollingtable"><table cellpadding="5.75pt" width="100%"> <caption> <span>Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF </span> </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="19%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"><span class="Bold">U.S. TRIAL</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"><span class="Bold">EUROPEAN TRIAL</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="middle"><span class="Bold">PROGRAF</span> <br/> <span class="Bold">(N = 250)</span></th><th align="center" class="Botrule Lrule Rrule" valign="middle"><span class="Bold">Cyclosporine/</span> <br/> <span class="Bold">AZA</span> <br/> <span class="Bold">(N = 250)</span></th><th align="center" class="Botrule Lrule Rrule" valign="middle"><span class="Bold">PROGRAF</span> <br/> <span class="Bold">(N = 264)</span></th><th align="center" class="Botrule Lrule Rrule" valign="middle"><span class="Bold">Cyclosporine/</span> <br/> <span class="Bold">AZA</span> <br/> <span class="Bold">(N = 265)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Nervous System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Headache </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">64%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">60%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">37%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">64%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">68%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">23%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Tremor</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">56%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">46%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">48%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Paresthesia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">40%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">72%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">47%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">37%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">27%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Nausea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">46%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">37%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">27%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    LFT Abnormal</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">36%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Anorexia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">34%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">27%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">14%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Constipation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">27%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">23%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">21%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Cardiovascular</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hypertension</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">47%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">56%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">38%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">43%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Urogenital</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Kidney Function Abnormal</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">40%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">27%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">36%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">23%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Creatinine Increased</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">39%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    BUN Increased</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Oliguria</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Urinary Tract Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">21%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Metabolic and Nutritional</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hypomagnesemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">48%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">45%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hyperglycemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">47%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">38%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">33%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hyperkalemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">45%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hypokalemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">34%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Hemic and Lymphatic</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Anemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">47%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">38%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Leukocytosis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Thrombocytopenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">14%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Miscellaneous</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">63%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">57%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Abdominal Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">59%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">54%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Asthenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">52%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">48%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Fever</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">48%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">56%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Back Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Ascites</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">27%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Peripheral Edema</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">14%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Respiratory System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Pleural Effusion</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">36%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">35%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Dyspnea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">23%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Atelectasis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">28%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Skin and Appendages</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Pruritus</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">36%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Rash</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4%</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 8. Pediatric Liver Transplantation: Adverse Reactions Occurring in &gt; 10% of Patients Treated with PROGRAF Granules (STUDY 01-13)</span> </caption> <col width="40%"/> <col width="32%"/> <col width="28%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">PROGRAF Granules</span> <br/> <span class="Bold">(N = 91)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Cyclosporine</span> <br/> <span class="Bold">(N = 90)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Body as a Whole</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Fever</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">46%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">51%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Sepsis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   CMV Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   EBV Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Ascites</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Peritonitis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Cardiovascular System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Hypertension</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">39%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">47%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Digestive System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Liver Function Tests Abnormal</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">37%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">28%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Diarrhea </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Gastrointestinal Hemorrhage</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Bile Duct Disorder</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Gastroenteritis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Hemic and Lymphatic System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Anemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Metabolic and Nutritional Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Hypomagnesemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">40%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Acidosis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Hyperkalemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Respiratory System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Pleural Effusion</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">22%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Bronchitis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Urogenital System</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Kidney Function Abnormal</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">14%</p> </td> </tr> </tbody> </table></div>

Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

Heart Transplantation

The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with PROGRAF (n = 157) or cyclosporine (n = 157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%).

The most common adverse reactions (≥ 15%) observed in PROGRAF-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.

Adverse reactions in heart transplant patients in the European trial are presented below:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF in Conjunction with Azathioprine (AZA)</span> </caption> <col width="46%"/> <col width="28%"/> <col width="26%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">PROGRAF/AZA</span> <br/> <span class="Bold">(N = 157)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Cyclosporine/AZA</span> <br/> <span class="Bold">(N = 157)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Cardiovascular System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hypertension </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">62%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">69%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Pericardial Effusion</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">14%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Body as a Whole</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    CMV Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">21%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Metabolic and Nutritional Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Diabetes Mellitus </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hyperglycemia </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">23%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Hyperlipemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">27%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Hemic and Lymphatic System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Anemia </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">50%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">36%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Leukopenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">48%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">39%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Urogenital System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Kidney Function Abnormal </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">56%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">57%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Urinary Tract Infection</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Respiratory System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Bronchitis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Nervous System</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Tremor </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6%</p> </td> </tr> </tbody> </table></div>

In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm.

In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and PROGRAF in combination with sirolimus (n=109), PROGRAF in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%).Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with PROGRAF and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin < 10.0 g/dL) (65%), fasting blood glucose > 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs < 3000 cells/mcL (34%), serious bacterial infections (30%), magnesium < 1.2 mEq/L (24%), platelet count < 75,000 cells/mcL (19%), and other opportunistic infections (15%).

Other targeted treatment-emergent adverse reactions in PROGRAF-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.”

New Onset Diabetes After Transplant

Kidney Transplantation

New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥ 126 mg/dL, HbA1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the PROGRAF-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies (14.1)].

<div class="scrollingtable"><table width="101.54%"> <caption> <span>Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)</span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="bottom"><span class="Bold">Parameter</span></th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Treatment Group</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">PROGRAF/MMF</span> <br/> <span class="Bold">(N = 212)</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">NEORAL/MMF</span> <br/> <span class="Bold">(N = 212)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">NODAT</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">112/150 (75%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">93/152 (61%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Fasting Plasma Glucose ≥ 126 mg/dL</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">96/150 (64%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">80/152 (53%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    HbA<span class="Sub">1C </span>≥ 6%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">59/150 (39%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28/152 (18%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Insulin Use ≥ 30 days</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9/150 (6%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4/152 (3%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Oral Hypoglycemic Use</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15/150 (10%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5/152 (3%)</p> </td> </tr> </tbody> </table></div>

In early trials of PROGRAF, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of “use of insulin for 30 or more consecutive days with < 5-day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14. PTDM was reported in 20% of PROGRAF/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 11). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)</span> </caption> <col width="58%"/> <col width="23%"/> <col width="19%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Status of PTDM</span><a class="Sup" href="#footnote-10" name="footnote-reference-10">*</a></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">PROGRAF/AZA</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">CsA/AZA</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-10" name="footnote-10">*</a> </dt> <dd>Use of insulin for 30 or more consecutive days, with &lt; 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Patients without pre-transplant history of diabetes mellitus</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">151</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">151</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    New onset PTDM<a class="Sup" href="#footnote-10">*</a>, 1<span class="Sup">st</span> Year</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30/151 (20%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6/151 (4%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">    Still insulin-dependent at one year in those without prior history of diabetes</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">25/151 (17%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">5/151 (3%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    New onset PTDM<a class="Sup" href="#footnote-10">*</a> post 1 year</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    Patients with PTDM<a class="Sup" href="#footnote-10">*</a> at 2 years</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16/151 (11%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5/151 (3%)</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial</span> </caption> <col width="28%"/> <col width="36%"/> <col width="36%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Patient Race</span></th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="middle"><span class="Bold">Patients Who Developed PTDM</span><a class="Sup" href="#footnote-11" name="footnote-reference-11">*</a></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">PROGRAF</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">Cyclosporine</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-11" name="footnote-11">*</a> </dt> <dd>Use of insulin for 30 or more consecutive days, with &lt; 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> African-American</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15/41 (37%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (8%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hispanic</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5/17 (29%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (6%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Caucasian</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10/82 (12%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Other</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/11 (0%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (10%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Total</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30/151 (20%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (4%)</p> </td> </tr> </tbody> </table></div>

Liver Transplantation

Insulin-dependent PTDM was reported in 18% and 11% of PROGRAF-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively (Table 13). Hyperglycemia was associated with the use of PROGRAF in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)].

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients</span> </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Status of PTDM</span><a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a></th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">US Trial</span></th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">European Trial</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">PROGRAF</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">Cyclosporine</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">PROGRAF</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">Cyclosporine</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>Use of insulin for 30 or more consecutive days, with &lt; 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>Patients without pre-transplant history of diabetes mellitus.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Patients at risk<a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">239</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">236</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">239</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">249</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">New Onset PTDM<a class="Sup" href="#footnote-12">*</a> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">42 (18%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30 (13%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">26 (11%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (5%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Patients still on insulin at 1 year</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">23 (10%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">19 (8%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">18 (8%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">6 (2%)</p> </td> </tr> </tbody> </table></div>

Heart Transplantation

Insulin-dependent PTDM was reported in 13% and 22% of PROGRAF-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 14). Hyperglycemia, defined as two fasting plasma glucose levels ≥ 126 mg/dL, was reported with the use of PROGRAF plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)].

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients</span> </caption> <col width="19%"/> <col width="20%"/> <col width="21%"/> <col width="21%"/> <col width="20%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"><span class="Bold">Status of PTDM</span><a class="Sup" href="#footnote-14" name="footnote-reference-14">*</a></th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">US Trial</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">European Trial</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">PROGRAF/MMF</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">Cyclosporine/MMF</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">PROGRAF/AZA</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">Cyclosporine/AZA</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-14" name="footnote-14">*</a> </dt> <dd>Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">†</a> </dt> <dd>Patients without pre-transplant history of diabetes mellitus.</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">‡</a> </dt> <dd>7-12 months for the U.S. trial.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Patients at risk<a class="Sup" href="#footnote-15" name="footnote-reference-15">†</a> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">75</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">83</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">132</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">138</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">New Onset PTDM<a class="Sup" href="#footnote-14">*</a> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">10 (13%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">6 (7%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">29 (22%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">5 (4%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Patients still on insulin at 1 year<a class="Sup" href="#footnote-16" name="footnote-reference-16">‡</a> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">7 (9%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">1 (1%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">24 (18%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4 (3%)</p> </td> </tr> </tbody> </table></div>

Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies

The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.

Lung Transplantation

Adverse reactions in lung transplant patients were similar to those in kidney, liver, or heart transplant patients treated with PROGRAF [see Adverse Reactions (6.2)].

The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug.

Other reactions include:

Postmarketing Adverse Reactions in Lung Transplantation

Based on U.S. Scientific Registry of Transplant Recipients (SRTR) data, published clinical trials, and postmarketing reports, the safety profile for lung transplant patients treated with PROGRAF is consistent with the safety profile in kidney, liver, and heart transplant patients treated with PROGRAF. The primary adverse reactions described include renal dysfunction, infection, diabetes, gastrointestinal disturbances (e.g., diarrhea), hypertension, and neurological events (e.g., tremor). As expected, lung transplant patients have a higher incidence of pulmonary complications (e.g., pneumonia, bronchiolitis obliterans syndrome) than other solid organ transplant patients, which is in part due to the underlying disease and to the nature of the transplanted organ.

When PROGRAF is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with PROGRAF co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.

Table 15 displays the effects of other drugs on PROGRAF.

<div class="scrollingtable"><table width="97.64%"> <caption> <span>Table 15. Effects of Other Drugs/Substances on PROGRAF<a class="Sup" href="#footnote-17" name="footnote-reference-17">*</a></span> </caption> <col width="36%"/> <col width="35%"/> <col width="29%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Drug/Substance Class or Name</span></th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Drug Interaction Effect</span></th><th align="left" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Recommendations</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-17" name="footnote-17">*</a> </dt> <dd>PROGRAF dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures <span class="Italics">[see <a href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</a> (<a href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</a>)]</span>, literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status.</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">†</a> </dt> <dd>High dose or double strength grapefruit juice is a <span class="Italics">strong</span> CYP3A inhibitor; low dose or single strength grapefruit juice is a <span class="Italics">moderate</span> CYP3A inhibitor.</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">‡</a> </dt> <dd>Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting <span class="Italics">in vitro</span> CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate).</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Grapefruit or grapefruit juice<a class="Sup" href="#footnote-18" name="footnote-reference-18">†</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <span class="Italics">[see <a href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</a> (<a href="#i4i_section_id_30c689c5-c4ac-4245-b169-23d784fda7f3">5.6</a>, <a href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</a>, <a href="#ID_d05977d5-ff84-489b-bffa-eebc1127623e">5.12</a>)]</span>.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Avoid grapefruit or grapefruit juice.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Strong CYP3A Inducers<a class="Sup" href="#footnote-19" name="footnote-reference-19">‡</a>:</p> <dl> <dt> </dt> <dd>Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s wort</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection <span class="Italics">[see <a href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</a> (<a href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</a>)]</span>.</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Increase PROGRAF dose and monitor tacrolimus whole blood trough concentrations <span class="Italics">[see <a href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</a> (<a href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</a>, <a href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</a>) and <a href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</a> (<a href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</a>)]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Strong CYP3A Inhibitors<a class="Sup" href="#footnote-19">‡</a>:</p> <dl> <dt> </dt> <dd>Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, <span class="Italics">Schisandra sphenanthera </span>extracts</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose<span class="Italics"> [see <a href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</a> (<a href="#i4i_section_id_30c689c5-c4ac-4245-b169-23d784fda7f3">5.6</a>, <a href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</a>, <a href="#ID_d05977d5-ff84-489b-bffa-eebc1127623e">5.12</a>)]</span>.</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Reduce PROGRAF dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations <span class="Italics">[see <a href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</a> (<a href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</a>, <a href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</a>) and <a href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</a> (<a href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</a>)]</span>. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary <span class="Italics">[see <a href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</a> (<a href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</a>)].</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Mild or Moderate CYP3A Inhibitors:</p> <dl> <dt> </dt> <dd>Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <span class="Italics">[see <a href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</a> (<a href="#i4i_section_id_30c689c5-c4ac-4245-b169-23d784fda7f3">5.6</a>, <a href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</a>, <a href="#ID_d05977d5-ff84-489b-bffa-eebc1127623e">5.12</a>)]</span>.</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Monitor tacrolimus whole blood trough concentrations and reduce PROGRAF dose if needed <span class="Italics">[see <a href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</a> (<a href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</a>, <a href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</a>) and <a href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</a> (<a href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</a>)]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Other drugs, such as:</p> <dl> <dt> </dt> <dd>Magnesium and aluminum hydroxide antacids</dd> <dt> </dt> <dd>Metoclopramide</dd> </dl> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <span class="Italics">[see <a href="#i4i_warnings_precautions_id_f394c7fc-4f30-417a-9dbd-623b45eb7b87">Warnings and Precautions</a> (<a href="#i4i_section_id_30c689c5-c4ac-4245-b169-23d784fda7f3">5.6</a>, <a href="#ID_7c76e1f8-38a8-447d-8f43-fd6fde88208b">5.11</a>, <a href="#ID_d05977d5-ff84-489b-bffa-eebc1127623e">5.12</a>)]</span>.</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Monitor tacrolimus whole blood trough concentrations and reduce PROGRAF dose if needed <span class="Italics">[see <a href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</a> (<a href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</a>, <a href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</a>) and <a href="#i4i_clinical_pharmacology_id_14d83978-0768-410f-abb6-b844bae5786a">Clinical Pharmacology</a> (<a href="#i4i_pharmacokinetics_id_80b057f4-69f3-4ea8-8225-df8ca30a4fe4">12.3</a>)]</span>.</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First">Mild or Moderate CYP3A Inducers</p> <dl> <dt> </dt> <dd>Methylprednisolone, prednisone</dd> </dl> </td><td class="Lrule Rrule" valign="top"> <p class="First">May decrease tacrolimus whole blood trough concentrations.</p> </td><td class="Lrule Rrule" valign="top"> <p class="First">Monitor tacrolimus whole blood trough concentrations and adjust PROGRAF dose if needed <span class="Italics">[see <a href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</a> (<a href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</a>, <a href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</a>)]</span>.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Caspofungin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">May decrease tacrolimus whole blood trough concentrations.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Monitor tacrolimus whole blood trough concentrations and adjust PROGRAF dose if needed <span class="Italics">[see <a href="#i4i_dosage_admin_id_30a26494-527b-443b-91cb-bb6550f68aac">Dosage and Administration</a> (<a href="#ID_44d69890-f601-4672-872b-2764ac77cabc">2.2</a>, <a href="#ID_7f5e6a75-adb4-4010-9052-98cc955247b5">2.6</a>)]</span>.</p> </td> </tr> </tbody> </table></div>

Direct Acting Antiviral (DAA) Therapy

The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of PROGRAF is warranted to ensure continued efficacy and safety [see Dosage and Administration (2.2, 2.6)].

The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. When cannabidiol and PROGRAF are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of PROGRAF should be considered as needed when PROGRAF is co-administered with cannabidiol [see Dosage and Administration (2.2, 2.6) and Warnings and Precautions (5.17)].

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to PROGRAF during pregnancy.

The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus. Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org/.

Risk Summary

Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress [see Human Data]. Advise pregnant women of the potential risk to the fetus.

Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses (0.5 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m2 basis).

Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 to 6.9 times the recommended clinical dose range, on a mg/m2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data].

The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Risks during pregnancy are increased in organ transplant recipients.

The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death.

Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported.

Maternal Adverse Reactions

PROGRAF may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions (5.4)].

PROGRAF may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions (5.7, 5.8)].

Fetal/Neonatal Adverse Reactions

Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking PROGRAF.

Labor or Delivery

There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to PROGRAF.

Data

Human Data

There are no adequate and well controlled studies on the effects of tacrolimus in human pregnancy. Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus in utero have an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress.

TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 16. In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for renal and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus</span> </caption> <col width="40%"/> <col width="29%"/> <col width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="middle"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Kidney</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Liver</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-20" name="footnote-20">*</a> </dt> <dd>Includes multiple births and terminations.</dd> <dt> <a href="#footnote-reference-21" name="footnote-21">†</a> </dt> <dd>Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Pregnancy Outcomes</span><a class="Sup" href="#footnote-20" name="footnote-reference-20">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">462</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">253</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  <span class="Bold">Miscarriage</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24.5%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  <span class="Bold">Live births</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">331</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">180</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">          Pre-term delivery (&lt; 37 weeks)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">49%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">42%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">          Low birth weight (&lt; 2500 g)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">42%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">          Birth defects</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8%<a class="Sup" href="#footnote-21" name="footnote-reference-21">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5%</p> </td> </tr> </tbody> </table></div>

Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients, and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients.

Animal Data

Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m2 basis). At 1 mg/kg (1.6 to 4.3 times the recommended clinical dose range), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (2.6 to 6.9 times the recommended clinical dose range) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.

In a peri-/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects on parturition, and reduced pup viability at 3.2 mg/kg (2.6 to 6.9 times the recommended clinical dose range); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1.0 mg/kg (0.8 to 2.2 times the recommended clinical dose range).

Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation, produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (2.6 to 6.9 times the recommended clinical dose range). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 to 2.2 times the recommended clinical dose range) [see Nonclinical Toxicology (13.1)].

Risk Summary

Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies; exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PROGRAF and any potential adverse effects on the breastfed child from PROGRAF or from the underlying maternal condition.

Contraception

PROGRAF can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment with PROGRAF [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].

Infertility

Based on findings in animals, male and female fertility may be compromised by treatment with PROGRAF [see Nonclinical Toxicology (13.1)].

Safety and effectiveness have been established in pediatric liver, kidney, heart, and lung transplant patients.

Liver Transplantation

Safety and efficacy using PROGRAF Granules in pediatric de novo liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received PROGRAF, and supported by two pharmacokinetic and safety studies in 151 children who received PROGRAF. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations. Pediatric patients generally required higher doses of PROGRAF to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)].

Kidney and Heart Transplantation

Use of PROGRAF capsules and PROGRAF Granules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Lung Transplantation

The use of PROGRAF capsules and PROGRAF Granules in pediatric lung transplantation is supported by the experience in the U.S. Scientific Registry of Transplant Recipients (SRTR) including 450 pediatric patients receiving tacrolimus immediate-release products in combination with mycophenolate mofetil and 72 pediatric patients receiving tacrolimus immediate-release products in combination with azathioprine between 1999-2017.

Clinical trials of PROGRAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The pharmacokinetics of PROGRAF in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing PROGRAF at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

The use of PROGRAF in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

African-American and Hispanic patients are at increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately [see Warnings and Precautions (5.4)].

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of PROGRAF [see Adverse Reactions (6.1, 6.2)], including tremors, abnormal renal function, hypertension, and peripheral edema; in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

{ "type": "p", "children": [], "text": "Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of PROGRAF [see Adverse Reactions (6.1, 6.2)], including tremors, abnormal renal function, hypertension, and peripheral edema; in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage." }

Tacrolimus, previously known as FK506, is the active ingredient in PROGRAF. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)], 4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate.

{ "type": "p", "children": [], "text": "Tacrolimus, previously known as FK506, is the active ingredient in PROGRAF. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)], 4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate." }

The chemical structure of tacrolimus is:

{ "type": "p", "children": [], "text": "The chemical structure of tacrolimus is:" }

Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

{ "type": "p", "children": [], "text": "Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform." }

PROGRAF is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, and magnesium stearate NF. The 0.5 mg capsule shell contains ferric oxide NF, gelatin NF and titanium dioxide USP, the 1 mg capsule shell contains gelatin NF and titanium dioxide USP, and the 5 mg capsule shell contains ferric oxide NF, gelatin NF, and titanium dioxide USP.

{ "type": "p", "children": [], "text": "PROGRAF is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, and magnesium stearate NF. The 0.5 mg capsule shell contains ferric oxide NF, gelatin NF and titanium dioxide USP, the 1 mg capsule shell contains gelatin NF and titanium dioxide USP, and the 5 mg capsule shell contains ferric oxide NF, gelatin NF, and titanium dioxide USP." }

PROGRAF is also available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg anhydrous tacrolimus USP in 1 mL for administration by intravenous infusion only. Each mL contains the following inactive ingredients: dehydrated alcohol USP, 80.0% v/v and polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg. PROGRAF injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use.

{ "type": "p", "children": [], "text": "PROGRAF is also available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg anhydrous tacrolimus USP in 1 mL for administration by intravenous infusion only. Each mL contains the following inactive ingredients: dehydrated alcohol USP, 80.0% v/v and polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg. PROGRAF injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use." }

PROGRAF Granules is available for oral administration as a suspension containing the equivalent of 0.2 mg or 1 mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, and lactose monohydrate NF.

{ "type": "p", "children": [], "text": "PROGRAF Granules is available for oral administration as a suspension containing the equivalent of 0.2 mg or 1 mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, and lactose monohydrate NF." }

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB).

Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean ± S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 17).

<div class="scrollingtable"><table cellpadding="5.75pt" width="100%"> <caption> <span>Table 17. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients</span> </caption> <col width="12%"/> <col width="6%"/> <col width="22%"/> <col width="10%"/> <col width="10%"/> <col width="12%"/> <col width="8%"/> <col width="11%"/> <col width="8%"/> <thead> <tr class="First"> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Population</span></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">N</span></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Route</span> <br/> <span class="Bold">(Dose)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="6" valign="top"><span class="Bold">Parameters</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">C<span class="Sub">max</span></span> <br/> <span class="Bold">(ng/mL)</span></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">T<span class="Sub">max</span></span> <br/> <span class="Bold">(hr)</span></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">AUC</span> <br/> <span class="Bold">(ng•hr/mL)</span></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">t<span class="Sub">1/2</span></span> <br/> <span class="Bold">(hr)</span></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">CL</span> <br/> <span class="Bold">(L/hr/kg)</span></th><th align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">V</span> <br/> <span class="Bold">(L/kg)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="9"> <dl class="Footnote"> <dt> <a href="#footnote-reference-22" name="footnote-22">*</a> </dt> <dd>Not applicable</dd> <dt> <a href="#footnote-reference-23" name="footnote-23">†</a> </dt> <dd>AUC<span class="Sub">0-inf</span> </dd> <dt> <a href="#footnote-reference-24" name="footnote-24">‡</a> </dt> <dd>Not available</dd> <dt> <a href="#footnote-reference-25" name="footnote-25">§</a> </dt> <dd>AUC<span class="Sub">0-t</span> </dd> <dt> <a href="#footnote-reference-26" name="footnote-26">¶</a> </dt> <dd>Determined after the first dose</dd> <dt> <a href="#footnote-reference-27" name="footnote-27">#</a> </dt> <dd>Median [range]</dd> <dt> <a href="#footnote-reference-28" name="footnote-28">Þ</a> </dt> <dd>AUC<span class="Sub">0-12</span> </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="3" valign="top"> <p class="First"> Healthy</p> <p> Volunteers</p> <p> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">IV (0.025 mg/kg/4 hr)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-22" name="footnote-reference-22">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-22">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">652<a class="Sup" href="#footnote-23" name="footnote-reference-23">†</a> ± 156</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">34.2 ± 7.7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.040 ± 0.009</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.91 ± 0.31</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First">30</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">PO (5 mg) (granules)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">35.6 ± 10.9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1.3 ± 0.5</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">320<a class="Sup" href="#footnote-23">†</a> ± 164</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">32.1 ± 5.9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24" name="footnote-reference-24">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">PO (5 mg) (capsules)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">28.8 ± 8.9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1.5 ± 0.7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">266<a class="Sup" href="#footnote-23">†</a> ± 95</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">32.3 ± 8.8</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="3" valign="middle"> <p class="First"> Kidney</p> <p> Transplant</p> <p> Patients</p> </td><td align="center" class="Botrule Lrule Rrule" rowspan="3" valign="middle"> <p class="First">26</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">IV (0.02 mg/kg/12 hr)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-22">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-22">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">294<a class="Sup" href="#footnote-23">†</a> ± 262</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">18.8 ± 16.7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.083 ± 0.050</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1.41 ± 0.66</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">PO (0.2 mg/kg/day)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">19.2 ± 10.3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">3.0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">203<a class="Sup" href="#footnote-23">†</a> ± 42</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">PO (0.3 mg/kg/day)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">24.2 ± 15.8</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1.5</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">288<a class="Sup" href="#footnote-23">†</a> ± 93</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First"> Liver</p> <p> Transplant</p> <p> Patients</p> </td><td align="center" class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First">17</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">IV (0.05 mg/kg/12 hr)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-22">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-22">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">3300<a class="Sup" href="#footnote-23">†</a> ± 2130</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">11.7 ± 3.9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.053 ± 0.017</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.85 ± 0.30</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">PO (0.3 mg/kg/day)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">68.5 ± 30.0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2.3 ± 1.5</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">519<a class="Sup" href="#footnote-23">†</a> ± 179</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="3" valign="middle"> <p class="First"> Heart</p> <p> Transplant Patients</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">11</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">IV (0.01 mg/kg/day as a continuous infusion)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-22">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-22">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">954<a class="Sup" href="#footnote-25" name="footnote-reference-25">§</a> ± 334</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">23.6 ± 9.22</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.051 ± 0.015</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">11</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">PO (0.075 mg/kg/day)<a class="Sup" href="#footnote-26" name="footnote-reference-26">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">14.7 ± 7.79</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2.1 <br/>[0.5-6.0]<a class="Sup" href="#footnote-27" name="footnote-reference-27">#</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">82.7<a class="Sup" href="#footnote-28" name="footnote-reference-28">Þ</a> ± 63.2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-22">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">14</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">PO (0.15 mg/kg/day)<a class="Sup" href="#footnote-26">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">24.5 ± 13.7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1.5 <br/>[0.4-4.0]<a class="Sup" href="#footnote-27">#</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">142<a class="Sup" href="#footnote-28">Þ</a> ± 116</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-22">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <a class="Sup" href="#footnote-24">‡</a> </p> </td> </tr> </tbody> </table></div>

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of the dosing regimen is necessary for optimal therapy [see Dosage and Administration (2.6)]. Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

Absorption

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17 ± 10% in adult kidney transplant patients (N = 26), 22 ± 6% in adult liver transplant patients (N = 17), 23 ± 9% in adult heart transplant patients (N = 11) and 18 ± 5% in healthy volunteers (N = 16).

A single dose trial conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg.

In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94. In 25 heart transplant patients over a concentration range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.

In a healthy volunteer adult study, the systemic exposure to tacrolimus (AUC) for PROGRAF Granules was approximately 16% higher than that for PROGRAF capsules when administered as single doses. If pediatric patients are converted between formulations, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.

Food Effects

The rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers.

The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean Cmax by 28% and 65%, respectively.

In healthy volunteers (N = 16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

In 11 liver transplant patients, PROGRAF administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 ± 18%) and Cmax (50 ± 19%), as compared to a fasted state.

PROGRAF capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of PROGRAF [see Dosage and Administration (2.1)].

Distribution

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5‑50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Elimination

Metabolism

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A4 and CYP3A5). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31‑demethyl metabolite has been reported to have the same activity as tacrolimus.

Excretion

The mean clearance following IV administration of tacrolimus is 0.040, 0.083, 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

In a mass balance study of IV-administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1.0% and the elimination half-life based on radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015 L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7%, urinary elimination accounted for 2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5 hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.

Specific Populations

Pediatric Patients

PROGRAF capsules Pharmacokinetics in Pediatric Patients

Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and Cmax were 337 ± 167 ng·hr/mL and 48.4 ± 27.9 ng/mL, respectively. The absolute bioavailability was 31 ± 24%.

Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2 ± 2.4 years of age. Following IV infusion of a 0.06 mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2 ± 5.0 hours and 0.12 ± 0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and Cmax were 181 ± 65 ng·hr/mL and 30 ± 11 ng/mL, respectively. The absolute bioavailability was 19 ± 14%.

Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration (2.3)].

PROGRAF Granules Pharmacokinetics in Pediatric Patients

A multicenter, open-label, single arm, pharmacokinetic study (OPTION, NCT01371331) was conducted using tacrolimus granules for oral suspension in pediatric patients undergoing de novo liver, kidney, or heart transplant. After an initial 24‑hour continuous IV infusion of tacrolimus (0.025 mg/kg/hour) for 12 hours to 4 days, oral PROGRAF Granules were dosed at 0.3 mg/kg/day in divided doses twice daily. Tacrolimus whole blood trough concentrations ranged from 5‑15 ng/mL for the first month post-transplant, and 5-10 ng/mL thereafter. Two pharmacokinetic (PK) profiles, AUC, Cmax, Tmax and Ctrough, were taken after the first oral dose (Day 1) and at steady state (Day 7). Subsequent oral doses of PROGRAF Granules were adjusted based on clinical evidence of efficacy, the whole-blood trough levels, and/or occurrence of adverse events. Of 52 patients enrolled, thirty-eight (38) had an evaluable PK profile. The mean pediatric age was 6.1 years for heart transplant, 1.1 years for liver transplant and 3.6 years for kidney transplant. Summary results of PK parameters are presented in Table 18.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 18. Summary of Whole Blood PK Parameters of Tacrolimus after Administration of PROGRAF Granules in Pediatric Patients</span> </caption> <col width="12%"/> <col width="16%"/> <col width="8%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Population</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">N</span> </p> <p> <span class="Bold">(age range)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="middle"> <p class="First"> <span class="Bold">Parameters</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">AUC<span class="Sub">tau</span> [hr*ng/mL]</span> </p> <p>mean ± SD</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">C<span class="Sub">max</span> [ng/mL]</span> </p> <p>mean ± SD</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">T<span class="Sub">max</span> [hr]</span> </p> <p>mean ± SD</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">C<span class="Sub">trough</span> [ng/mL]</span> </p> <p>mean ± SD</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Heart Transplant Patients</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">12 </p> <p>(0.58-13 years)</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Day 1</p> <p>Day 7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">224.13 ± 114.30</p> <p>165.17 ± 39.12</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">45.61 ± 19.55</p> <p>32.69 ± 9.78</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2.95 ± 4.33</p> <p>0.84 ± 0.44</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">12.60 ± 13.40</p> <p>7.57 ± 1.80</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Liver Transplant Patients</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">14 </p> <p>(0.33-12 years)</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Day 1</p> <p>Day 7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">210.56 ± 84.01</p> <p>195.08 ± 94.63</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">25.11 ± 10.78</p> <p>30.52 ± 19.35</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2.73 ± 1.84</p> <p>1.71 ± 1.12</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">13.41 ± 7.11</p> <p>9.71 ± 4.03</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Kidney Transplant Patients</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">12 </p> <p>(2.42-11 years)</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Day 1</p> <p>Day 7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">97.40 ± 36.77</p> <p>208.32 ± 68.75</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">18.04 ± 8.10</p> <p>36.63 ± 13.97</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1.78 ± 0.88</p> <p>1.09 ± 0.61</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">3.54 ± 1.45</p> <p>8.92 ± 3.59</p> </td> </tr> </tbody> </table></div>

Renal and Hepatic Impaired Patients

The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients</span> </caption> <col width="17%"/> <col width="17%"/> <col width="17%"/> <col width="17%"/> <col width="17%"/> <col width="17%"/> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-29" name="footnote-29">*</a> </dt> <dd>Corrected for bioavailability</dd> <dt> <a href="#footnote-reference-30" name="footnote-30">†</a> </dt> <dd>1 patient did not receive the PO dose</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Population</span> </p> <p> <span class="Bold">(No. of Patients)</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Dose</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-t</span></span> </p> <p> <span class="Bold">(ng·hr/mL)</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">t<span class="Sub">1/2</span></span> </p> <p> <span class="Bold">(hr)</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">V</span> </p> <p> <span class="Bold">(L/kg)</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">CI</span> </p> <p> <span class="Bold">(L/hr/kg)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Renal</p> <p> Impairment</p> <p> (n = 12)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.02</p> <p>mg/kg/4 hr</p> <p>IV</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">393 ± 123</p> <p>(t = 60 hr)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">26.3 ± 9.2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.07 ± 0.20</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.038 ± 0.014</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First"> Mild Hepatic </p> <p> Impairment</p> <p> (n = 6)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.02</p> <p>mg/kg/4 hr</p> <p>IV</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">367 ± 107</p> <p>(t = 72 hr)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">60.6 ± 43.8</p> <p>Range: 27.8 – 141</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.1 ± 1.6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.042 ± 0.02</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7.7 mg</p> <p>PO</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">488 ± 320</p> <p>(t = 72 hr)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">66.1 ± 44.8</p> <p>Range: 29.5 – 138</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.7 ± 4.7<a class="Sup" href="#footnote-29" name="footnote-reference-29">*</a> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.034 ± 0.019<a class="Sup" href="#footnote-29">*</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> Severe</p> <p> Hepatic</p> <p> Impairment</p> <p> (n = 6, IV)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.02 mg/kg/4 hr</p> <p>IV (n = 2)<br/> <br/>0.01 mg/kg/8 hr</p> <p>IV (n = 4)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">762 ± 204</p> <p>(t = 120 hr)<br/> <br/>289 ± 117</p> <p>(t = 144 hr)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">198 ± 158</p> <p>Range: 81 – 436</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.9 ± 1.0</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.017 ± 0.013</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> (n = 5, PO)<a class="Sup" href="#footnote-30" name="footnote-reference-30">†</a> </p> </td><td align="center" class="Rrule" valign="top"> <p class="First">8 mg PO</p> <p>(n = 1)<br/> <br/>5 mg PO</p> <p>(n = 4)</p> <p>4 mg PO</p> <p>(n = 1)</p> </td><td align="center" class="Rrule" valign="top"> <p class="First">658</p> <p>(t = 120 hr)<br/> <br/>533 ± 156</p> <p>(t = 144 hr)</p> </td><td align="center" class="Rrule" valign="top"> <p class="First">119 ± 35</p> <p>Range: 85 – 178</p> </td><td align="center" class="Rrule" valign="top"> <p class="First">3.1 ± 3.4<a class="Sup" href="#footnote-29">*</a> </p> </td><td align="center" class="Rrule" valign="top"> <p class="First">0.016 ± 0.011<a class="Sup" href="#footnote-29">*</a> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> </tbody> </table></div>

Patients with Renal Impairment

Tacrolimus pharmacokinetics, following a single IV administration, were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 19) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)].

Patients with Cystic Fibrosis

Lower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration (2.2, 2.3)].

Racial or Ethnic Groups

The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of PROGRAF to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (± SD) tacrolimus Cmax in African-Americans (23.6 ± 12.1 ng/mL) was significantly lower than in Caucasians (40.2 ± 12.6 ng/mL) and the Latino-Americans (36.2 ± 15.8 ng/mL) (p < 0.01). Mean AUC0-inf tended to be lower in African-Americans (203 ± 115 ng·hr/mL) than Caucasians (344 ± 186 ng·hr/mL) and Latino-Americans (274 ± 150 ng·hr/mL). The mean (± SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was significantly lower than in Caucasians (19 ± 5.8%, p = 0.011). There was no significant difference in mean terminal T1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration (2.2)].

Male and Female Patients

A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences.

Drug Interaction Studies

Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see Drug Interactions (7)].

Carcinogenesis

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions (5.1)].

A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.

The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis.

Mutagenesis

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Impairment of Fertility

Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

PROGRAF/Azathioprine (AZA)

PROGRAF-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded.

There were 205 patients randomized to PROGRAF-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids, and azathioprine. Overall, 1-year patient and graft survivals were 96.1% and 89.6%, respectively.

Data from this trial of PROGRAF in conjunction with azathioprine indicate that during the first 3 months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year.

PROGRAF/Mycophenolate Mofetil (MMF)

PROGRAF-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multicenter trial (Study 1), 1589 kidney transplant patients received PROGRAF (Group C, n = 401), sirolimus (Group D, n = 399), or one of two cyclosporine (CsA) regimens (Group A, n = 390 and Group B, n = 399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving PROGRAF/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the PROGRAF group exhibited higher estimated creatinine clearance rates (eCLcr) using the Cockcroft-Gault formula (Table 20) and experienced fewer efficacy failures, defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or loss to follow-up (Table 21) in comparison to each of the other three groups. Patients randomized to PROGRAF/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions (6.1)].

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 20. Estimated Creatinine Clearance at 12 Months (Study 1)</span> </caption> <col width="34%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <col width="21%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"><span class="Bold">Group</span></th><th align="center" class="Botrule Rrule Toprule" colspan="5" valign="top"><span class="Bold">eCL<span class="Sub">cr</span> [mL/min] at Month 12</span><a class="Sup" href="#footnote-31" name="footnote-reference-31">*</a></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="middle"><span class="Bold">N</span></th><th align="center" class="Botrule Rrule" valign="middle"><span class="Bold">MEAN</span></th><th align="center" class="Botrule Rrule" valign="middle"><span class="Bold">SD</span></th><th align="center" class="Botrule Rrule" valign="middle"><span class="Bold">MEDIAN</span></th><th align="center" class="Botrule Rrule" valign="middle"><span class="Bold">Treatment Difference with Group C <br/>(99.2% CI</span><a class="Sup" href="#footnote-32" name="footnote-reference-32">†</a><span class="Bold">)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-31" name="footnote-31">*</a> </dt> <dd>All death/graft loss (n = 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month 3 visit (n = 10, 9, 7, and 9 in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n = 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. </dd> <dt> <a href="#footnote-reference-32" name="footnote-32">†</a> </dt> <dd>Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (A) CsA/MMF/CS </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">390</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">56.5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">25.8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">56.9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-8.6 (-13.7, -3.7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (B)  CsA/MMF/CS/Daclizumab</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">399</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">58.9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">25.6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">60.9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-6.2 (-11.2, -1.2)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (C)  Tac/MMF/CS/Daclizumab </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">401</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">65.1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27.4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">66.2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (D)  Siro/MMF/CS/Daclizumab </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">399</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">56.2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27.4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">57.3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-8.9 (-14.1, -3.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Total</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1589</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">59.2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">26.8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">60.5</p> </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="6" valign="top"> <p class="First"> Key: CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 21. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1)</span> </caption> <col width="29%"/> <col width="16%"/> <col width="19%"/> <col width="16%"/> <col width="19%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Group A</span> <br/> <span class="Bold">N = 390</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Group B</span> <br/> <span class="Bold">N = 399</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Group C</span> <br/> <span class="Bold">N = 401</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Group D</span> <br/> <span class="Bold">N = 399</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-33" name="footnote-33">*</a> </dt> <dd>Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Overall Failure</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">141 (36.2%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">126 (31.6%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">82 (20.4%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">185 (46.4%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Components of efficacy failure</p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">       BPAR</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">113 (29.0%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">106 (26.6%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">60 (15.0%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">152 (38.1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">       Graft loss excluding death</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28 (7.2%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20 (5.0%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (3.0%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30 (7.5%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">       Mortality</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (3.3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (1.8%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (2.7%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (3.0%) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">       Lost to follow-up</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (1.3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (1.8%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (1.3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (1.5%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> Treatment Difference of efficacy failure compared to Group C (99.2% CI<a class="Sup" href="#footnote-33" name="footnote-reference-33">*</a>)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">15.8%</p> <p>(7.1%, 24.3%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">11.2%</p> <p>(2.7%, 19.5%)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">-</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">26.0%</p> <p>(17.2%, 34.7%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab</p> </td> </tr> </tbody> </table></div>

The protocol-specified target tacrolimus trough concentrations (Ctrough,Tac) were 3-7 ng/mL; however, the observed median Ctroughs,Tac approximated 7 ng/mL throughout the 12-month trial (Table 22). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 22. Tacrolimus Whole Blood Trough Concentration Range (Study 1)</span> </caption> <col width="25%"/> <col width="75%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Time </span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Median (P10-P90</span><a class="Sup" href="#footnote-34" name="footnote-reference-34">*</a><span class="Bold">) tacrolimus whole blood trough concentration range</span> <br/> <span class="Bold">(ng/mL)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-34" name="footnote-34">*</a> </dt> <dd>10 to 90<span class="Sup">th</span> Percentile: range of C<span class="Sub">trough</span>,<span class="Sub">Tac </span>that excludes lowest 10% and highest 10% of C<span class="Sub">trough</span>,<span class="Sub">Tac</span> </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 30 (N = 366)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6.9 (4.4 – 11.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 90 (N = 351)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6.8 (4.1 – 10.7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 180 (N = 355)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6.5 (4.0 – 9.6)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 365 (N = 346)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6.5 (3.8 – 10.0)</p> </td> </tr> </tbody> </table></div>

The protocol-specified target cyclosporine trough concentrations (Ctrough,CsA) for Group B were 50-100 ng/mL; however, the observed median Ctroughs,CsA approximated 100 ng/mL throughout the 12-month trial. The protocol-specified target Ctroughs,CsA for Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median Ctroughs,CsA approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12.

While patients in all groups started MMF at 1 gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 23); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 23. MMF Dose Over Time in PROGRAF/MMF (Group C) (Study 1)</span> </caption> <col width="22%"/> <col width="24%"/> <col width="27%"/> <col width="27%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"><span class="Bold">Time period (Days)</span></th><th align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"><span class="Bold">Time-averaged MMF dose (grams per day)</span><a class="Sup" href="#footnote-35" name="footnote-reference-35">*</a></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="top">Less than 2.0</th><th align="center" class="Botrule Rrule" valign="top">2.0</th><th align="center" class="Botrule Rrule" valign="top">Greater than 2.0</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-35" name="footnote-35">*</a> </dt> <dd>Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-30 (N = 364)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">37%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">60%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-90 (N = 373)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">47%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">51%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-180 (N = 377)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">56%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">42%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-365 (N = 380)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">63%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">36%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</p> </td> </tr> </tbody> </table></div>

In a second randomized, open-label, multicenter trial (Study 2), 424 kidney transplant patients received PROGRAF (N = 212) or cyclosporine (N = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the PROGRAF/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving PROGRAF/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to over-immunosuppression (Table 24).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 24. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2)</span> </caption> <col width="39%"/> <col width="30%"/> <col width="31%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule Toprule" valign="top"> </th><th align="center" class="Rrule Toprule" valign="top"><span class="Bold">PROGRAF/MMF</span></th><th align="center" class="Rrule Toprule" valign="top"><span class="Bold">Cyclosporine/MMF</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" valign="top"> </th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N = 212)</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N = 212)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-36" name="footnote-36">*</a> </dt> <dd>95% confidence interval calculated using Fisher's Exact Test.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Overall Failure</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32 (15.1%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">36 (17.0%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Components of efficacy failure</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">  </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">       BPAR</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16 (7.5%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">29 (13.7%) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">       Graft loss excluding death</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (2.8%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (1.9%) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">       Mortality</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9 (4.2%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (2.4%) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">       Lost to follow-up</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (1.9%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (0.5%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Treatment Difference of efficacy failure compared to PROGRAF/MMF group (95% CI<a class="Sup" href="#footnote-36" name="footnote-reference-36">*</a>)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1.9% (-5.2%, 9.0%)</p> </td> </tr> </tbody> </table></div>

The protocol-specified target tacrolimus whole blood trough concentrations (Ctrough,Tac) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median Ctroughs,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 25). Approximately 80% of patients maintained tacrolimus whole blood trough concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 25. Tacrolimus Whole Blood Trough Concentration Range (Study 2)</span> </caption> <col width="30%"/> <col width="70%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Time </span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Median (P10-P90</span><a class="Sup" href="#footnote-37" name="footnote-reference-37">*</a><span class="Bold">) tacrolimus whole blood trough concentration range</span> <br/> <span class="Bold">(ng/mL)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-37" name="footnote-37">*</a> </dt> <dd>10 to 90<span class="Sup">th</span> Percentile: range of C<span class="Sub">trough</span>,<span class="Sub">Tac</span> that excludes lowest 10% and highest 10% of C<span class="Sub">trough</span>,<span class="Sub">Tac.</span> </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 30 (N = 174)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10.5 (6.3 – 16.8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 60 (N = 179)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9.2 (5.9 – 15.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 120 (N = 176)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8.3 (4.6 – 13.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 180 (N = 171)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7.8 (5.5 – 13.2)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Day 365 (N = 178)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7.1 (4.2 – 12.4)</p> </td> </tr> </tbody> </table></div>

The protocol-specified target cyclosporine whole blood concentrations (Ctrough,CsA) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median Ctroughs,CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12.

Patients in both groups started MMF at 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the PROGRAF/MMF group (Table 26) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the PROGRAF/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions (6.1)].

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 26. MMF Dose Over Time in the PROGRAF/MMF Group (Study 2)</span> </caption> <col width="24%"/> <col width="24%"/> <col width="26%"/> <col width="26%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"><span class="Bold">Time period (Days)</span></th><th align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"><span class="Bold">Time-averaged MMF dose (g/day)</span><a class="Sup" href="#footnote-38" name="footnote-reference-38">*</a></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="top">Less than 2.0</th><th align="center" class="Botrule Rrule" valign="top">2.0</th><th align="center" class="Botrule Rrule" valign="top">Greater than 2.0</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-38" name="footnote-38">*</a> </dt> <dd>Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods. </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-30 (N = 212)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">25%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">69%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-90 (N = 212)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">41%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">53%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-180 (N = 212)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">52%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">41%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> 0-365 (N = 212)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">62%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">34%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First">Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)</p> </td> </tr> </tbody> </table></div>

The safety and efficacy of PROGRAF-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation.

In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the PROGRAF-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed.

In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the PROGRAF-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases.

One-year patient survival and graft survival in the PROGRAF-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and PROGRAF-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and PROGRAF-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral PROGRAF dosing was 2 days.

Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients are often maintained at the low end of this target range.

Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.

Pediatric Liver Transplantation Using PROGRAF Granules

The efficacy and safety of PROGRAF Granules plus corticosteroids were compared with a triple regimen of cyclosporine/corticosteroids/azathioprine in a randomized, open-label study, in de novo pediatric liver transplant patients. The study was conducted outside the United States and enrolled patients aged 16 years or younger. The distribution of pediatric patients by age was similar in both treatment groups, with a majority < 5 years. Patients were randomized to either tacrolimus for oral suspension 0.3 mg/kg/day (N = 91) or cyclosporine 10 mg/kg/day orally (N = 90) initiated 6 hours after completion of transplant surgery. Doses throughout the 1-year study period were adjusted to maintain whole blood trough levels within 5-20 ng/mL [see Dosage and Administration (2.3)]. Based on trough levels, doses of tacrolimus were adjusted to 0.17 mg/kg/day and 0.14 mg/kg/day by days 2 and 3, respectively. At 12 months, the incidence rate of BPAR, graft loss, death, or loss to follow-up was 52.7% in the tacrolimus group and 61.1% in the cyclosporine group (Table 27).

<div class="scrollingtable"><table cellpadding="0pt" width="99.04%"> <caption> <span>Table 27. Key Efficacy Results at 12 Months in Pediatric Liver Transplant Recipients Receiving PROGRAF Granules or Cyclosporine</span> </caption> <col width="50%"/> <col width="26%"/> <col width="24%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">PROGRAF Granules</span> <br/> <span class="Bold">(N = 91)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Cyclosporine</span> <br/> <span class="Bold">(N = 90)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-39" name="footnote-39">*</a> </dt> <dd>95% confidence interval calculated using normal approximation.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Overall Failure</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">48 (52.7%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">55 (61.1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> Components of efficacy failure</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      BPAR</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">40 (44.0%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">49 (54.4%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      Graft loss</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7 (7.7%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13 (14.4%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">         Graft loss excluding death</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (1.1%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (6.7%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      Mortality</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (6.6%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7 (7.8%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      Lost to follow-up</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (2.2%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Treatment Difference of efficacy failure compared to cyclosporine (95% CI<a class="Sup" href="#footnote-39" name="footnote-reference-39">*</a>)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">-8.4% (-22.7%, 6.0%)</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> </tbody> </table></div>

Two open-label, randomized, comparative trials evaluated the safety and efficacy of PROGRAF-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with PROGRAF or cyclosporine modified for 18 months. In a 3-arm trial conducted in the U.S., 331 patients received corticosteroids and PROGRAF plus sirolimus, PROGRAF plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year.

In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the PROGRAF plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from 1 week to 3 months post-transplant, approximately 80% of patients maintained trough concentrations between 8 to 20 ng/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to 18 ng/mL.

The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose PROGRAF; however, this regimen was associated with increased risk of wound-healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions (5.10)].

The efficacy and safety of PROGRAF-based immunosuppression in primary lung transplantation were assessed in a non-interventional (observational) study using data from the U.S. Scientific Registry of Transplant Recipients (SRTR). The study analyzed outcomes based on discharge immunosuppression treatment regimen in recipients of a primary lung transplant between 1999 and 2017 who were alive at the time of discharge. In adult patients receiving tacrolimus immediate-release products in combination with MMF (n=15,478) or tacrolimus immediate-release products in combination with AZA (n=4,263), the one-year graft survival estimates from time of discharge were 90.9% and 90.8%, respectively. In pediatric patients receiving tacrolimus immediate-release products in combination with MMF (n= 450) or tacrolimus immediate-release products in combination with AZA (n=72), the one-year graft survival estimates from time of discharge were 91.7% and 84.7%, respectively.

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

{ "type": "p", "children": [], "text": "1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html\n" }

<div class="scrollingtable"><table width="100%"> <col width="22%"/> <col width="26%"/> <col width="25%"/> <col width="26%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Strength</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">0.5 mg</span> </p> <p>(containing the equivalent of 0.5 mg anhydrous tacrolimus USP)</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">1 mg</span> </p> <p>(containing the equivalent of 1 mg anhydrous tacrolimus USP)</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">5 mg</span> </p> <p>(containing the equivalent of 5 mg anhydrous tacrolimus USP)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Shape/color</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">oblong/light yellow</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">oblong/white</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">oblong/grayish red</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Branding on</span> </p> <p> <span class="Bold"> capsule cap/body</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <a name="id437417429"></a><img alt="f" src="/dailymed/image.cfm?name=image-05.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/>607</p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <a name="id764193592"></a><img alt="f" src="/dailymed/image.cfm?name=image-06.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/>617</p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <a name="id944889064"></a><img alt="f" src="/dailymed/image.cfm?name=image-07.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/>657</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> 100 count bottle</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">NDC 0469-0607-73</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">NDC 0469-0617-73</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">NDC 0469-0657-73</span> </p> </td> </tr> </tbody> </table></div>

Note: PROGRAF capsules USP are not filled to maximum capsule capacity. Capsule contains labeled amount.

Store and Dispense

Store at 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

(for Intravenous infusion only)

NDC 0469-3016-01 Product Code 301601

5 mg/mL (equivalent of 5 mg of anhydrous tacrolimus USP per mL) supplied as a sterile solution in a 1 mL ampule, in boxes of 10 ampules

Store and Dispense

Store between 5°C and 25°C (41°F and 77°F).

<div class="scrollingtable"><table width="100%"> <col width="26%"/> <col width="34%"/> <col width="41%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Strength</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">0.2 mg</span> </p> <p>(containing the equivalent of 0.2 mg anhydrous tacrolimus USP)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">1 mg</span> </p> <p>(containing the equivalent of 1 mg anhydrous tacrolimus USP)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Shape/color</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">White granules</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">White granules</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">1 carton containing 50 packets</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">NDC 0469-1230-50</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">NDC 0469-1330-50</span> </p> </td> </tr> </tbody> </table></div>

Store and Dispense

Store at 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

Tacrolimus can cause fetal harm. PROGRAF capsules should not be opened or crushed. Wearing disposable gloves is recommended during dilution of the injection or when preparing the oral suspension in the hospital and when wiping any spills. Avoid inhalation or direct contact with skin or mucous membranes of the powder or granules contained in PROGRAF capsules and PROGRAF Granules, respectively. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures1.

Advise the patient or caregiver to:

Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Warnings and Precautions (5.1)].

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Warnings and Precautions (5.2)].

Inform patients that PROGRAF can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst, or hunger [see Warnings and Precautions (5.4)].

Inform patients that PROGRAF can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions (5.5)].

Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions (5.6)].

Inform patients that PROGRAF can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions (5.7)].

Inform patients that PROGRAF can cause high blood pressure which may require treatment with antihypertensive therapy. Advise patients to monitor their blood pressure [see Warnings and Precautions (5.8)].

Inform patients that PROGRAF can cause blood clotting problems. The risk of this occurring increases when patients take PROGRAF and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria. [see Warnings and Precautions (5.16)]

Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription medicines and nonprescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice [see Drug Interactions (7)].

Inform women of childbearing potential that PROGRAF can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations (8.1, 8.2, 8.3)].

Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ [see Use in Specific Populations (8.1)].

Based on animal studies, PROGRAF may affect fertility in males and females [see Nonclinical Toxicology (13.1)].

Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure).

Inform patients that PROGRAF can interfere with the usual response to immunizations and that they should avoid live vaccines. [see Warnings and Precautions (5.14)].

Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062

PROGRAF® is a registered trademark of Astellas Pharma Inc. All other trademarks and registered trademarks are the property of their respective owners.

398977-PRG

<div class="scrollingtable"><table width="100%"> <col width="2%"/> <col width="41%"/> <col width="57%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Patient Information</span> </p> <p>PROGRAF<span class="Sup">®</span> (PRO-graf) (tacrolimus) capsules, for oral use</p> <p>PROGRAF<span class="Sup">®</span> (PRO-graf) Granules (tacrolimus for oral suspension)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First">Read this Patient Information before you start taking PROGRAF and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What is the most important information I should know about PROGRAF?</span> </p> <p> <span class="Bold">PROGRAF can cause serious side effects, including:</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">Increased risk of cancer. </span>People who take PROGRAF have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).</dd> <dt>•</dt> <dd> <span class="Bold">Increased risk of infection. </span>PROGRAF is a medicine that affects your immune system. PROGRAF can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving PROGRAF that can cause death. <span class="Bold">Call your healthcare provider right away if you have any symptoms of an infection, including:</span> </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule" valign="top"> <dl> <dt>o</dt> <dd>fever</dd> <dt>o</dt> <dd>sweats or chills</dd> <dt>o</dt> <dd>cough or flu-like symptoms</dd> </dl> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>o</dt> <dd>muscle aches</dd> <dt>o</dt> <dd>warm, red, or painful areas on your skin</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What is PROGRAF?</span> </p> <dl> <dt>•</dt> <dd>PROGRAF is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, heart, or lung transplant. </dd> <dt>•</dt> <dd>PROGRAF capsules and PROGRAF GRANULES are types of tacrolimus immediate-release drugs and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Who should not take PROGRAF?</span> </p> <p> <span class="Bold">Do not take PROGRAF if you:</span> </p> <dl> <dt>•</dt> <dd>are allergic to tacrolimus or any of the ingredients in PROGRAF. See the end of this leaflet for a complete list of ingredients in PROGRAF.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What should I tell my healthcare provider before taking PROGRAF?</span> </p> <p> <span class="Bold">Before taking PROGRAF, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <dl> <dt>•</dt> <dd>plan to receive any vaccines. People taking PROGRAF should not receive live vaccines. </dd> <dt>•</dt> <dd>have or have had liver, kidney, or heart problems.</dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. PROGRAF can harm your unborn baby.<dl> <dt>o</dt> <dd>If you are able to become pregnant, you should use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you.</dd> <dt>o</dt> <dd>Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you. </dd> <dt>o</dt> <dd>There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with PROGRAF. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to <a href="https://www.transplantpregnancyregistry.org/">https://www.transplantpregnancyregistry.org/</a>.</dd> </dl> </dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. PROGRAF passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking PROGRAF.</dd> <dt>•</dt> <dd>plan to have children. PROGRAF may affect the ability to have children in females and males (fertility problems).</dd> </dl> <p> <span class="Bold">Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine</span>, including prescription and over-the-counter medicines, vitamins, natural, herbal, or nutritional supplements.</p> <p> <span class="Bold">Especially tell your healthcare provider if you take:</span> </p> <dl> <dt>•</dt> <dd>sirolimus (RAPAMUNE): You should not take PROGRAF if you take sirolimus </dd> <dt>•</dt> <dd>cyclosporine (GENGRAF, NEORAL, and SANDIMMUNE)</dd> <dt>•</dt> <dd>medicines called aminoglycosides that are used to treat bacterial infections</dd> <dt>•</dt> <dd>ganciclovir (CYTOVENE IV, VALCYTE)</dd> <dt>•</dt> <dd>amphotericin B (ABELCET, AMBISOME)</dd> <dt>•</dt> <dd>cisplatin</dd> <dt>•</dt> <dd>antiviral medicines called nucleoside reverse transcriptase inhibitors </dd> <dt>•</dt> <dd>antiviral medicines called protease inhibitors </dd> <dt>•</dt> <dd>water pill (diuretic)</dd> <dt>•</dt> <dd>medicine to treat high blood pressure </dd> <dt>•</dt> <dd>nelfinavir (VIRACEPT)</dd> <dt>•</dt> <dd>telaprevir (INCIVEK)</dd> <dt>•</dt> <dd>boceprevir </dd> <dt>•</dt> <dd>ritonavir (KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR)</dd> <dt>•</dt> <dd>letermovir (PREVYMIS)</dd> <dt>•</dt> <dd>ketoconazole </dd> <dt>•</dt> <dd>itraconazole (ONMEL, SPORANOX)</dd> <dt>•</dt> <dd>voriconazole (VFEND) </dd> <dt>•</dt> <dd>caspofungin (CANCIDAS)</dd> <dt>•</dt> <dd>clarithromycin (BIAXIN, BIAXIN XL, PREVPAC)</dd> <dt>•</dt> <dd>rifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE)</dd> <dt>•</dt> <dd>rifabutin (MYCOBUTIN) </dd> <dt>•</dt> <dd>amiodarone (NEXTERONE, PACERONE) </dd> <dt>•</dt> <dd>cannabidiol (EPIDIOLEX)</dd> </dl> <p>Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above.</p> <p>PROGRAF may affect the way other medicines work, and other medicines may affect how PROGRAF works.</p> <p>Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">How should I take PROGRAF?</span> </p> <dl> <dt>•</dt> <dd>Take PROGRAF exactly as your healthcare provider tells you to take it.</dd> <dt>•</dt> <dd>Your healthcare provider will tell you how much PROGRAF to take and when to take it.</dd> <dt> </dt> <dd>Your healthcare provider may change your PROGRAF dose if needed. <span class="Bold">Do not </span>stop taking or change your dose of PROGRAF without talking to your healthcare provider.</dd> <dt>•</dt> <dd>Take PROGRAF with or without food.</dd> <dt>•</dt> <dd>Take PROGRAF the same way every day. For example, if you choose to take PROGRAF with food, you should always take PROGRAF with food.</dd> <dt>•</dt> <dd>Take PROGRAF at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m.</dd> <dt>•</dt> <dd>Taking PROGRAF at the same time each day helps to keep the amount of medicine in your body at a steady level.</dd> <dt>•</dt> <dd>If you take too much PROGRAF, call your healthcare provider or go to the nearest hospital emergency room right away.</dd> </dl> <p> <span class="Bold">PROGRAF capsules:</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">Do not</span> open or crush PROGRAF capsules.</dd> </dl> <p> <span class="Bold">PROGRAF Granules:</span> </p> <dl> <dt>•</dt> <dd>Children who have trouble swallowing capsules can be given PROGRAF Granules.</dd> <dt>•</dt> <dd>Give the dose of PROGRAF Granules right after preparing. Do not save prepared PROGRAF Granules as a liquid to take at a later time. </dd> <dt>•</dt> <dd> <span class="Bold">See the Instructions for Use at the end of this Patient Information</span> for detailed instructions about how to mix and give PROGRAF Granules as a liquid in a glass cup or oral syringe.</dd> <dt>•</dt> <dd>If you get the granules or prepared oral suspension on your skin, wash the area well with soap and water. </dd> <dt>•</dt> <dd>If you get the granules or prepared oral suspension in your eyes, rinse with plain water.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What should I avoid while taking PROGRAF?</span> </p> <dl> <dt>•</dt> <dd>While you take PROGRAF you should not receive any live vaccines. </dd> <dt>•</dt> <dd>Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).</dd> <dt>•</dt> <dd> <span class="Bold">Do not</span> eat grapefruit or drink grapefruit juice during treatment with PROGRAF.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of PROGRAF?</span> </p> <p> <span class="Bold">PROGRAF may cause serious side effects, including:</span> </p> <dl> <dt>•</dt> <dd>See<span class="Bold"> “What is the most important information I should know about PROGRAF?”</span> </dd> <dt>•</dt> <dd> <span class="Bold">problems from medicine errors. </span>People who take PROGRAF have sometimes been given the wrong type of tacrolimus product. <span class="Bold">Tacrolimus extended-release medicines are not the same as PROGRAF capsules or granules </span>and cannot be substituted for each other. <span class="Bold">Check your PROGRAF when you get a new prescription and before you take it to make sure you have received PROGRAF capsules or PROGRAF Granules.</span> </dd> <dt>•</dt> <dd>Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine. </dd> <dt>•</dt> <dd> <span class="Bold">high blood sugar (diabetes). </span>Your healthcare provider may do blood tests to check for diabetes while you take PROGRAF. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:</dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>o</dt> <dd>frequent urination</dd> <dt>o</dt> <dd>increased thirst or hunger</dd> <dt>o</dt> <dd>blurred vision</dd> <dt>o</dt> <dd>confusion</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>o</dt> <dd>drowsiness</dd> <dt>o</dt> <dd>loss of appetite</dd> <dt>o</dt> <dd>fruity smell on your breath</dd> <dt>o</dt> <dd>nausea, vomiting, or stomach pain</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">kidney problems. </span>Kidney problems are a serious and common side effect of PROGRAF. Your healthcare provider may do blood tests to check your kidney function while you take PROGRAF. </dd> <dt>•</dt> <dd> <span class="Bold">nervous system problems. </span>Nervous system problems are a serious and common side effect of PROGRAF. Call your healthcare provider right away if you get any of these symptoms while taking PROGRAF. These could be signs of a serious nervous system problem:</dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>o</dt> <dd>headache</dd> <dt>o</dt> <dd>confusion</dd> <dt>o</dt> <dd>seizures</dd> <dt>o</dt> <dd>changes in your vision</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>o</dt> <dd>changes in behavior</dd> <dt>o</dt> <dd>coma</dd> <dt>o</dt> <dd>tremors</dd> <dt>o</dt> <dd>numbness and tingling</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">high levels of potassium in your blood. </span>Your healthcare provider may do blood tests to check your potassium level while you take PROGRAF.</dd> <dt>•</dt> <dd> <span class="Bold">high blood pressure.</span> High blood pressure is a serious and common side effect of PROGRAF. Your healthcare provider will monitor your blood pressure while you take PROGRAF and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.</dd> <dt>•</dt> <dd> <span class="Bold">changes in the electrical activity of your heart (QT prolongation).</span> </dd> <dt>•</dt> <dd> <span class="Bold">heart problems (myocardial hypertrophy).</span> Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking PROGRAF:</dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>o</dt> <dd>shortness of breath</dd> <dt>o</dt> <dd>chest pain</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>o</dt> <dd>feel lightheaded</dd> <dt>o</dt> <dd>feel faint</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">severe low red blood cell count (anemia). </span> </dd> <dt>•</dt> <dd> <span class="Bold">blood clotting problems:</span> Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">The most common side effects of PROGRAF in people who have received a kidney, liver, heart, or lung transplant are:</span> </p> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>•</dt> <dd>infections in general, including cytomegalovirus (cmv) infection</dd> <dt>•</dt> <dd>tremors (shaking of the body)</dd> <dt>•</dt> <dd>constipation</dd> <dt>•</dt> <dd>diarrhea</dd> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>stomach pain</dd> <dt>•</dt> <dd>trouble sleeping</dd> <dt>•</dt> <dd>nausea</dd> <dt>•</dt> <dd>high blood sugar (diabetes)</dd> <dt>•</dt> <dd>low levels of magnesium in your blood</dd> <dt>•</dt> <dd>low levels of phosphate in your blood</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>•</dt> <dd>swelling of the hands, legs, ankles, or feet</dd> <dt>•</dt> <dd>weakness</dd> <dt>•</dt> <dd>pain</dd> <dt>•</dt> <dd>high levels of fat in your blood</dd> <dt>•</dt> <dd>high levels of potassium in your blood</dd> <dt>•</dt> <dd>low red blood cell count (anemia)</dd> <dt>•</dt> <dd>low white blood cell count</dd> <dt>•</dt> <dd>fever</dd> <dt>•</dt> <dd>numbness or tingling in your hands and feet</dd> <dt>•</dt> <dd>inflammation of your airway (bronchitis)</dd> <dt>•</dt> <dd>fluid around your heart</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First">Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of PROGRAF. For more information, ask your healthcare provider or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">How should I store PROGRAF?</span> </p> <p> <span class="Bold">PROGRAF capsules</span> </p> <dl> <dt>•</dt> <dd>Store PROGRAF capsules at room temperature between 68°F to 77°F (20°C to 25°C). </dd> </dl> <p> <span class="Bold">PROGRAF Granules</span> </p> <dl> <dt>•</dt> <dd>Store PROGRAF Granules packets at room temperature between 68°F to 77°F (20°C to 25°C).</dd> </dl> <p> <span class="Bold">Keep PROGRAF and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of PROGRAF.</span> </p> <dl> <dt>•</dt> <dd>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROGRAF for a condition for which it was not prescribed. Do not give PROGRAF to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PROGRAF that is written for health professionals. </dd> <dt>•</dt> <dd>This Patient Information leaflet summarizes the most important information about PROGRAF. If you would like more information, talk to your healthcare provider.</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in PROGRAF?</span> </p> <p> <span class="Bold">Active ingredient:</span> tacrolimus</p> <p> <span class="Bold">Inactive ingredients:</span> </p> <p>PROGRAF capsules: croscarmellose sodium, hypromellose, lactose monohydrate, and magnesium stearate. The 0.5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide. The 1 mg capsule shell contains gelatin and titanium dioxide. The 5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide.</p> <p>PROGRAF Granules: croscarmellose sodium, hypromellose, and lactose monohydrate.</p> <p>Distributed by: <span class="Bold">Astellas Pharma US, Inc. </span>Northbrook, IL 60062</p> <p>PROGRAF<span class="Sup">®</span> is a registered trademark of Astellas Pharma Inc. All other trademarks and registered trademarks are the property of their respective owners.</p> <p>398977-PRG </p> <p>For more information, go to www.astellas.com/us or call 1-800-727-7003.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"2%\"/>\n<col width=\"41%\"/>\n<col width=\"57%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Patient Information</span>\n</p>\n<p>PROGRAF<span class=\"Sup\">®</span> (PRO-graf) (tacrolimus) capsules, for oral use</p>\n<p>PROGRAF<span class=\"Sup\">®</span> (PRO-graf) Granules (tacrolimus for oral suspension)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">Read this Patient Information before you start taking PROGRAF and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about PROGRAF?</span>\n</p>\n<p>\n<span class=\"Bold\">PROGRAF can cause serious side effects, including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased risk of cancer. </span>People who take PROGRAF have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased risk of infection. </span>PROGRAF is a medicine that affects your immune system. PROGRAF can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving PROGRAF that can cause death. <span class=\"Bold\">Call your healthcare provider right away if you have any symptoms of an infection, including:</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule\" valign=\"top\"></td><td class=\"Botrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>fever</dd>\n<dt>o</dt>\n<dd>sweats or chills</dd>\n<dt>o</dt>\n<dd>cough or flu-like symptoms</dd>\n</dl>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>muscle aches</dd>\n<dt>o</dt>\n<dd>warm, red, or painful areas on your skin</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is PROGRAF?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>PROGRAF is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, heart, or lung transplant. </dd>\n<dt>•</dt>\n<dd>PROGRAF capsules and PROGRAF GRANULES are types of tacrolimus immediate-release drugs and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take PROGRAF?</span>\n</p>\n<p>\n<span class=\"Bold\">Do not take PROGRAF if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>are allergic to tacrolimus or any of the ingredients in PROGRAF. See the end of this leaflet for a complete list of ingredients in PROGRAF.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I tell my healthcare provider before taking PROGRAF?</span>\n</p>\n<p>\n<span class=\"Bold\">Before taking PROGRAF, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>plan to receive any vaccines. People taking PROGRAF should not receive live vaccines. </dd>\n<dt>•</dt>\n<dd>have or have had liver, kidney, or heart problems.</dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. PROGRAF can harm your unborn baby.<dl>\n<dt>o</dt>\n<dd>If you are able to become pregnant, you should use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you.</dd>\n<dt>o</dt>\n<dd>Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you. </dd>\n<dt>o</dt>\n<dd>There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with PROGRAF. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to <a href=\"https://www.transplantpregnancyregistry.org/\">https://www.transplantpregnancyregistry.org/</a>.</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. PROGRAF passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking PROGRAF.</dd>\n<dt>•</dt>\n<dd>plan to have children. PROGRAF may affect the ability to have children in females and males (fertility problems).</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine</span>, including prescription and over-the-counter medicines, vitamins, natural, herbal, or nutritional supplements.</p>\n<p>\n<span class=\"Bold\">Especially tell your healthcare provider if you take:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>sirolimus (RAPAMUNE): You should not take PROGRAF if you take sirolimus </dd>\n<dt>•</dt>\n<dd>cyclosporine (GENGRAF, NEORAL, and SANDIMMUNE)</dd>\n<dt>•</dt>\n<dd>medicines called aminoglycosides that are used to treat bacterial infections</dd>\n<dt>•</dt>\n<dd>ganciclovir (CYTOVENE IV, VALCYTE)</dd>\n<dt>•</dt>\n<dd>amphotericin B (ABELCET, AMBISOME)</dd>\n<dt>•</dt>\n<dd>cisplatin</dd>\n<dt>•</dt>\n<dd>antiviral medicines called nucleoside reverse transcriptase inhibitors </dd>\n<dt>•</dt>\n<dd>antiviral medicines called protease inhibitors </dd>\n<dt>•</dt>\n<dd>water pill (diuretic)</dd>\n<dt>•</dt>\n<dd>medicine to treat high blood pressure </dd>\n<dt>•</dt>\n<dd>nelfinavir (VIRACEPT)</dd>\n<dt>•</dt>\n<dd>telaprevir (INCIVEK)</dd>\n<dt>•</dt>\n<dd>boceprevir </dd>\n<dt>•</dt>\n<dd>ritonavir (KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR)</dd>\n<dt>•</dt>\n<dd>letermovir (PREVYMIS)</dd>\n<dt>•</dt>\n<dd>ketoconazole </dd>\n<dt>•</dt>\n<dd>itraconazole (ONMEL, SPORANOX)</dd>\n<dt>•</dt>\n<dd>voriconazole (VFEND) </dd>\n<dt>•</dt>\n<dd>caspofungin (CANCIDAS)</dd>\n<dt>•</dt>\n<dd>clarithromycin (BIAXIN, BIAXIN XL, PREVPAC)</dd>\n<dt>•</dt>\n<dd>rifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE)</dd>\n<dt>•</dt>\n<dd>rifabutin (MYCOBUTIN) </dd>\n<dt>•</dt>\n<dd>amiodarone (NEXTERONE, PACERONE) </dd>\n<dt>•</dt>\n<dd>cannabidiol (EPIDIOLEX)</dd>\n</dl>\n<p>Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above.</p>\n<p>PROGRAF may affect the way other medicines work, and other medicines may affect how PROGRAF works.</p>\n<p>Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take PROGRAF?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Take PROGRAF exactly as your healthcare provider tells you to take it.</dd>\n<dt>•</dt>\n<dd>Your healthcare provider will tell you how much PROGRAF to take and when to take it.</dd>\n<dt> </dt>\n<dd>Your healthcare provider may change your PROGRAF dose if needed. <span class=\"Bold\">Do not </span>stop taking or change your dose of PROGRAF without talking to your healthcare provider.</dd>\n<dt>•</dt>\n<dd>Take PROGRAF with or without food.</dd>\n<dt>•</dt>\n<dd>Take PROGRAF the same way every day. For example, if you choose to take PROGRAF with food, you should always take PROGRAF with food.</dd>\n<dt>•</dt>\n<dd>Take PROGRAF at the same time each day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m.</dd>\n<dt>•</dt>\n<dd>Taking PROGRAF at the same time each day helps to keep the amount of medicine in your body at a steady level.</dd>\n<dt>•</dt>\n<dd>If you take too much PROGRAF, call your healthcare provider or go to the nearest hospital emergency room right away.</dd>\n</dl>\n<p>\n<span class=\"Bold\">PROGRAF capsules:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Do not</span> open or crush PROGRAF capsules.</dd>\n</dl>\n<p>\n<span class=\"Bold\">PROGRAF Granules:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Children who have trouble swallowing capsules can be given PROGRAF Granules.</dd>\n<dt>•</dt>\n<dd>Give the dose of PROGRAF Granules right after preparing. Do not save prepared PROGRAF Granules as a liquid to take at a later time. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">See the Instructions for Use at the end of this Patient Information</span> for detailed instructions about how to mix and give PROGRAF Granules as a liquid in a glass cup or oral syringe.</dd>\n<dt>•</dt>\n<dd>If you get the granules or prepared oral suspension on your skin, wash the area well with soap and water. </dd>\n<dt>•</dt>\n<dd>If you get the granules or prepared oral suspension in your eyes, rinse with plain water.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking PROGRAF?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>While you take PROGRAF you should not receive any live vaccines. </dd>\n<dt>•</dt>\n<dd>Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Do not</span> eat grapefruit or drink grapefruit juice during treatment with PROGRAF.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of PROGRAF?</span>\n</p>\n<p>\n<span class=\"Bold\">PROGRAF may cause serious side effects, including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>See<span class=\"Bold\"> “What is the most important information I should know about PROGRAF?”</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">problems from medicine errors. </span>People who take PROGRAF have sometimes been given the wrong type of tacrolimus product. <span class=\"Bold\">Tacrolimus extended-release medicines are not the same as PROGRAF capsules or granules </span>and cannot be substituted for each other. <span class=\"Bold\">Check your PROGRAF when you get a new prescription and before you take it to make sure you have received PROGRAF capsules or PROGRAF Granules.</span>\n</dd>\n<dt>•</dt>\n<dd>Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">high blood sugar (diabetes). </span>Your healthcare provider may do blood tests to check for diabetes while you take PROGRAF. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\"></td><td valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>frequent urination</dd>\n<dt>o</dt>\n<dd>increased thirst or hunger</dd>\n<dt>o</dt>\n<dd>blurred vision</dd>\n<dt>o</dt>\n<dd>confusion</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>drowsiness</dd>\n<dt>o</dt>\n<dd>loss of appetite</dd>\n<dt>o</dt>\n<dd>fruity smell on your breath</dd>\n<dt>o</dt>\n<dd>nausea, vomiting, or stomach pain</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">kidney problems. </span>Kidney problems are a serious and common side effect of PROGRAF. Your healthcare provider may do blood tests to check your kidney function while you take PROGRAF. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">nervous system problems. </span>Nervous system problems are a serious and common side effect of PROGRAF. Call your healthcare provider right away if you get any of these symptoms while taking PROGRAF. These could be signs of a serious nervous system problem:</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\"></td><td valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>headache</dd>\n<dt>o</dt>\n<dd>confusion</dd>\n<dt>o</dt>\n<dd>seizures</dd>\n<dt>o</dt>\n<dd>changes in your vision</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>changes in behavior</dd>\n<dt>o</dt>\n<dd>coma</dd>\n<dt>o</dt>\n<dd>tremors</dd>\n<dt>o</dt>\n<dd>numbness and tingling</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">high levels of potassium in your blood. </span>Your healthcare provider may do blood tests to check your potassium level while you take PROGRAF.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">high blood pressure.</span> High blood pressure is a serious and common side effect of PROGRAF. Your healthcare provider will monitor your blood pressure while you take PROGRAF and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">changes in the electrical activity of your heart (QT prolongation).</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">heart problems (myocardial hypertrophy).</span> Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking PROGRAF:</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\"></td><td valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>shortness of breath</dd>\n<dt>o</dt>\n<dd>chest pain</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>feel lightheaded</dd>\n<dt>o</dt>\n<dd>feel faint</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">severe low red blood cell count (anemia). </span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">blood clotting problems:</span> Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of PROGRAF in people who have received a kidney, liver, heart, or lung transplant are:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\"></td><td valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>infections in general, including cytomegalovirus (cmv) infection</dd>\n<dt>•</dt>\n<dd>tremors (shaking of the body)</dd>\n<dt>•</dt>\n<dd>constipation</dd>\n<dt>•</dt>\n<dd>diarrhea</dd>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>stomach pain</dd>\n<dt>•</dt>\n<dd>trouble sleeping</dd>\n<dt>•</dt>\n<dd>nausea</dd>\n<dt>•</dt>\n<dd>high blood sugar (diabetes)</dd>\n<dt>•</dt>\n<dd>low levels of magnesium in your blood</dd>\n<dt>•</dt>\n<dd>low levels of phosphate in your blood</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>swelling of the hands, legs, ankles, or feet</dd>\n<dt>•</dt>\n<dd>weakness</dd>\n<dt>•</dt>\n<dd>pain</dd>\n<dt>•</dt>\n<dd>high levels of fat in your blood</dd>\n<dt>•</dt>\n<dd>high levels of potassium in your blood</dd>\n<dt>•</dt>\n<dd>low red blood cell count (anemia)</dd>\n<dt>•</dt>\n<dd>low white blood cell count</dd>\n<dt>•</dt>\n<dd>fever</dd>\n<dt>•</dt>\n<dd>numbness or tingling in your hands and feet</dd>\n<dt>•</dt>\n<dd>inflammation of your airway (bronchitis)</dd>\n<dt>•</dt>\n<dd>fluid around your heart</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p>\n<p>These are not all the possible side effects of PROGRAF. For more information, ask your healthcare provider or pharmacist.</p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store PROGRAF?</span>\n</p>\n<p>\n<span class=\"Bold\">PROGRAF capsules</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store PROGRAF capsules at room temperature between 68°F to 77°F (20°C to 25°C). </dd>\n</dl>\n<p>\n<span class=\"Bold\">PROGRAF Granules</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store PROGRAF Granules packets at room temperature between 68°F to 77°F (20°C to 25°C).</dd>\n</dl>\n<p>\n<span class=\"Bold\">Keep PROGRAF and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of PROGRAF.</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROGRAF for a condition for which it was not prescribed. Do not give PROGRAF to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PROGRAF that is written for health professionals. </dd>\n<dt>•</dt>\n<dd>This Patient Information leaflet summarizes the most important information about PROGRAF. If you would like more information, talk to your healthcare provider.</dd>\n</dl>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in PROGRAF?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span> tacrolimus</p>\n<p>\n<span class=\"Bold\">Inactive ingredients:</span>\n</p>\n<p>PROGRAF capsules: croscarmellose sodium, hypromellose, lactose monohydrate, and magnesium stearate. The 0.5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide. The 1 mg capsule shell contains gelatin and titanium dioxide. The 5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide.</p>\n<p>PROGRAF Granules: croscarmellose sodium, hypromellose, and lactose monohydrate.</p>\n<p>Distributed by: <span class=\"Bold\">Astellas Pharma US, Inc. </span>Northbrook, IL 60062</p>\n<p>PROGRAF<span class=\"Sup\">®</span> is a registered trademark of Astellas Pharma Inc. All other trademarks and registered trademarks are the property of their respective owners.</p>\n<p>398977-PRG </p>\n<p>For more information, go to www.astellas.com/us or call 1-800-727-7003.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration.             Revised: 08/2023

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration.             Revised: 08/2023" }

PROGRAF® Granules (PRO-graf) (tacrolimus for oral suspension)

{ "type": "p", "children": [], "text": "\nPROGRAF® Granules\n\n(PRO-graf)\n\n(tacrolimus for oral suspension)\n" }

Your healthcare provider has prescribed PROGRAF® Granules, which comes in individual packets that will need to be mixed with water before giving the medicine to your child.

{ "type": "p", "children": [], "text": "Your healthcare provider has prescribed PROGRAF® Granules, which comes in individual packets that will need to be mixed with water before giving the medicine to your child." }

Read this Instructions for Use and the Patient Information for the first time and each time you get a refill of PROGRAF Granules (tacrolimus for oral suspension). There may be new information.

{ "type": "p", "children": [], "text": "Read this Instructions for Use and the Patient Information for the first time and each time you get a refill of PROGRAF Granules (tacrolimus for oral suspension). There may be new information. " }

This Instructions for Use does not take the place of talking to your child’s healthcare provider about their medical condition or treatment. Ask the healthcare provider if you have any questions about how to mix or give a dose of PROGRAF Granules the right way.

{ "type": "p", "children": [], "text": "This Instructions for Use does not take the place of talking to your child’s healthcare provider about their medical condition or treatment. Ask the healthcare provider if you have any questions about how to mix or give a dose of PROGRAF Granules the right way." }

Important information: These instructions are for preparing PROGRAF Granules only.These instructions should not be used for PROGRAF capsules.

{ "type": "p", "children": [], "text": "\nImportant information: These instructions are for preparing PROGRAF Granules only.These instructions should not be used for PROGRAF capsules.\n" }

{ "type": "", "children": [], "text": "" }

If you spill the granules, wipe the surface with a wet paper towel. If you spill the prepared oral suspension, dry the area with a dry paper towel and then wipe the area with a wet paper towel. Throw away the paper towels in the trash and wash your hands well with soap and water.

{ "type": "p", "children": [], "text": "If you spill the granules, wipe the surface with a wet paper towel. If you spill the prepared oral suspension, dry the area with a dry paper towel and then wipe the area with a wet paper towel. Throw away the paper towels in the trash and wash your hands well with soap and water." }

For each dose of PROGRAF Granules mixed with water that will be given using a glass cup, you will need the following supplies (See Figure A):

{ "type": "p", "children": [], "text": "\nFor each dose of PROGRAF Granules mixed with water that will be given using a glass cup, you will need the following supplies (See Figure A):" }

{ "type": "", "children": [], "text": "" }

Figure A

{ "type": "p", "children": [], "text": "\nFigure A\n" }

<div class="scrollingtable"><table width="105.56%"> <col width="9%"/> <col width="38%"/> <col width="53%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Step 1</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Choose a clean flat work surface. Place a clean paper towel on the work surface. Place the supplies to prepare the dose on the paper towel. </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 2</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Wash and dry your hands.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 3</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Remove the prescribed number of PROGRAF Granules packets from the carton.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"><a name="id1664822285"></a><img alt="Step 3" src="/dailymed/image.cfm?name=image-09.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 4</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Using a pair of scissors, cut along the dotted line on 1 PROGRAF Granules packet to open it.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"><a name="id-1819790658"></a><img alt="Step 4" src="/dailymed/image.cfm?name=image-10.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 5</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Empty all of the granules in the packet into the glass cup. Check for any remaining granules in the packet and empty these into the glass cup.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"><a name="id518742511"></a><img alt="Step 5" src="/dailymed/image.cfm?name=image-11.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 6</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">If more than 1 packet of PROGRAF Granules is needed for your child’s prescribed dose, repeat Steps 4 and 5 using the number of packets needed for the prescribed dose.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 7</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the glass cup containing the granules.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"><a name="id549035501"></a><img alt="Step 7" src="/dailymed/image.cfm?name=image-12.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 8</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Gently stir the granules and water in the glass cup with a metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the water.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"><a name="id863712973"></a><img alt="Step 8" src="/dailymed/image.cfm?name=image-13.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 9</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Give the granules and water suspension in the glass cup to your child. Make sure your child drinks all of the medicine in the cup.</p> <p>Give all of the medicine to your child right away after preparing. <span class="Bold">Do not</span> save the medicine for later use.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"><a name="id-1178811645"></a><img alt="Step 9" src="/dailymed/image.cfm?name=image-14.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 10</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">To make sure all of the medicine is given to your child, refill the glass cup with the same amount of water used in Step 7.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 11</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Gently swirl the glass cup to mix any remaining granules.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 12</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Give all of the medicine in the cup to the child.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 13</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"105.56%\">\n<col width=\"9%\"/>\n<col width=\"38%\"/>\n<col width=\"53%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 1</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Choose a clean flat work surface. Place a clean paper towel on the work surface. Place the supplies to prepare the dose on the paper towel. </p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 2</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Wash and dry your hands.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 3</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Remove the prescribed number of PROGRAF Granules packets from the carton.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\"><a name=\"id1664822285\"></a><img alt=\"Step 3\" src=\"/dailymed/image.cfm?name=image-09.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 4</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Using a pair of scissors, cut along the dotted line on 1 PROGRAF Granules packet to open it.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"id-1819790658\"></a><img alt=\"Step 4\" src=\"/dailymed/image.cfm?name=image-10.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 5</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Empty all of the granules in the packet into the glass cup. Check for any remaining granules in the packet and empty these into the glass cup.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"id518742511\"></a><img alt=\"Step 5\" src=\"/dailymed/image.cfm?name=image-11.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 6</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">If more than 1 packet of PROGRAF Granules is needed for your child’s prescribed dose, repeat Steps 4 and 5 using the number of packets needed for the prescribed dose.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 7</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the glass cup containing the granules.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"id549035501\"></a><img alt=\"Step 7\" src=\"/dailymed/image.cfm?name=image-12.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 8</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Gently stir the granules and water in the glass cup with a metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the water.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"id863712973\"></a><img alt=\"Step 8\" src=\"/dailymed/image.cfm?name=image-13.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 9</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Give the granules and water suspension in the glass cup to your child. Make sure your child drinks all of the medicine in the cup.</p>\n<p>Give all of the medicine to your child right away after preparing. <span class=\"Bold\">Do not</span> save the medicine for later use.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"id-1178811645\"></a><img alt=\"Step 9\" src=\"/dailymed/image.cfm?name=image-14.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 10</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">To make sure all of the medicine is given to your child, refill the glass cup with the same amount of water used in Step 7.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 11</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Gently swirl the glass cup to mix any remaining granules.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 12</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Give all of the medicine in the cup to the child.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 13</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n</tbody>\n</table></div>" }

For each dose of PROGRAF Granules (tacrolimus for oral suspension) mixed with water that will be drawn up and given using an oral syringe, you will need the following supplies (See Figure B):

{ "type": "p", "children": [], "text": "\nFor each dose of PROGRAF Granules (tacrolimus for oral suspension) mixed with water that will be drawn up and given using an oral syringe, you will need the following supplies (See Figure B):" }

{ "type": "", "children": [], "text": "" }

Figure B

{ "type": "p", "children": [], "text": "\nFigure B\n" }

<div class="scrollingtable"><table width="96.54%"> <col width="10%"/> <col width="40%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Step 1</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Choose a clean flat work surface. Place a clean paper towel on the work surface. Place the supplies to prepare the dose on the paper towel.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 2</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Wash and dry your hands.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 3</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Remove the prescribed number of PROGRAF Granules packets from the carton.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"><a name="id247864569"></a><img alt="Step 3" src="/dailymed/image.cfm?name=image-16.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 4</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Using a pair of scissors, cut along the dotted line on 1 PROGRAF Granules packet to open it.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"><a name="id-1214580070"></a><img alt="Step 4" src="/dailymed/image.cfm?name=image-17.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 5 </span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Empty all of the granules in the packet into the glass cup. Check for any remaining granules in the packet and empty these into the glass cup. </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"><a name="id-88923255"></a><img alt="Step 5" src="/dailymed/image.cfm?name=image-18.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 6</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">If more than 1 packet of PROGRAF Granules is needed for your child’s prescribed dose, repeat Steps 4 and 5 using the number of packets needed for the prescribed dose.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 7</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the glass cup containing the granules.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"><a name="id-1822190021"></a><img alt="Step 7" src="/dailymed/image.cfm?name=image-19.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 8</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Gently stir the granules and drinking water in the glass cup with a metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the drinking water.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"><a name="id-916936612"></a><img alt="Step 8" src="/dailymed/image.cfm?name=image-20.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 9</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Insert the tip of the oral syringe into the glass cup.</p> <p>Pull back on the plunger of the oral syringe to draw up the suspension.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"><a name="id1264640926"></a><img alt="Step 9" src="/dailymed/image.cfm?name=image-21.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 10</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Place the tip of the oral syringe in your child’s mouth along the inner cheek. Slowly push the plunger all the way down to give your child <span class="Bold">all</span> of the medicine in the oral syringe.<br/> <br/>Repeat Steps 9 and 10 until the glass cup is empty.<br/> <br/>Give all of the medicine to your child right away after preparing. <span class="Bold">Do not</span> save the medicine for later use.</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"><a name="id-1734084650"></a><img alt="Step 10" src="/dailymed/image.cfm?name=image-22.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b"/></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 11</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">To make sure all of the medicine is given to your child, refill the glass cup with the same amount of drinking water used in Step 7.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 12</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Gently swirl the glass cup to mix any remaining granules. </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 13</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Repeat Steps 9 and 10 until the glass cup is empty.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 14</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rinse the plunger and barrel of the syringe well with drinking water and dry well before storing the oral syringe.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Step 15</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands.</p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"96.54%\">\n<col width=\"10%\"/>\n<col width=\"40%\"/>\n<col width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 1</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Choose a clean flat work surface. Place a clean paper towel on the work surface. Place the supplies to prepare the dose on the paper towel.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 2</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Wash and dry your hands.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 3</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Remove the prescribed number of PROGRAF Granules packets from the carton.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\"><a name=\"id247864569\"></a><img alt=\"Step 3\" src=\"/dailymed/image.cfm?name=image-16.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 4</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Using a pair of scissors, cut along the dotted line on 1 PROGRAF Granules packet to open it.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\"><a name=\"id-1214580070\"></a><img alt=\"Step 4\" src=\"/dailymed/image.cfm?name=image-17.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 5 </span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Empty all of the granules in the packet into the glass cup. Check for any remaining granules in the packet and empty these into the glass cup. </p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"id-88923255\"></a><img alt=\"Step 5\" src=\"/dailymed/image.cfm?name=image-18.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 6</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">If more than 1 packet of PROGRAF Granules is needed for your child’s prescribed dose, repeat Steps 4 and 5 using the number of packets needed for the prescribed dose.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 7</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Add 1 to 2 tablespoons (15 to 30 milliliters) of room temperature drinking water to the glass cup containing the granules.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"id-1822190021\"></a><img alt=\"Step 7\" src=\"/dailymed/image.cfm?name=image-19.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 8</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Gently stir the granules and drinking water in the glass cup with a metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the drinking water.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"id-916936612\"></a><img alt=\"Step 8\" src=\"/dailymed/image.cfm?name=image-20.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 9</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Insert the tip of the oral syringe into the glass cup.</p>\n<p>Pull back on the plunger of the oral syringe to draw up the suspension.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\"><a name=\"id1264640926\"></a><img alt=\"Step 9\" src=\"/dailymed/image.cfm?name=image-21.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 10</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Place the tip of the oral syringe in your child’s mouth along the inner cheek. Slowly push the plunger all the way down to give your child <span class=\"Bold\">all</span> of the medicine in the oral syringe.<br/>\n<br/>Repeat Steps 9 and 10 until the glass cup is empty.<br/>\n<br/>Give all of the medicine to your child right away after preparing. <span class=\"Bold\">Do not</span> save the medicine for later use.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><a name=\"id-1734084650\"></a><img alt=\"Step 10\" src=\"/dailymed/image.cfm?name=image-22.jpg&amp;setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b\"/></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 11</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">To make sure all of the medicine is given to your child, refill the glass cup with the same amount of drinking water used in Step 7.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 12</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Gently swirl the glass cup to mix any remaining granules. </p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 13</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Repeat Steps 9 and 10 until the glass cup is empty.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 14</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Rinse the plunger and barrel of the syringe well with drinking water and dry well before storing the oral syringe.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 15</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands.</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td>\n</tr>\n</tbody>\n</table></div>" }

How should I store PROGRAF Granules packets?

{ "type": "p", "children": [], "text": "\nHow should I store PROGRAF Granules packets?\n" }

Store PROGRAF Granules packets at room temperature between 68°F to 77°F (20°C to 25°C).

{ "type": "p", "children": [], "text": "Store PROGRAF Granules packets at room temperature between 68°F to 77°F (20°C to 25°C)." }

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use.

{ "type": "p", "children": [], "text": "Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use." }

Keep PROGRAF Granules and all medicine out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep PROGRAF Granules and all medicine out of the reach of children. \n" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration. " }

Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062

{ "type": "p", "children": [], "text": "Distributed by:\nAstellas Pharma US, Inc.\nNorthbrook, IL 60062" }

PROGRAF® is a registered trademark of Astellas Pharma Inc.

{ "type": "p", "children": [], "text": "PROGRAF® is a registered trademark of Astellas Pharma Inc. " }

341124-PRG

{ "type": "p", "children": [], "text": "341124-PRG " }

Revised: 11/2022

{ "type": "p", "children": [], "text": "Revised: 11/2022 " }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

0.2 mg Carton

{ "type": "p", "children": [], "text": "\n0.2 mg Carton\n" }

1 mg Carton

{ "type": "p", "children": [], "text": "\n1 mg Carton\n" }

ENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants [see Clinical Studies (14.1)].

ENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants [see Clinical Studies (14.2)].

The recommended starting dose of ENVARSUS XR in de novo kidney transplant patients is 0.14 mg/kg/day. Titrate ENVARSUS XR dosage based on clinical assessments of rejection and tolerability and to achieve whole blood trough concentration ranges (see Table 1).

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 1. Recommended Tacrolimus Whole Blood Trough Concentration Ranges in Kidney Transplant Patients with Antibody Induction</span> </caption> <col width="20%"/> <col width="40%"/> <tbody class="Headless"> <tr> <td align="left" class="Bold Botrule Lrule Rrule Toprule">Time Period Post Transplant</td><td align="center" class="Bold Botrule Lrule Rrule Toprule">Target Tacrolimus Whole Blood Trough Concentration Ranges</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> During Month 1</td><td align="center" class="Botrule Lrule Rrule Toprule">6 to 11 ng/mL</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">&gt; Month 1</td><td align="center" class="Botrule Lrule Rrule Toprule">4 to 11 ng/mL</td> </tr> </tbody> </table></div>

To convert from a tacrolimus immediate-release product to ENVARSUS XR, administer ENVARSUS XR once daily at a dose that is 80% of the total daily dose of the tacrolimus immediate-release product. Monitor tacrolimus whole blood trough concentrations and titrate ENVARSUS XR dosage to achieve whole blood trough concentration ranges of 4 to 11 ng/mL.

African-American patients, compared to Caucasian patients, may need to be titrated to higher ENVARSUS XR dosages to attain comparable trough concentrations [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].

Due to reduced clearance and prolonged half-life seen in patients with severe hepatic impairment (Child-Pugh ≥10) these patients may require a lower starting dosage of ENVARSUS XR [see Clinical Pharmacology (12.3)].

Dose adjustments of ENVARSUS XR may be necessary when administered concomitantly with CYP3A inducers or CYP3A inhibitors or cannabidiol [see Warnings and Precautions (5.9, 5.13), Drug Interactions (7.2, 7.3)].

Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors or cannabidiol [see Drug Interactions (7)], or after a change in renal or hepatic function [see Use in Specific Populations (8.6, 8.7)]. When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the ENVARSUS XR dose.

Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)]. The immunosuppressive activity of tacrolimus is mainly due to the parent drug rather than to its metabolites. Immunoassays may react with metabolites as well as the parent drug. Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be numerically higher than concentrations obtained with an assay using HPLC/MS/MS. Comparison of the whole blood tacrolimus trough concentrations of patients to those described in the prescribing information and other published literature must be made with knowledge of the assay method(s) employed.

Oval, white to off-white uncoated extended-release tablets debossed with “TCS” on one side:

{ "type": "p", "children": [], "text": "Oval, white to off-white uncoated extended-release tablets debossed with “TCS” on one side:" }

{ "type": "ul", "children": [ "0.75 mg extended-release tablet: debossed with “0.75” on the other side.", "1 mg extended-release tablet: debossed with “1” on the other side.", "4 mg extended-release tablet: debossed with “4” on the other side." ], "text": "" }

ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus or to any of the ingredients in ENVARSUS XR.

{ "type": "p", "children": [], "text": "ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus or to any of the ingredients in ENVARSUS XR." }

Immunosuppressants, including ENVARSUS XR, increase the risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protection factor.

Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. The risk of PTLD appears greatest in those individuals who are EBV seronegative. Monitor EBV serology during treatment.

Immunosuppressants, including ENVARSUS XR, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:

Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions (6.1)].

Medication errors, including substitution and dispensing errors, between tacrolimus capsules and tacrolimus extended-release capsules were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or over-exposure to tacrolimus. ENVARSUS XR is not interchangeable or substitutable with tacrolimus extended-release capsules, tacrolimus capsules or tacrolimus for oral suspension. Instruct patients and caregivers to recognize the appearance of ENVARSUS XR tablet [see Dosage Forms and Strengths (3)] and to confirm with their healthcare provider if a different product is dispensed or if dosing instructions have changed.

ENVARSUS XR caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Monitor blood glucose concentrations and treat appropriately [see Adverse Reactions (6.1) and Use in Specific Populations (8.8)].

ENVARSUS XR, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration.

The risk for nephrotoxicity may increase when ENVARSUS XR is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). When tacrolimus is used concurrently with CYP3A inhibitors or other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust dose of both tacrolimus and/or concomitant medications during concurrent use [see Adverse Reactions (6.1, 6.2) and Drug Interactions (7.2)].

ENVARSUS XR may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions (6.1, 6.2)]. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of ENVARSUS XR if neurotoxicity occurs.

Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including ENVARSUS XR. Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia [see Adverse Reactions (6.1)]. Monitor serum potassium levels periodically during treatment.

Hypertension is a common adverse reaction of ENVARSUS XR therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)]. Some antihypertensive drugs can increase the risk for hyperkalemia [see Warnings and Precautions (5.7)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ENVARSUS XR [see Drug Interactions (7.2)].

The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10)]. Therefore, adjust ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations when co-administering ENVARSUS XR with strong CYP3A inhibitors (e.g., including but not limited to telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., including but not limited to rifampin, rifabutin) [see Dosage and Administration (2.4, 2.5), Drug Interactions (7.2)]. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with strong CYP3A4 inhibitors despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions (7.2)].

ENVARSUS XR may prolong the QT/QTc interval and cause Torsades de pointes. Avoid ENVARSUS XR in patients with congenital long QT syndrome. Consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other products that lead to QT prolongation, and those with electrolyte disturbances (e.g., hypokalemia, hypocalcemia, or hypomagnesemia).

When co-administering ENVARSUS XR with other substrates and/or inhibitors of CYP3A, especially those that also have the potential to prolong the QT interval, a reduction in ENVARSUS XR dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended [see Dosage and Administration (2.5), Drug Interactions (7.2)].

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with ENVARSUS XR.

Avoid the use of live attenuated vaccines during treatment with ENVARSUS XR (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with ENVARSUS XR.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All of these patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. A mechanism for tacrolimus-induced PRCA has not been elucidated. If PRCA is diagnosed, consider discontinuation of ENVARSUS XR.

When cannabidiol and ENVARSUS XR are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of ENVARSUS XR should be considered as needed when ENVARSUS XR is co-administered with cannabidiol [see Dosage and Administration (2.4, 2.5), Drug Interactions (7.3)].

Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with ENVARSUS XR. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA.

In patients with signs and symptoms of TMA, consider ENVARSUS XR as a risk factor. Concurrent use of ENVARSUS XR and mTOR inhibitors may contribute to the risk of TMA.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In addition, the clinical studies were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

Study 1- Phase 3 Clinical Study in De Novo Kidney Transplant Recipients

Study 1 (NCT 01187953), was a Phase 3 randomized study in de novo kidney transplant patients that were treated with ENVARSUS XR (N=268) or tacrolimus [immediate-release] capsules (N=275) and concomitant immunosuppressants in a double-blind, randomized, multinational study [see Clinical Studies (14.1)]. The proportion of patients who discontinued treatment due to adverse reactions was 8.6% and 9.8% in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation of study drug in the ENVARSUS XR treatment group were esophagitis, polyomavirus-associated nephropathy, graft dysfunction, complications of transplanted kidney, and diabetes mellitus, each resulting in 0.7% discontinuations among ENVARSUS XR treatment patients. In Study 1, de novo kidney transplant patients who received a starting dose of 0.17 mg/kg/day, which is higher than the recommended ENVARSUS XR starting dose of 0.14 mg/kg/day, exceeded the recommended target tacrolimus trough concentrations as high as 57 ng/mL during the first 1 to 2 weeks post-transplant [see Dosage and Administration (2.2)].

Infections

The overall incidence of infections, serious infections, and infections with identified etiology reported in de novo kidney transplant recipients treated with ENVARSUS XR or tacrolimus [immediate-release] capsules in Study 1 are shown in Table 2.

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 2 Percentage of Patients with Infections Through 1 Year Post-Kidney Transplant in Study 1 <span class="Sup">a</span></span> </caption> <col width="40%"/> <col width="30%"/> <col width="30%"/> <tfoot> <tr> <td colspan="3">MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprine<br/> <br/> <span class="Sup">a</span> Study 1 was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus [immediate-release] capsules for the adverse reactions reported in this table.</td> </tr> <tr> <td colspan="3"><span class="Sup">b</span> BK virus-associated nephropathy (BKVAN) occurred in 1.5% (4/268) and 0.7% (2/275) in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Bold Botrule Lrule Rrule Toprule"></td><td align="center" class="Bold Botrule Lrule Rrule Toprule">ENVARSUS XR ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA <br/> <br/> N=268 </td><td align="center" class="Bold Botrule Lrule Rrule Toprule">Tacrolimus [immediate-release] capsules ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA<br/> <br/> N=275 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> All infections</td><td align="center" class="Botrule Lrule Rrule Toprule">70%</td><td align="center" class="Botrule Lrule Rrule Toprule">65%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">             Urinary Tract Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">29%</td><td align="center" class="Botrule Lrule Rrule Toprule">27%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">             Respiratory Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">28%</td><td align="center" class="Botrule Lrule Rrule Toprule">24%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">             Bacterial Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">13%</td><td align="center" class="Botrule Lrule Rrule Toprule">18%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">             Cytomegalovirus Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">11%</td><td align="center" class="Botrule Lrule Rrule Toprule">9%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">             Fungal Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">9%</td><td align="center" class="Botrule Lrule Rrule Toprule">8%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">             Gastrointestinal Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">             BK virus <span class="Sup">b</span></td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td><td align="center" class="Botrule Lrule Rrule Toprule">9%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"> Serious Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">26%</td><td align="center" class="Botrule Lrule Rrule Toprule">24%</td> </tr> </tbody> </table></div>

New Onset Diabetes After Transplantation

New onset diabetes after transplantation (NODAT) was defined by the composite occurrence of fasting plasma glucose values ≥126 mg/dL, 2-hour post-prandial plasma glucose of at least 200 mg/dL (in oral glucose tolerance test) on two or more consecutive occasions post-baseline, insulin requirement for ≥31 days, an oral hypoglycemic agent use ≥31 days, or HbA1c ≥6.5% (at least 3 months after randomization) among kidney transplant patients with no medical history of diabetes. The incidence of NODAT for Study 1 through one year post-transplant is summarized in Table 3 below [see Warnings and Precautions (5.4)].

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 3. Percentage of Patients with NODAT Through 1 Year Post-Kidney Transplant in Study 1 <span class="Sup">a</span></span> </caption> <col width="50%"/> <col width="25%"/> <col width="25%"/> <tfoot> <tr> <td colspan="3">MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprine<br/> <br/> <span class="Sup">a</span> Study 1 was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus [immediate-release] capsules for the adverse reactions reported in this table.</td> </tr> <tr> <td colspan="3"><span class="Sup">b</span> Analyses restricted to patients at risk for NODAT.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Bold Botrule Lrule Rrule Toprule"></td><td align="center" class="Bold Botrule Lrule Rrule Toprule">ENVARSUS XR ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA <br/>(N=88) </td><td align="center" class="Bold Botrule Lrule Rrule Toprule">Tacrolimus [immediate-release] capsules ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA<br/>(N=74) </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Composite NODAT <span class="Sup">b</span></td><td align="center" class="Botrule Lrule Rrule Toprule">21%</td><td align="center" class="Botrule Lrule Rrule Toprule">15%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     HbA<span class="Sub">1c</span> ≥6.5%</td><td align="center" class="Botrule Lrule Rrule Toprule"> 13% </td><td align="center" class="Botrule Lrule Rrule Toprule">8%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     Fasting Plasma Glucose Values ≥126 mg/dL on 2       consecutive occurrences</td><td align="center" class="Botrule Lrule Rrule Toprule">8%</td><td align="center" class="Botrule Lrule Rrule Toprule">11%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     Oral hypoglycemic use</td><td align="center" class="Botrule Lrule Rrule Toprule">7%</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     Insulin use ≥31 days</td><td align="center" class="Botrule Lrule Rrule Toprule">1% </td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td> </tr> </tbody> </table></div>

Common Adverse Reactions

The incidence of adverse reactions that occurred in ≥10% of ENVARSUS XR-treated patients compared to tacrolimus [immediate-release] capsules through one year of treatment in Study 1 is shown by treatment group in Table 4 .

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 4. Adverse Reactions ( ≥ 10%) in Kidney Transplant Patients Through 1 Year Post-Transplant in Study 1<span class="Sup">a</span></span> </caption> <col width="50%"/> <col width="25%"/> <col width="25%"/> <tfoot> <tr> <td colspan="3"><span class="Sup">a</span> Study 1 was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus [immediate-release] capsules for the adverse reactions reported in this table.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Bold Botrule Lrule Rrule Toprule" valign="top"> Adverse Reaction</td><td align="center" class="Bold Botrule Lrule Rrule Toprule">ENVARSUS XR<br/> N=268 </td><td align="center" class="Bold Botrule Lrule Rrule Toprule">Tacrolimus [immediate-release] capsules<br/> N=275 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Diarrhea</td><td align="center" class="Botrule Lrule Rrule Toprule">31%</td><td align="center" class="Botrule Lrule Rrule Toprule">34%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Anemia</td><td align="center" class="Botrule Lrule Rrule Toprule">26%</td><td align="center" class="Botrule Lrule Rrule Toprule">29%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Urinary Tract Infection</td><td align="center" class="Botrule Lrule Rrule Toprule">25%</td><td align="center" class="Botrule Lrule Rrule Toprule">25%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Hypertension</td><td align="center" class="Botrule Lrule Rrule Toprule">23%</td><td align="center" class="Botrule Lrule Rrule Toprule">23%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Tremor</td><td align="center" class="Botrule Lrule Rrule Toprule">19%</td><td align="center" class="Botrule Lrule Rrule Toprule">17%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Constipation</td><td align="center" class="Botrule Lrule Rrule Toprule">18%</td><td align="center" class="Botrule Lrule Rrule Toprule">25%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Diabetes Mellitus</td><td align="center" class="Botrule Lrule Rrule Toprule">16%</td><td align="center" class="Botrule Lrule Rrule Toprule">14%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Peripheral Edema</td><td align="center" class="Botrule Lrule Rrule Toprule">16%</td><td align="center" class="Botrule Lrule Rrule Toprule">21%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Hyperkalemia</td><td align="center" class="Botrule Lrule Rrule Toprule">15%</td><td align="center" class="Botrule Lrule Rrule Toprule">11%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Headache</td><td align="center" class="Botrule Lrule Rrule Toprule">15%</td><td align="center" class="Botrule Lrule Rrule Toprule">10%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Hypophosphatemia</td><td align="center" class="Botrule Lrule Rrule Toprule">13%</td><td align="center" class="Botrule Lrule Rrule Toprule">15%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Leukopenia</td><td align="center" class="Botrule Lrule Rrule Toprule">13%</td><td align="center" class="Botrule Lrule Rrule Toprule">14%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Nausea</td><td align="center" class="Botrule Lrule Rrule Toprule">13%</td><td align="center" class="Botrule Lrule Rrule Toprule">15%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Insomnia</td><td align="center" class="Botrule Lrule Rrule Toprule">13%</td><td align="center" class="Botrule Lrule Rrule Toprule">11%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Increased Blood Creatinine</td><td align="center" class="Botrule Lrule Rrule Toprule">12%</td><td align="center" class="Botrule Lrule Rrule Toprule">14%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Hypomagnesemia</td><td align="center" class="Botrule Lrule Rrule Toprule">12%</td><td align="center" class="Botrule Lrule Rrule Toprule">12%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Hypokalemia</td><td align="center" class="Botrule Lrule Rrule Toprule">12%</td><td align="center" class="Botrule Lrule Rrule Toprule">12%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Hyperglycemia</td><td align="center" class="Botrule Lrule Rrule Toprule">11%</td><td align="center" class="Botrule Lrule Rrule Toprule">12%</td> </tr> </tbody> </table></div>

Study 2- Phase 2 Clinical Study in De Novo Kidney Transplant Recipients

Study 2 (NCT00765661) was an open-label Phase 2 study conducted in de novo kidney transplant patients randomized to once daily ENVARSUS XR (N=32) or twice daily tacrolimus [immediate-release] capsules (N=31). The study was conducted in the US and patients received an organ from a deceased or living donor. Pharmacokinetics were evaluated during the first 2 weeks with an additional 50-week treatment and follow-up to evaluate safety and efficacy [see Clinical Studies (14.1)].

The starting dosage was 0.14 mg/kg/day (given once daily) for ENVARSUS XR and 0.2 mg/kg/day (given twice daily) for tacrolimus [immediate-release] capsules. On Day 2 predose, the proportion of patients in the ENVARSUS XR group with tacrolimus trough concentration that were within, above, and below 6 to 11 ng/mL was 53%, 11%, and 37%, respectively. The starting dose of 0.14 mg/kg/day in Study 2 formed the basis of dosing recommendations in de novo kidney transplant patients.

There were no deaths or graft failures in Study 2. Two patients in each arm discontinued due to adverse events. The most common adverse reactions included infections and cardiovascular events, and were generally similar to those reported in Study 1.

Study 3- Phase 3 Clinical Studies in Stable Kidney Transplant Recipients Converted from Tacrolimus Capsules

In Study 3 (NCT00817206) stable kidney transplant patients were treated with ENVARSUS XR (N=162) or tacrolimus [immediate-release] capsules (N=162) and concomitant immunosuppressants in an open-label, randomized, multinational study [see Clinical Studies (14.2)]. The proportion of patients who discontinued treatment due to adverse reactions was 7.4% and 1.2% in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation of study drug in the ENVARSUS XR treatment group was cardiac arrest (2 events).

Infections

The overall incidence of infections, serious infections, and infections with identified etiology reported in stable kidney transplant recipients treated with ENVARSUS XR or tacrolimus capsules are shown in Table 5.

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 5. Percentage of Stable Patients with Infections Through 1 Year Post-Treatment in Study 3 <span class="Sup">a</span></span> </caption> <col width="40%"/> <col width="30%"/> <col width="30%"/> <tfoot> <tr> <td colspan="3">MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprine <br/> <span class="Sup">a</span> The stable kidney transplant study was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus capsules for the adverse reactions reported in this table.</td> </tr> <tr> <td colspan="3"><span class="Sup">b</span> BK virus associated nephropathy (BKVAN) occurred in 1.2% (2/162) and 0.6% (1/162) in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Bold Botrule Lrule Rrule Toprule"> </td><td align="center" class="Bold Botrule Lrule Rrule Toprule">ENVARSUS XR ± steroids, MMF/MPS or AZA <br/> <br/>N=162</td><td align="center" class="Bold Botrule Lrule Rrule Toprule">Tacrolimus [immediate-release] capsules± steroids, MMF/MPS or AZA<br/> <br/>N=162 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">  All infections</td><td align="center" class="Botrule Lrule Rrule Toprule">46%</td><td align="center" class="Botrule Lrule Rrule Toprule">48%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">       Respiratory Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">26%</td><td align="center" class="Botrule Lrule Rrule Toprule">28%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">       Urinary Tract Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">10%</td><td align="center" class="Botrule Lrule Rrule Toprule">14%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">       Bacterial Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">7%</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">       Fungal Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">       Gastrointestinal Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">       BK virus <span class="Sup">b</span></td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">       Cytomegalovirus Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td><td align="center" class="Botrule Lrule Rrule Toprule">1%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">  Serious Infections</td><td align="center" class="Botrule Lrule Rrule Toprule">8%</td><td align="center" class="Botrule Lrule Rrule Toprule">9%</td> </tr> </tbody> </table></div>

New Onset Diabetes After Transplantation

New onset diabetes after transplantation (NODAT) was defined by the composite occurrence of fasting plasma glucose values ≥126 mg/dL, 2-hour postprandial plasma glucose of at least 200 mg/dL (in oral glucose tolerance test) on 2 or more consecutive occasions post-baseline, insulin requirement for ≥31 days, an oral hypoglycemic agent use ≥31 days, or HbA1c ≥6.5% (at least 3 months after randomization) among kidney transplant patients with no medical history of diabetes. The incidence of NODAT for the stable kidney transplant study through one year post-transplant is summarized in Table 6 below [see Warnings and Precautions (5.4)].

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 6. Percentage of Stable Patients with NODAT Through 1 Year Post- Treatment in Study 3 <span class="Sup">a</span></span> </caption> <col width="50%"/> <col width="25%"/> <col width="25%"/> <tfoot> <tr> <td colspan="3">MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprine<br/> <span class="Sup">a</span> The stable kidney transplant study was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus capsules for the adverse reactions reported in this table.</td> </tr> <tr> <td colspan="3"><span class="Sup">b</span> Analyses restricted to patients at risk for NODAT.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Bold Botrule Lrule Rrule Toprule"> </td><td align="center" class="Bold Botrule Lrule Rrule Toprule">ENVARSUS XR ± steroids, MMF/MPS or AZA <br/>(N=90) </td><td align="center" class="Bold Botrule Lrule Rrule Toprule">Tacrolimus [immediate-release] capsules ± steroids, MMF/MPS or AZA<br/>(N=95) </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Composite NODAT <span class="Sup">b</span></td><td align="center" class="Botrule Lrule Rrule Toprule">10%</td><td align="center" class="Botrule Lrule Rrule Toprule">11%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     HbA<span class="Sub">1c</span> ≥6.5%</td><td align="center" class="Botrule Lrule Rrule Toprule">3%</td><td align="center" class="Botrule Lrule Rrule Toprule">7%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     Fasting Plasma Glucose Values ≥126 mg/dL<br/>     on 2 consecutive occurrences</td><td align="center" class="Botrule Lrule Rrule Toprule">8%</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     Oral hypoglycemic use</td><td align="center" class="Botrule Lrule Rrule Toprule">1%</td><td align="center" class="Botrule Lrule Rrule Toprule">1%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     Insulin use ≥31 days</td><td align="center" class="Botrule Lrule Rrule Toprule">1%</td><td align="center" class="Botrule Lrule Rrule Toprule">0%</td> </tr> </tbody> </table></div>

Common Adverse Reactions

In Study 3, the most common (≥10%) adverse reactions observed with Envarsus XR were diarrhea (14%), and blood creatinine increased (12%).

The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following reactions have been included due to either their seriousness, frequency of reporting or strength of causal connection to ENVARSUS XR:

When ENVARSUS XR is prescribed with a given dose of mycophenolic acid (MPA) product, exposure to MPA is higher with ENVARSUS XR co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA associated adverse reactions and reduce the dose of concomitantly administered MPA products as needed.

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 7. Effects of Other Drugs/Substances on ENVARSUS XR<span class="Sup">a, d</span></span> </caption> <col width="35%"/> <col width="30%"/> <col width="35%"/> <tfoot> <tr> <td colspan="5"><span class="Sup">a</span> ENVARSUS XR dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>, literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status<br/> <span class="Sup">b</span> High dose or double strength grapefruit juice is a <span class="Italics">strong</span> CYP3A inhibitor; low dose or single strength grapefruit juice is a <span class="Italics">moderate</span> CYP3A inhibitor<br/> <span class="Sup">c</span> Strong CYP3A inhibitor/inducer, based on reported effect on exposures to immediate-release tacrolimus along with supporting <span class="Italics">in vitro</span> CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate) <br/> <span class="Sup">d</span> A drug interaction study with voriconazole was conducted for ENVARSUS XR <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>. No other drug-drug interaction studies were conducted with ENVARSUS XR. </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"> Drug/Substance Class or Name</td><td align="left" class="Botrule Lrule Rrule Toprule"> Drug Interaction Effect</td><td align="left" class="Botrule Lrule Rrule Toprule"> Recommendations</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"> Grapefruit or grapefruit juice<span class="Sup">b</span></td><td align="left" class="Botrule Lrule Rrule Toprule">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <span class="Italics">[see <a href="#S5.6">Warnings and Precautions (5.6</a>, <a href="#S5.9">5.9</a>, <a href="#S5.10"> 5.10)</a>].</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Avoid grapefruit or grapefruit juice.</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> Alcohol</td><td align="left" class="Botrule Lrule Rrule Toprule">May modify the rate of tacrolimus release.</td><td align="left" class="Botrule Lrule Rrule Toprule">Avoid alcoholic beverages.</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"> Strong CYP3A Inducers<span class="Sup">c,</span> such as: <br/>    Antimycobacterials (e.g., <br/>    rifampin, rifabutin), <br/>    anticonvulsants (e.g., phenytoin, <br/>    carbamazepine and <br/>    phenobarbital), St John’s Wort</td><td align="left" class="Botrule Lrule Rrule Toprule">May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection <span class="Italics">[see <a href="#S5.9">Warnings and Precautions (5.9)</a>].</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Increase ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations <span class="Italics">[see <a href="#S2.5">Dosage and Administration (2.5)</a> and <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"> Strong CYP3A Inhibitors<span class="Sup">c,</span>, such as:<br/>    Protease inhibitors (e.g., <br/>    nelfinavir, telaprevir, boceprevir,     ritonavir or ritonavir containing<br/>     products), azole antifungals (e.g., <br/>    voriconazole, posaconazole, <br/>    itraconazole, ketoconazole), <br/>    antibiotics (e.g., clarithromycin, <br/>    troleandomycin, chloramphenicol),     nefazodone, <span class="Italics">Schisandra sphenanthera</span> extracts, cobicistat </td><td align="left" class="Botrule Lrule Rrule Toprule">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose <span class="Italics">[see <a href="#S5.6">Warnings and Precautions (5.6,</a><a href="#S5.9"> 5.9,</a><a href="#S5.10"> 5.10)</a>].</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Reduce ENVARSUS XR dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations <span class="Italics">[see <a href="#S2.5">Dosage and Administration (2.5)</a> and <a href="#S12.3"> Clinical Pharmacology (12.3)</a>].</span> Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary <span class="Italics">[see <a href="#S5.9">Warnings and Precautions (5.9)]</a>.</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"> Mild or Moderate CYP3A<br/> Inhibitors, such as:<br/>     antibiotics (e.g., erythromycin), <br/>    calcium channel blockers (e.g., <br/>    verapamil, diltiazem, nifedipine, <br/>    nicardipine), amiodarone, <br/>    danazol, ethinyl estradiol, <br/>    cimetidine, lansoprazole and <br/>    omeprazole, azole antifungals <br/>    (e.g., clotrimazole, fluconazole,     isavuconazole), imatinib, nilotinib,     letermovir </td><td align="left" class="Botrule Lrule Rrule Toprule">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <span class="Italics">[see <a href="#S5.6">Warnings and Precautions (5.6</a>, <a href="#S5.9">5.9</a>, <a href="#S5.10"> 5.10)</a>].</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed <span class="Italics">[see <a href="#S2.5">Dosage and Administration (2.5)</a> and <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"> Other drugs, such as:<br/>     Magnesium and aluminum <br/>     hydroxide antacids<br/> <br/>     Metoclopramide </td><td align="left" class="Botrule Lrule Rrule Toprule">May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) <span class="Italics">[see <a href="#S5.6">Warnings and Precautions (5.6</a> and <a href="#S5.10"> 5.10)</a>].</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed <span class="Italics">[see <a href="#S2.5">Dosage and Administration (2.5)</a> and <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"> Mild or Moderate CYP3A Inducers,<br/>  such as:<br/>     Methylprednisolone, prednisone <br/> </td><td align="left" class="Botrule Lrule Rrule Toprule">May decrease tacrolimus whole blood trough concentrations.</td><td align="left" class="Botrule Lrule Rrule Toprule">Monitor tacrolimus whole blood trough concentrations and adjust ENVARSUS XR dose if needed <span class="Italics">[see <a href="#S2.5">Dosage and Administration (2.5)</a>].</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">Caspofungin</td><td align="left" class="Botrule Lrule Rrule Toprule">May decrease tacrolimus whole blood trough concentrations.</td><td align="left" class="Botrule Lrule Rrule Toprule">Monitor tacrolimus whole blood trough concentrations and adjust ENVARSUS XR dose if needed <span class="Italics">[see <a href="#S2.5">Dosage and Administration (2.5)</a>].</span></td> </tr> </tbody> </table></div>

Direct Acting Antiviral (DAA) Therapy

The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of tacrolimus is warranted to ensure continued efficacy.

The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. When cannabidiol and ENVARSUS XR are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of ENVARSUS XR should be considered as needed when ENVARSUS XR is co-administered with cannabidiol [see Dosage and Administration (2.5) and Warnings and Precautions (5.13)].

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to ENVARSUS XR during pregnancy. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus. Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.

Risk Summary

Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress [see Human Data]. Advise pregnant women of the potential risk to the fetus.

Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses (0.7 to 3.7 times the recommended clinical dose [0.14 mg/kg/day], on a mg/m² basis). Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (1.2 to 3.7 times the recommended clinical dose, on a mg/m² basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (1.2 to 3.7 times the recommended clinical dose, on a mg/m² basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data].

The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Risks during pregnancy are increased in organ transplant recipients.

The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death.

Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported.

Maternal Adverse Reactions

ENVARSUS XR may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions (5.4)].

ENVARSUS XR may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions (5.7, 5.8)].

Fetal/Neonatal Adverse Reactions

Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking ENVARSUS XR.

Labor or Delivery

There is an increased risk for premature delivery (<37 weeks) following transplantation and maternal exposure to ENVARSUS XR.

Data

Human Data

There are no adequate and well controlled studies on the effects of tacrolimus in human pregnancy.

Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus in utero have an increased risk for miscarriage, pre-term delivery (<37 weeks), low birth weight (<2500 g), birth defects/congenital anomalies and fetal distress.

TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 8. In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for renal and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 8. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus</span> </caption> <col width="50%"/> <col width="25%"/> <col width="25%"/> <tbody class="Headless"> <tr> <td align="left" class="Bold Botrule Lrule Rrule Toprule"> </td><td align="center" class="Bold Botrule Lrule Rrule Toprule">Kidney</td><td align="center" class="Bold Botrule Lrule Rrule Toprule">Liver</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Pregnancy Outcomes*</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">462</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">253</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">  Miscarriage</span></td><td align="center" class="Botrule Lrule Rrule Toprule">24.5%</td><td align="center" class="Botrule Lrule Rrule Toprule">25%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">  Live births</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">331</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">180</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     Pre-term delivery (&lt; 37 weeks)</td><td align="center" class="Botrule Lrule Rrule Toprule">49%</td><td align="center" class="Botrule Lrule Rrule Toprule">42%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     Low birth weight (&lt; 2500 g)</td><td align="center" class="Botrule Lrule Rrule Toprule">42%</td><td align="center" class="Botrule Lrule Rrule Toprule">30%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">     Birth defects</td><td align="center" class="Botrule Lrule Rrule Toprule">8%†</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td> </tr> </tbody> </table></div>

*Includes multiple births and terminations. †Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects.

Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients.

Animal Data

Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.7 times the recommended clinical dose based on body surface area). At 1 mg/kg (2.3 times the recommended clinical dose) embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (3.7 times the recommended clinical dose) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.

In a peri/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects of parturition, and reduced pup viability at 3.2 mg/kg (3.7 times the recommended clinical dose); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1mg/kg (1.2 times the recommended clinical dose).

Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (3.7 times the recommended clinical dose). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (1.2 times the recommended clinical dose) [see Nonclinical Toxicology (13.1)].

Risk Summary

Controlled lactation studies have not been conducted in humans; however tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies, exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses [see Pregnancy (8.1), Nonclinical Toxicology (13.1)].

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENVARSUS XR and any potential adverse effects on the breastfed child from ENVARSUS XR or from the underlying maternal condition.

Contraception

ENVARSUS XR can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak with their healthcare provider on family planning options including appropriate contraception prior to starting treatment with ENVARSUS XR [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)].

Infertility

Based on findings in animals, male and female fertility may be compromised by treatment with ENVARSUS XR [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of ENVARSUS XR in pediatric patients have not been established.

Clinical studies of ENVARSUS XR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In Studies 1, 2 and 3, there were 37 patients 65 years of age and older, and no patients were over 75 years [see Clinical Studies (14)]. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function. However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended [see Dosage and Administration (2.4)]. For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations. For patients with mild hepatic impairment, no dosage adjustments are needed.

African-American patients may need to be titrated to higher ENVARSUS XR dosages to attain comparable trough concentrations compared to Caucasian patients. The pharmacokinetics of ENVARSUS XR were evaluated in a study of 46 stable African-American kidney transplant recipients converted from tacrolimus immediate-release to ENVARSUS XR and indicated that an 80% conversion factor is appropriate for African-American patients [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

African-American and Hispanic kidney transplant patients are at an increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately [see Warnings and Precautions (5.4)].

Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:

{ "type": "p", "children": [], "text": "Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:" }

{ "type": "ul", "children": [ "nervous system disorders (tremor, headache, confusional state, balance disorders, encephalopathy, lethargy and\nsomnolence)", "gastrointestinal disturbances (nausea, vomiting, and diarrhea)", "abnormal renal function (increased blood urea nitrogen and elevated serum creatinine)", "urticaria", "hypertension", "peripheral edema, and ", "infections (one fatal postmarketing case of bilateral pneumopathy and CMV infection was attributed to\ntacrolimus extended-release capsules overdose)." ], "text": "" }

Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

{ "type": "p", "children": [], "text": "Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that\ntacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of\nactivated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant\nrecommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of\noverdosage." }

Tacrolimus is the active ingredient in ENVARSUS XR. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclo-hexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate.

{ "type": "p", "children": [], "text": "Tacrolimus is the active ingredient in ENVARSUS XR. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclo-hexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate." }

The chemical structure of tacrolimus is:

{ "type": "p", "children": [], "text": "The chemical structure of tacrolimus is:" }

Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

{ "type": "p", "children": [], "text": "Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol\nand chloroform." }

ENVARSUS XR is available for oral administration as extended-release tablets containing the equivalent of 0.75 mg, 1 mg, or 4 mg of anhydrous tacrolimus USP. Inactive ingredients include hypromellose USP, lactose monohydrate NF, polyethylene glycol NF, poloxamer NF, magnesium stearate NF, tartaric acid NF, butylated hydroxytoluene NF, and dimethicone NF.

{ "type": "p", "children": [], "text": "ENVARSUS XR is available for oral administration as extended-release tablets containing the equivalent of 0.75 mg,\n1 mg, or 4 mg of anhydrous tacrolimus USP. Inactive ingredients include hypromellose USP, lactose monohydrate NF,\npolyethylene glycol NF, poloxamer NF, magnesium stearate NF, tartaric acid NF, butylated hydroxytoluene NF, and\ndimethicone NF." }

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (an ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).

Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

Table 9 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of once-daily ENVARSUS XR in healthy subjects and in kidney transplant patients, under fasted conditions. Whole blood tacrolimus concentrations in the pharmacokinetic studies were measured using validated HPLC/MS/MS assays.

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 9. Pharmacokinetic Parameters of ENVARSUS XR by Study Day in Healthy Subjects and Kidney Transplant Patients Under Fasted Conditions</span> </caption> <col width="20%"/> <col width="14%"/> <col width="10%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <tfoot> <tr> <td colspan="7">a) Healthy adult subjects (administered mg/day dose); Adult <span class="Italics">de novo</span> kidney transplant patients (group average of administered mg/day dose); Adult kidney ≥ 6 months post-transplant (group average of administered mg/day dose of ENVARSUS XR, following conversion to 67% to 80% of the daily tacrolimus immediate -release capsules dose)<br/> b) Day of ENVARSUS XR dosing and PK profiling<br/> c) Arithmetic means ± S.D.<br/> d) Median [range]<br/> e) “<span class="Italics">De novo</span>” refers to immunosuppression starting at the time of transplantation<br/> f) Starting ENVARSUS XR dose = 0.14 mg/kg/day<br/> g) Starting ENVARSUS XR dose = 0.17 mg/kg/day. <span class="Italics">De novo</span> kidney transplant patients who received ENVARSUS XR starting dose of 0.17 mg/kg/day achieved higher than recommended target tacrolimus trough concentrations, as high as 57 ng/mL during the first 1 to 2 weeks post-transplant.<br/> h) Tacrolimus trough concentration before the next dose<br/> i) After 7 days of stable dosing with ENVARSUS XR<br/> j) AUC<span class="Sub">0-24</span> –to- C<span class="Sub">24</span> correlation coefficient (r) at steady state was 0.80 or higher<br/> k) Conversion to ENVARSUS XR at a mean dose of 80% of the total daily dose of tacrolimus immediate-release resulted in equivalent exposure with a 30% reduction in C<span class="Sub">max</span>.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Lrule Rrule Toprule" rowspan="2"><span class="Bold">Population</span></td><td align="center" class="Lrule Rrule Toprule" rowspan="2"><span class="Bold">ENVARSUS<br/>XR Dose </span></td><td align="center" class="Lrule Rrule Toprule" rowspan="2"><span class="Bold">Day<span class="Sup">b</span></span></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">Pharmacokinetic Parameters of ENVARSUS XR</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">C<span class="Sub">max</span><span class="Sup">c</span> <br/>(ng/mL)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">T<span class="Sub">max</span><span class="Sup">d</span> <br/>(hr)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">AUC<span class="Sub">24</span><span class="Sup">c</span> <br/>(ng•hr/mL)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">C<span class="Sub">24</span><span class="Sup">h</span> <br/>(ng/mL)</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Healthy Subjects<span class="Sup">a</span> <br/>(n=19)</td><td class="Botrule Lrule Rrule Toprule">2 mg<br/>2 mg</td><td class="Botrule Lrule Rrule Toprule">Day 1<br/>Day 10</td><td align="center" class="Botrule Lrule Rrule Toprule">11.9 ± 3.8<br/>8.3 ± 2.9</td><td align="center" class="Botrule Lrule Rrule Toprule">14.0 [6 - 28]<br/>8.0 [1.0-12.0]</td><td align="center" class="Botrule Lrule Rrule Toprule">50 ± 14<br/>140 ± 50</td><td align="center" class="Botrule Lrule Rrule Toprule">1.8 ± 0.6<br/>4.6 ± 1.7</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Adult Kidney<span class="Sup">a</span> <br/> <span class="Italics">De novo</span><span class="Sup">e</span> (n=21)</td><td class="Botrule Lrule Rrule Toprule">11.8 mg <span class="Sup">f</span> <br/>10 mg <br/>9.5 mg</td><td class="Botrule Lrule Rrule Toprule">Day 1<br/>Day 7<br/>Day 14</td><td align="center" class="Botrule Lrule Rrule Toprule">11.8 ± 7.2<br/>25.1 ± 16.3<br/>27.1 ± 13.4</td><td align="center" class="Botrule Lrule Rrule Toprule">8.0 [4-24]<br/>6.0 [2-12]<br/>4.0 [1-8]</td><td align="center" class="Botrule Lrule Rrule Toprule">138 ± 80<br/>335 ± 129<br/>371 ± 104</td><td align="center" class="Botrule Lrule Rrule Toprule">5.2 ± 2.7<br/>9.9 ± 4.4<br/>11.4 ± 4.1<span class="Sup">j</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Adult Kidney<span class="Sup">a</span> <br/> <span class="Italics">De novo</span> (n=10)</td><td class="Botrule Lrule Rrule Toprule">15.5 mg <span class="Sup">g</span> <br/>11.4 mg <br/>11.1 mg</td><td class="Botrule Lrule Rrule Toprule">Day 1<br/>Day 14<br/>Day 28</td><td align="center" class="Botrule Lrule Rrule Toprule">33.6 ± 21.8<br/>31.1 ± 14.6<br/>35.9± 18.7</td><td align="center" class="Botrule Lrule Rrule Toprule">6.0 [4-24]<br/>4.0 [1-18]<br/>4.0 [1-14]</td><td align="center" class="Botrule Lrule Rrule Toprule">377 ± 257<br/>376 ± 140<br/>396 ± 150</td><td align="center" class="Botrule Lrule Rrule Toprule">11.0 ± 6.1<br/>9.1 ± 3.0<br/>10.5 ± 3.2</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Adult Kidney<span class="Sup">a</span> <br/>(≥ 6 months post-<br/>transplant) (n=47)</td><td class="Botrule Lrule Rrule Toprule">5.3 mg</td><td class="Botrule Lrule Rrule Toprule">Day 7<span class="Sup">i</span></td><td align="center" class="Botrule Lrule Rrule Toprule">13.5 ± 4.8</td><td align="center" class="Botrule Lrule Rrule Toprule">6.0 [1 - 16]</td><td align="center" class="Botrule Lrule Rrule Toprule">216 ± 63</td><td align="center" class="Botrule Lrule Rrule Toprule">7.0 ± 2.3 <span class="Sup">j</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Adult African-<br/>American Kidney<span class="Sup">k</span> <br/>(≥ 6 months post-transplant) (n=46)</td><td class="Botrule Lrule Rrule Toprule">7.8 mg</td><td class="Botrule Lrule Rrule Toprule">Day 7<span class="Sup">i</span></td><td align="center" class="Botrule Lrule Rrule Toprule">18.4 ± 7.2</td><td align="center" class="Botrule Lrule Rrule Toprule">5.0 [1 - 16]</td><td align="center" class="Botrule Lrule Rrule Toprule">272 ± 97</td><td align="center" class="Botrule Lrule Rrule Toprule">7.8 ± 2.9 <span class="Sup">j</span></td> </tr> </tbody> </table></div>

In de novo adult kidney transplant patients, the administration of ENVARSUS XR once daily at a starting dose of 0.14 mg/kg/day results in a tacrolimus systemic exposure (AUC24) on Day 1 post-transplant that is up to 10% lower than that of tacrolimus immediate-release capsules twice daily administered at a starting dose of 0.1 mg/kg/day, while similar tacrolimus trough concentrations (C24) are achieved. As steady state is achieved (typically within 7 days of stable ENVARSUS XR dosing), the AUC24 of ENVARSUS XR is approximately 15% higher than that of tacrolimus immediate-release capsules, at comparable trough concentrations (C24).

In adult kidney transplant patients ≥ 6 months post-transplant switched to ENVARSUS XR at 67% to 80% of the daily dose of tacrolimus immediate-release capsules, the steady state tacrolimus exposures (AUC24) and tacrolimus trough concentrations (C24) were comparable to the AUC24 and C24 measured prior to the switch. However, the mean Cmax estimate was 30% lower and the median Tmax was more prolonged (6 hours versus 2 hours) following administration of Envarsus XR as compared to that of tacrolimus immediate-release capsules.

Absorption

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. In de novo kidney transplant patients, the median time to achieve maximum blood concentrations (Cmax) of ENVARSUS XR was approximately 6 to 10 hours (Tmax) on day 1 post-transplant; the median Tmax at steady state was 4 to 6 hours. In healthy subjects, the oral bioavailability of ENVARSUS XR was approximately 50% higher as compared with both tacrolimus immediate-release and extended-release capsule formulations at steady state. In healthy subjects who received single ENVARSUS XR doses ranging from 5 mg to 10 mg, the mean AUC and C24 of tacrolimus increased linearly and the elimination half-life did not change with increasing doses.

Food Effects

The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions. In 26 healthy subjects, administration of ENVARSUS XR following a high-fat breakfast reduced the systemic exposure (AUC) to tacrolimus by approximately 55% and the peak plasma concentration of tacrolimus (Cmax) by 22%, with no effect on the time to reach maximum plasma concentration (Tmax), compared to when ENVARSUS XR was administered under fasted conditions. ENVARSUS XR tablets should be taken preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.

Chronopharmacokinetic Effect

In 26 healthy subjects, administration of ENVARSUS XR tablets in the evening resulted in a 15% lower AUC0-inf and a 20% lower C24, as compared to morning dosing.

Distribution

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial in which tacrolimus was administered as immediate-release formulation, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Metabolism

The desired pharmacological activity of tacrolimus is primarily due to the parent drug. Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system 3A (CYP3A4 and CYP3A5). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Excretion

In a mass balance study of orally administered radiolabeled tacrolimus to 6 healthy subjects, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered. The elimination half-life based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.

The elimination half-life of tacrolimus after oral administration of 2 mg ENVARSUS XR once-daily for 10 days was 31.0 ± 8.1 hours (mean ± SD) in 25 healthy subjects.

Specific Populations

Patients With Renal Impairment

Tacrolimus pharmacokinetics following a single administration of tacrolimus (administered as a continuous IV infusion) were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their kidney transplant. The mean clearance of tacrolimus in patients with renal dysfunction given IV tacrolimus was similar to that in healthy subjects given tacrolimus IV and in healthy subjects given oral tacrolimus immediate-release [see Use In Specific Populations (8.6)].

Patients With Hepatic Impairment

Tacrolimus pharmacokinetics have been determined in 6 patients with mild hepatic impairment (mean Pugh score: 6.2) following single oral administration of tacrolimus immediate-release. The mean clearance of tacrolimus in patients with mild hepatic impairment was not substantially different from that in healthy subjects. Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic impairment (mean Pugh score: >10). The mean clearance was substantially lower in patients with severe hepatic impairment [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].

Racial or Ethnic Groups

The pharmacokinetics of ENVARSUS XR were evaluated in a study of 46 stable African American kidney transplant recipients converted from tacrolimus immediate-release to ENVARSUS XR. Approximately 80% of the African American patients were carriers of the active, wild type CYP3A5*1 allele. Regardless of genotype status, the PK results demonstrated similar exposure, lower Cmax, prolonged Tmax, and increased bioavailability compared to tacrolimus immediate-release [see Dosage and Administration (2.3) and Use in Specific Populations (8.8)].

Male and Female Patients

A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted. In a sub-group analysis from the two combined Phase 3 studies in kidney transplant recipients (Study 1 and Study 3) performed with ENVARSUS XR over one year of treatment, no gender-dependent differences in tacrolimus systemic exposures were observed.

Drug Interaction Studies

Because tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes and/or are known CYP3A substrates may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations [see Warnings and Precautions (5.9) and Drug Interactions (7.2)].

Voriconazole: Co-administration of ENVARSUS XR with voriconazole following 400 mg BID of voriconazole resulted in a tacrolimus mean AUCinf increase by 2.62 fold and Cmax by 2.03 fold.

Carcinogenesis

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3mg/kg/day (0.84 times the AUC at the recommended clinical dose of 0.14 mg/kg/day ) and in the rat was 5 mg/kg/day (0.24 times the AUC at the recommended clinical dose of 0.14 mg/kg/day) [see Boxed Warning and Warnings and Precautions (5.1)].

A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03%-3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment; 2.5-fold the human exposure in stable adult renal transplant patients converted from tacrolimus immediate-release product to ENVARSUS XR). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.

The implications of these carcinogenicity studies are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis.

Mutagenesis

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Impairment of Fertility

Tacrolimus subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (2.3 times the recommended clinical dose based on body surface area) or 3 mg/kg/day (3.4 times the recommended clinical dose based on body surface area) resulted in a dose-related decrease in sperm count. Tacrolimus administered orally at 1mg/kg (1.2 times the recommended clinical dose based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (3.7 times the recommended clinical dose based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

Study 1

Study 1 (NCT 01187953) was a Phase 3, 12-month, randomized, double-blind, multinational study comparing once daily ENVARSUS XR (N=268) to twice daily tacrolimus [immediate-release] capsules (N=275) in patients who received a de novo kidney transplant. Patients received the first dose of the study drug anytime within 48 hours of graft reperfusion. All patients received only IL-2 receptor antagonist induction therapy and concomitant treatment with mycophenolate mofetil (MMF) and corticosteroids. Approximately 97% of all patients received antibody induction therapy with basiliximab and 91% of all patients received corticosteroids and MMF.

The mean age of the study population was 46 years; 65% were male; 77% were Caucasian, 5% were African-American, 4% were Asian and 14% were categorized as other races. Living donors provided 49% of the organs and 51% of patients received a kidney transplant from a deceased donor. Patients with clinically relevant ECG abnormalities (including QTc prolongation and reversible ischemia) and clinically symptomatic congestive heart failure or patients with documented left ventricular ejection fraction of less than 45% were excluded. Patients with a panel reactive antibody (PRA) >30%, who received a kidney from a non-heart-beating donor or with cold ischemia time >30 hours were also excluded. Premature discontinuation from treatment at the end of one year occurred in 22% of ENVARSUS XR patients and 19% of tacrolimus [immediate-release] capsules patients.

Tacrolimus Therapy

In Study 1, de novo kidney transplant patients were dosed initially at a starting dosage of 0.17 mg/kg given once daily for ENVARSUS XR (approximately 1.2-fold higher than the recommended starting dosage) and 0.1 mg/kg/day (given twice daily) for tacrolimus [immediate-release] capsule, with doses then modified to maintain tacrolimus trough concentrations between 6-11 ng/mL for the first 30 days and then between 4-11 ng/L for the remainder of the study. In the first week of dosing, the tacrolimus doses administered were, on average, ~40% higher in the ENVARSUS XR group compared to the tacrolimus capsule group and were similar in both treatment groups from Day 10 to Week 3. Thereafter, tacrolimus doses were, on average, 10% to 20% lower for ENVARSUS XR than in the tacrolimus capsule group.

Tacrolimus whole blood trough concentrations were monitored on Days 2, 3, 4, 7, 10, 14, 21, 30, 45, 60, 90, 120, 180, 270, and 360. On Day 2 predose, the proportion of patients in the ENVARSUS XR group with tacrolimus trough concentration that were within, above and below the target tacrolimus trough concentration range of 6 to 11 ng/mL was 33%, 39%, and 28%, respectively, compared to 27%, 12%, and 61%, in the tacrolimus [immediate release] capsule group. The average tacrolimus trough concentrations (per local laboratory reading) for the ENVARSUS XR group were above the target range during the first week post-transplant, and higher than in the tacrolimus capsule group during the first 2 weeks post-transplant (see Figure 1). Thereafter, the mean tacrolimus trough concentrations were similar between the treatment groups.

                                     Figure 1. Study 1 Tacrolimus Trough Concentrations by Treatment Group and Visits

Concomitant Immunosuppressive Drugs

In Study 1, the concomitant use of mycophenolate products was comparable between the ENVARSUS XR and tacrolimus [immediate-release] capsule treatment groups. Patients in both groups started MMF at an average dose of 1 gram twice daily. The MMF daily dose was reduced to less than 2 grams over the course of the study; the mean MMF equivalent total daily dose was approximately 1.5 grams at Month 12 in both treatment groups. Likewise, the average doses of corticosteroids were comparable between the two treatment groups throughout the 12-month study period. Majority (96% ENVARSUS XR and 99% tacrolimus [immediate-release] capsules) of the patients received two 20 mg doses of basiliximab for antibody induction.

Efficacy Results

The efficacy failure rates including patients who developed biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow-up at 12 months, as well as the rates of the individual events, are shown by treatment group in Table 10 for the intent-to-treat population.

Table 10. Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months in De Novo Kidney Transplant Patients in Study 1

<div class="scrollingtable"><table class="Noautorules" width="850"> <col width="50%"/> <col width="25%"/> <col width="25%"/> <tfoot> <tr> <td colspan="3"><span class="Sup">a</span> 95% CI was calculated using normal approximation.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Bold Botrule Lrule Rrule Toprule"></td><td align="center" class="Bold Botrule Lrule Rrule Toprule">ENVARSUS XR, MMF, steroids, and IL-2 receptor antagonist induction therapy <br/>N=268 </td><td align="center" class="Bold Botrule Lrule Rrule Toprule">Tacrolimus [Immediate-Release] capsules, MMF, steroids, and IL-2 receptor antagonist induction therapy<br/>N=275 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Overall Treatment Difference of efficacy failure compared to tacrolimus immediate-release (95% CI)<span class="Sup">a</span></td><td align="center" class="Botrule Lrule Rrule Toprule">-1.0%<br/> (-7.6%, 5.6%)<br/> <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Treatment Failure</td><td align="center" class="Botrule Lrule Rrule Toprule">50 (18.7%)</td><td align="center" class="Botrule Lrule Rrule Toprule">54 (19.6%)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">           Biopsy Proven Acute Rejection </td><td align="center" class="Botrule Lrule Rrule Toprule">36 (13.4%)</td><td align="center" class="Botrule Lrule Rrule Toprule">37 (13.5%)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">           Graft Failure</td><td align="center" class="Botrule Lrule Rrule Toprule">9 (3.4%)</td><td align="center" class="Botrule Lrule Rrule Toprule">11 (4.0%)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">           Death </td><td align="center" class="Botrule Lrule Rrule Toprule">8 (3.0%)</td><td align="center" class="Botrule Lrule Rrule Toprule">8 (2.9%)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">           Lost to Follow-up</td><td align="center" class="Botrule Lrule Rrule Toprule">4 (1.5%)</td><td align="center" class="Botrule Lrule Rrule Toprule">5 (1.8%)</td> </tr> </tbody> </table></div>

Glomerular Filtration Rates

Renal function was assessed as change from Day 30 (baseline) by eGFR calculated using the MDRD7 equation. Baseline eGFR values were 53.8 ml/min/1.73 m2 and 54.4 ml/min/1.73 m2, and 12 month eGFR values were 58.6 ml/min/1.73 m2 and 59.8 ml/min/1.73 m2 in the ENVARSUS XR and the tacrolimus [immediate-release] capsule groups, respectively, maintaining the small difference of approximately 1ml/min/1.73 m2 between the treatment groups.

Study 2

Study 2 (NCT 00765661) was an open-label Phase 2 study conducted in de novo kidney transplant patients randomized to once daily ENVARSUS XR (N=32) or twice daily tacrolimus [immediate-release] capsule(N=31). The study was conducted in the US and patients received an organ from a deceased or living donor. Pharmacokinetics were evaluated during the first 2 weeks with an additional 50-week treatment and follow-up to evaluate safety and efficacy.

Study 2 did not have any exclusion criteria based on cardiac disease or ECG findings but patients who received a kidney from a non-heart-beating donor or with cold ischemia time ≥ 36 hours were excluded. Patients were randomized within 12 hours after transplantation and received the first dose of the study drug within 48 hours of graft reperfusion. Induction treatment and concomitant immunosuppressive therapy were allowed per center-specific practices.

The mean age of study population was 47 years (range 23-69); 68% were male; 75% were Caucasian, 21% were African- American, 5% were Asian. Two patients in each group withdrew early from the study due to adverse events.

Tacrolimus Therapy

In Study 2, de novo kidney transplant patients received a starting dosage of 0.14 mg/kg/day (given once daily) for ENVARSUS XR and 0.20 mg/kg/day (given twice daily) for tacrolimus [immediate-release] capsule. On Day 2 predose, the proportion of patients in the ENVARSUS XR group with tacrolimus trough concentration that were within, above, and below 6 to 11 ng/mL was 53%, 11%, and 37%, respectively. In Study 1, the proportion of de novo kidney transplant patients receiving a starting dose of 0.1 mg/kg/day of tacrolimus capsules that were within, above, and below 6 to 11 ng/mL on Day 2 predose was 27%, 12%, and 61%, respectively.

Concomitant Immunosuppressive Drugs

In Study 2, concomitant therapy with mycophenolate products or azathioprine, corticosteroids, and antibody induction was permitted but not required. The mean daily MMF, prednisone, and antibody induction doses were similar between the ENVARSUS XR and tacrolimus capsules treatment groups.

Efficacy

There were no deaths or graft failures in Study 2. Acute rejection rates at 12 months were 3.1% (1/32) in the ENVARSUS XR group and 6.5% (2/31) in the tacrolimus capsules group and 2 patients (one in each group) were lost to follow-up.

Study 3

The conversion study, Study 3 (NCT00817206), was a Phase 3 randomized, open-label, multinational study evaluating once daily ENVARSUS XR when used to replace tacrolimus [immediate-release] capsules administered twice daily for maintenance immunosuppression to prevent acute allograft rejection in stable adult kidney transplant patients. Patients who received a kidney transplant 3 months to 5 years before study entry and on a stable dose of tacrolimus [immediate-release] capsules of at least 2 mg per day and tacrolimus whole blood trough concentrations between 4 and 15 ng/mL were randomized to 1) switch from twice daily tacrolimus capsules to once daily ENVARSUS XR (N=163) or 2) continue tacrolimus capsules twice daily (N=163). MMF or mycophenolate sodium (MPS), or azathioprine (AZA) and/or corticosteroids were allowed as concomitant immunosuppressants during the study period according to the standard of care at the participating site.

The mean age of study population was 50 years; 67% were male; 73% were Caucasian, 22% were African-American, 2% were Asian and 3% were categorized as other races. Living donors provided 35% of the organs and 65% of patients received a kidney transplant from a deceased donor. Premature discontinuation from treatment at the end of one year occurred in 13% of ENVARSUS XR patients and 6% of tacrolimus capsule patients.

Tacrolimus Therapy

In Study 3, stable kidney transplant patients converted to ENVARSUS XR at an average daily dose that was 80% of their tacrolimus [immediate-release] capsules daily dose prior to conversion. Mean tacrolimus whole blood trough concentrations were maintained within a relatively narrow range throughout the duration of the study for both the ENVARSUS XR conversion group and the tacrolimus capsules continuation group. At Week 1 (after 7 days of stable dosing), the mean ± SD tacrolimus trough concentrations were 7.2 ± 3.1 ng/mL for the ENVARSUS XR conversion group and 7.7 ± 2.5 for the tacrolimus capsules continuation group; the baseline values were 7.8 ± 2.3, and 8.0 ± 2.3, respectively.

MMF Therapy

In Study 3, the average daily mycophenolate equivalent doses were comparable between the ENVARSUS XR and tacrolimus capsules treatment groups.

Efficacy Results

The efficacy failure rates including patients who developed BPAR, graft failure, death, and/or lost to follow-up at 12 months, as well as the rates of the individual events, are shown by treatment group in Table 11 for the modified intent-to-treat population.

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 11. Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months in Stable Kidney Transplant Patients in Study 3</span> </caption> <col width="50%"/> <col width="25%"/> <col width="25%"/> <tfoot> <tr> <td colspan="3"><span class="Sup">a</span> 95% CI was calculated using an exact method that is based on the standardized statistic and inverting a 2-sided test</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Bold Botrule Lrule Rrule Toprule"></td><td align="center" class="Bold Botrule Lrule Rrule Toprule">ENVARSUS XR ± Steroids ± MMF, MPS, or AZA <br/>N=162 </td><td align="center" class="Bold Botrule Lrule Rrule Toprule">Tacrolimus [Immediate-Release] Capsules ± Steroids ± MMF, MPS, or AZA <br/>N=162 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> Treatment Failure</td><td align="center" class="Botrule Lrule Rrule Toprule">4 (2.5%)</td><td align="center" class="Botrule Lrule Rrule Toprule">4 (2.5%)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Overall Treatment Difference of efficacy failure compared to tacrolimus immediate-release<br/> (95% CI)<span class="Sup">a</span></td><td align="center" class="Botrule Lrule Rrule Toprule">0%<br/> (-4.2%, 4.2%) </td><td align="center" class="Botrule Lrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">              Biopsy Proven Acute Rejection </td><td align="center" class="Botrule Lrule Rrule Toprule">2 (1.2%) </td><td align="center" class="Botrule Lrule Rrule Toprule">2 (1.2%)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">              Graft Failure</td><td align="center" class="Botrule Lrule Rrule Toprule">0%</td><td align="center" class="Botrule Lrule Rrule Toprule">0%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">              Death </td><td align="center" class="Botrule Lrule Rrule Toprule">2 (1.2%)</td><td align="center" class="Botrule Lrule Rrule Toprule">1 (0.6%)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">              Lost to Follow-up</td><td align="center" class="Botrule Lrule Rrule Toprule">0%</td><td align="center" class="Botrule Lrule Rrule Toprule">1 (0.6%)</td> </tr> </tbody> </table></div>

Glomerular Filtration Rates

The mean estimated glomerular filtration rates (eGFR), using the Modification of Diet in Renal Disease 7 (MDRD7) formula, were 61.5 ml/min/1.73 m2 and 60.0 ml/min/1.73 m2 at baseline (Day 0) and 62.0 ml/min/1.73 m2 and 61.4 ml/min/1.73 m2 at 12 months in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively.

ENVARSUS XR is supplied in round HDPE bottles with twist-off caps (see Table 12); the statement ‘ONCE-DAILY’ appears on its labels.

{ "type": "p", "children": [], "text": "ENVARSUS XR is supplied in round HDPE bottles with twist-off caps (see Table 12); the statement ‘ONCE-DAILY’ appears on its labels." }

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 12. Strengths of ENVARSUS XR</span> </caption> <col width="10%"/> <col width="50%"/> <col width="30%"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule">Strength</td><td class="Botrule Lrule Rrule Toprule">Description</td><td class="Botrule Lrule Rrule Toprule">NDC</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">0.75 mg</td><td class="Botrule Lrule Rrule Toprule">Oval, white to off-white uncoated extended-release tablet, debossed with “0.75” on one side and “TCS” on the other side.</td><td class="Botrule Lrule Rrule Toprule">30-count (NDC 68992-3075-3) <br/>100-count (NDC 68992-3075-1)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">1 mg</td><td class="Botrule Lrule Rrule Toprule">Oval, white to off-white uncoated extended-release tablet, debossed with “1” on one side and “TCS” on the other side.</td><td class="Botrule Lrule Rrule Toprule">30-count (NDC 68992-3010-3)<br/>100-count (NDC 68992-3010-1)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">4 mg</td><td class="Botrule Lrule Rrule Toprule">Oval, white to off-white uncoated extended-release tablet, debossed with “4” on one side and “TCS” on the other side.</td><td class="Botrule Lrule Rrule Toprule">30-count (NDC 68992-3040-3)<br/>100-count (NDC 68992-3040-1)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"750\">\n<caption>\n<span>Table 12. Strengths of ENVARSUS XR</span>\n</caption>\n<col width=\"10%\"/>\n<col width=\"50%\"/>\n<col width=\"30%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">Strength</td><td class=\"Botrule Lrule Rrule Toprule\">Description</td><td class=\"Botrule Lrule Rrule Toprule\">NDC</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">0.75 mg</td><td class=\"Botrule Lrule Rrule Toprule\">Oval, white to off-white uncoated extended-release tablet, debossed with “0.75” on one side and “TCS” on the other side.</td><td class=\"Botrule Lrule Rrule Toprule\">30-count (NDC 68992-3075-3) <br/>100-count (NDC 68992-3075-1)</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">1 mg</td><td class=\"Botrule Lrule Rrule Toprule\">Oval, white to off-white uncoated extended-release\ntablet, debossed with “1” on one side and “TCS” on the\nother side.</td><td class=\"Botrule Lrule Rrule Toprule\">30-count (NDC 68992-3010-3)<br/>100-count (NDC 68992-3010-1)</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">4 mg</td><td class=\"Botrule Lrule Rrule Toprule\">Oval, white to off-white uncoated extended-release\ntablet, debossed with “4” on one side and “TCS” on the\nother side.</td><td class=\"Botrule Lrule Rrule Toprule\">30-count (NDC 68992-3040-3)<br/>100-count (NDC 68992-3040-1)</td>\n</tr>\n</tbody>\n</table></div>" }

Store and Dispense Store at 25 °C (77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "\nStore and Dispense\nStore at 25 °C (77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature]." }

Advise patients to:

Inform patients that they are at an increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor [see Boxed Warning and Warnings and Precautions (5.1)].

Inform patients that they are at an increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Boxed Warning and Warnings and Precautions (5.2)].

Inform patients that ENVARSUS XR can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger [see Warnings and Precautions (5.4)].

Inform patients that ENVARSUS XR can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions (5.5)].

Inform patients that they are at risk of developing adverse neurologic effects including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions (5.6)].

Inform patients that ENVARSUS XR can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions (5.7)].

Inform patients that ENVARSUS XR can cause high blood pressure which may require treatment with anti-hypertensive therapy. Advise patients to monitor their blood pressure [see Warnings and Precautions (5.8)].

Inform patients that ENVARSUS XR can cause blood clotting problems. The risk of this occurring increases when patients take ENVARSUS XR and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria [see Warnings and Precautions (5.13)].

Instruct patients to tell their healthcare providers when they start or stop taking any concomitant medications, including prescription and non-prescription medicines, natural or herbal remedies, dietary supplements and vitamins. Some medications could alter tacrolimus concentrations in the blood and thus may require the adjustment of the dosage of ENVARSUS XR. Advise patients to avoid grapefruit, grapefruit juice and alcoholic beverages [see Warnings and Precautions (5.9, 5.13) and Drug Interactions (7)].

Inform women of childbearing potential that ENVARSUS XR can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations (8.1, 8.2, 8.3)].

Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll-free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org.

Based on animal studies, ENVARSUS XR may affect fertility in males and females [see Nonclinical Toxicology (13.1)].

Inform patients that ENVARSUS XR can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.11)].

Product of Germany

Manufactured by: Rottendorf Pharma GmbH 59320 Ennigerloh North Rhine-Westphalia Germany

Manufactured for: Veloxis Pharmaceuticals, Inc. Cary, North Carolina 27518 United States

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="28%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="40%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="3">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="right" colspan="2">Revised: 4/2024</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">MEDICATION GUIDE</span> <br/> <span class="Bold">ENVARSUS XR® </span>(En var' sus XR)<br/> <span class="Bold">(tacrolimus extended-release tablets)</span> <br/> for oral use </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top">Read this Medication Guide before you start taking ENVARSUS XR and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about ENVARSUS XR, ask your healthcare provider or pharmacist.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What is the most important information I should know about ENVARSUS XR?<br/> ENVARSUS XR can cause serious side effects, including:</span> </p> <ol class="Arabic"> <li> <span class="Bold">Increased risk of cancer.</span> People who take ENVARSUS XR have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).</li> <li> <span class="Bold">Increased risk of infection.</span> ENVARSUS XR is a medicine that affects your immune system. ENVARSUS XR can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving ENVARSUS XR that can cause death.<br/> <span class="Bold">Call your healthcare provider right away if you have symptoms of an infection such as:</span> </li> </ol> </td> </tr> <tr> <td align="left" class="Botrule Lrule"></td><td align="left" class="Botrule"> <ul class="Circle"> <li>fever</li> <li>sweats or chills</li> </ul> </td><td align="left" class="Botrule"> <ul class="Circle"> <li>cough or flu-like symptoms</li> <li>muscle aches</li> </ul> </td><td align="left" class="Botrule Rrule"> <ul class="Circle"> <li>warm, red, or painful areas on your skin</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What is ENVARSUS XR?</span> </p> <ul> <li>ENVARSUS XR is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney transplant.</li> <li>ENVARSUS XR is an extended-release tablet and is not the same as tacrolimus extended-release capsules, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Your healthcare provider should decide what medicine is right for you.</li> </ul> <p> It is not known if Envarsus XR is safe and effective in children.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Who should not take ENVARSUS XR?</span> </p> <p> <span class="Bold">Do not take ENVARSUS XR if you:</span> </p> <ul> <li>are allergic to tacrolimus or any of the ingredients in ENVARSUS XR. See the end of this Medication Guide for a complete <a href="#INGREDIENT01">list of ingredients</a> in ENVARSUS XR.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What should I tell my doctor before taking ENVARSUS XR?</span> </p> <p> <span class="Bold">Before you take ENVARSUS XR, tell your healthcare provider about all your medication conditions, including if you:</span> </p> <ul> <li>plan to receive any live vaccines. Ask your healthcare provider if you are not sure if your vaccine is a live vaccine.</li> <li>have or have had liver, kidney or heart problems.</li> <li>are pregnant or plan to become pregnant. ENVARSUS XR may harm your unborn baby. <ul class="Circle"> <li>If you are able to become pregnant, you should use effective birth control before and during treatment with ENVARSUS XR. Talk to your healthcare provider about birth control methods that may be right for you.</li> <li>Males who have female partners that are able to become pregnant should also use effective birth control before and during treatment with ENVARSUS XR. Talk to your healthcare provider before starting treatment with ENVARSUS XR about birth control methods that may be right for you.</li> <li>There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with ENVARSUS XR. The purpose of this registry is to collect information about your health and of your baby. To enroll in this voluntary registry, call 1-877- 955-6877 or register at <a href="https://www.transplantpregnancyregistry.org">https://www.transplantpregnancyregistry.org</a>.</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. ENVARSUS XR passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking ENVARSUS XR</li> </ul> <p> <span class="Bold"> Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements.</p> <p>ENVARSUS XR may affect the way other medicines work, and other medicines may affect how ENVARSUS XR works.</p> <p> <span class="Bold">Especially tell your healthcare provider if you take:</span> </p> <ul> <li>sirolimus (RAPAMUNE):</li> <li>everolimus</li> <li>cyclosporine (GENGRAF, NEORAL, and SANDIMMUNE)</li> <li>medicines called aminoglycosides that are used to treat bacterial infections</li> <li>ganciclovir (CYTOVENE IV, VALCYTE)</li> <li>amphotericin B (ABELCET, AMBISOME)</li> <li>cisplatin</li> <li>antiviral medicines called nucleoside reverse transcriptase inhibitors</li> <li>antiviral medicines called protease inhibitors</li> <li>water pill (diuretic)</li> <li>medicine to treat high blood pressure</li> <li>erythromycin</li> <li>danazol</li> <li>ethyinyl estradiol</li> <li>cimetidine</li> <li>lansoprazole</li> <li>omeprazole</li> <li>azole antifungals</li> <li>imatinib</li> <li>nilotinib</li> <li>nelfinavir (VIRACEPT)</li> <li>telaprevir (INCIVEK)</li> <li>boceprevir)</li> <li>ritonavir (PAXLOVID, KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR)</li> <li>letermovir (PREVYMIS)</li> <li>ketoconazole</li> <li>itraconazole (ONMEL, SPORANOX)</li> <li>voriconazole (VFEND)</li> <li>posaconazole</li> <li>caspofungin (CANCIDAS)</li> <li>clarithromycin (BIAXIN, BIAXIN XL, PREVPAC)</li> <li>troleandomycin</li> <li>chloramphenicol</li> <li>nefazodone</li> <li>Schisandra sphenanthera extracts</li> <li>cobicistat</li> <li>rifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE)</li> <li>rifabutin (MYCOBUTIN)</li> <li>medicine to treat seizures (phenytoin, carbamazepine, phenobarbital</li> <li>St. John’s Wort</li> <li>amiodarone (NEXTERONE, PACERONE)</li> <li>cannabidiol (EPIDIOLEX)</li> <li>magnesium and aluminum hydroxide antacids</li> <li>metoclopramide</li> <li>methylprednisolone</li> <li>prednisone </li> </ul> <p>Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. ENVARSUS XR may affect the way other medicines work, and other medicines may affect how ENVARSUS XR works.</p> <p>Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">How should I take ENVARSUS XR?</span> </p> <ul> <li>Take ENVARSUS XR exactly as your healthcare provider tells you to take it.</li> <li>Your healthcare provider may change your dose of ENVARSUS XR if needed. <span class="Bold">Do not</span> stop taking or change your dose of ENVARSUS XR without talking to your healthcare provider.</li> <li>Take ENVARSUS XR 1-time daily with fluid (preferably water) on an empty stomach, at least 1 hour before or at least 2 hours after a meal, at the same time each day (preferably in the morning). Taking ENVARSUS XR at the same time each day helps to keep the amount of ENVARSUS XR in your body at a steady level.</li> <li>Take ENVARSUS XR tablets whole. <span class="Bold">Do not</span> chew, divide, crush, or dissolve ENVARSUS XR tablets before swallowing. If you cannot swallow ENVARSUS XR tablets whole, tell your healthcare provider.</li> <li>If you miss your dose of ENVARSUS XR, it should be taken as soon as possible, but no longer than 15 hours after missing your dose. If the time after missing your dose is more than 15 hours, the missed dose should be skipped and the next dose should be taken the following morning at your regularly scheduled time. <span class="Bold">Do not</span> take 2 doses at the same time.</li> <li>If you take too much ENVARSUS XR, call your healthcare provider or go to the nearest hospital emergency room right away.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What should I avoid while taking ENVARSUS XR?</span> </p> <ul> <li>Live vaccines such as the flu vaccine through your nose, measles, mumps, rubella, polio by mouth, BCG (TB vaccine), yellow fever, chicken pox (varicella), or typhoid.</li> <li>Exposure to sunlight and UV light such as tanning machines. Wear protective clothing and use a sunscreen.</li> <li>You should not eat grapefruit or drink grapefruit juice while taking ENVARSUS XR.</li> <li>You should not drink alcohol while taking ENVARSUS XR.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of ENVARSUS XR?</span> </p> <p> <span class="Bold">ENVARSUS XR may cause serious side effects, including:</span> </p> <ul> <li> <span class="Bold">See “What the most important information I should know about ENVARSUS XR?”</span> </li> <li> <span class="Bold">problems from medication errors such as graft rejection and other serious reactions.</span> People who take ENVARSUS XR have sometimes been given the wrong medicine because some medicines have the same ingredient (tacrolimus) as ENVARSUS XR. <span class="Bold">Check your ENVARSUS XR when you get a new prescription to make sure you have received the right medicine.</span> <ul> <li>Call your healthcare provider right away if you think you were given the wrong medicine.</li> <li>Ask your healthcare provider or pharmacist if you are not sure what ENVARSUS XR should look like.</li> </ul> </li> <li> <span class="Bold">high blood sugar (diabetes)</span>. High blood sugar is a serious, but common side effect of ENVARSUS XR. Your healthcare provider may do certain tests to check for diabetes while you take ENVARSUS XR. Call your healthcare provider right away if you have:</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul class="Circle"> <li>frequent urination</li> <li>confusion</li> <li>fruity smell on your breath</li> </ul> </td><td align="left"> <ul class="Circle"> <li>increased thirst or hunger</li> <li>drowsiness</li> <li>nausea, vomiting, or stomach pain</li> </ul> </td><td align="left" class="Rrule"> <ul class="Circle"> <li>blurred vision</li> <li>loss of appetite</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4" valign="top"> <ul> <li> <span class="Bold">kidney problems</span>. Kidney problems are serious, but common side effects of ENVARSUS XR. Your healthcare provider may do certain tests to check for kidney function while you take ENVARSUS XR.</li> <li> <span class="Bold">nervous system problems</span>. Nervous system problems are a serious, but common side effect of ENVARSUS XR. Call your healthcare provider right away if you get any of these symptoms while taking ENVARSUS XR:</li> <li> <span class="Bold">high levels of potassium in your blood</span>. High levels of potassium in your blood are a serious, but common side effect of ENVARSUS XR. Your healthcare provider may do certain tests to check your potassium level while you take ENVARSUS XR.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul class="Circle"> <li>confusion</li> <li>numbness and tingling</li> <li>vision changes</li> </ul> </td><td align="left"> <ul class="Circle"> <li>coma</li> <li>headache</li> <li>muscle tremors</li> </ul> </td><td align="left" class="Rrule"> <ul class="Circle"> <li>seizures</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4" valign="top"> <ul> <li> <span class="Bold">high blood pressure</span>. High blood pressure is a serious, but common side effect of ENVARSUS XR. Your healthcare provider will monitor your blood pressure while you take ENVARSUS XR.</li> <li> <span class="Bold">changes in the electrical activity of your heart (QT prolongation).</span> Your healthcare provider may do certain tests to check your heart function while you take ENVARSUS XR. </li> <li> <span class="Bold">severe low blood cell count (anemia)</span>. Your healthcare provider may stop your treatment with ENVARSUS XR if you develop a severe low blood cell count. </li> <li> <span class="Bold">blood clotting problems: </span> Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, or when you develop certain infections, the risk of developing these symptoms may increase. </li> </ul> <p class="First"> <span class="Bold">The most common side effects of ENVARSUS XR in people who received a kidney transplant are:</span> </p> </td> </tr> <tr> <td align="left" class="Lrule" colspan="2"> <ul class="Disc"> <li>diarrhea</li> <li>low red blood cell count (anemia)</li> </ul> </td><td align="left"> <ul class="Disc"> <li>urinary tract infection</li> <li>constipation</li> </ul> </td><td align="left" class="Rrule"> <ul class="Disc"> <li>swelling in the arms, hands, or legs (peripheral edema)</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">The most common side effects of ENVARSUS XR in people who are switching from immediate-release tacrolimus to ENVARSUS XR are </span> diarrhea and high blood creatinine.</p> <p>These are not all the possible side effects of ENVARSUS XR. For more information, ask your healthcare provider or pharmacist.<br/> <br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">How should I store ENVARSUS XR?</span> </p> <ul> <li>Store ENVARSUS XR at room temperature between 68 ºF to 77 ºF (20 °C to 25 ºC).</li> <li>Safely throw away medicine that is out of date or no longer needed.</li> </ul> <p class="Bold">Keep ENVARSUS XR and all medicines out of reach of children.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of ENVARSUS XR.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ENVARSUS XR for a condition for which it was not prescribed. Do not give ENVARSUS XR to other people, even if they have the same symptoms that you have. It may harm them.</p> <br/> <p>This Medication Guide summarizes the most important information about ENVARSUS XR. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ENVARSUS XR that is written for health professionals.</p> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in ENVARSUS XR?</span> </p> <p> <a name="INGREDIENT01"></a><span class="Bold">Active ingredient:</span> tacrolimus USP.<br/> <span class="Bold">Inactive ingredients:</span> hypromellose USP, lactose monohydrate NF, polyethylene glycol NF, poloxamer NF, magnesium stearate NF, tartaric acid NF, butylated hydroxytoluene NF, and dimethicone NF.</p> <br/> <p>Manufactured by: <span class="Bold">Rottendorf Pharma GmbH,</span> 59320 Ennigerloh, North Rhine-Westphalia, Germany <br/> Manufactured for: <span class="Bold">Veloxis Pharmaceuticals, Inc.,</span> Cary, North Carolina 27518, United States <br/> For more information, go to www.ENVARSUSXR.com or call 1-844-Veloxis (1-844-835-6947). </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"28%\"/>\n<col align=\"left\" valign=\"top\" width=\"30%\"/>\n<col align=\"left\" valign=\"top\" width=\"40%\"/>\n</colgroup>\n<tfoot>\n<tr class=\"First First Last Last\">\n<td align=\"left\" colspan=\"3\">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\" colspan=\"2\">Revised: 4/2024</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">MEDICATION GUIDE</span>\n<br/>\n<span class=\"Bold\">ENVARSUS XR® </span>(En var' sus XR)<br/>\n<span class=\"Bold\">(tacrolimus extended-release tablets)</span>\n<br/>\n for oral use\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">Read this Medication Guide before you start taking ENVARSUS XR and each time you get a refill.\nThere may be new information. This information does not take the place of talking with your healthcare\nprovider about your medical condition or your treatment. If you have any questions about ENVARSUS\nXR, ask your healthcare provider or pharmacist.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about ENVARSUS XR?<br/> ENVARSUS XR can cause serious side effects, including:</span>\n</p>\n<ol class=\"Arabic\">\n<li>\n<span class=\"Bold\">Increased risk of cancer.</span> People who take ENVARSUS XR have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).</li>\n<li>\n<span class=\"Bold\">Increased risk of infection.</span> ENVARSUS XR is a medicine that affects your immune system. ENVARSUS XR can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving ENVARSUS XR that can cause death.<br/>\n<span class=\"Bold\">Call your healthcare provider right away if you have symptoms of an infection such as:</span>\n</li>\n</ol>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule\"></td><td align=\"left\" class=\"Botrule\">\n<ul class=\"Circle\">\n<li>fever</li>\n<li>sweats or chills</li>\n</ul>\n</td><td align=\"left\" class=\"Botrule\">\n<ul class=\"Circle\">\n<li>cough or flu-like symptoms</li>\n<li>muscle aches</li>\n</ul>\n</td><td align=\"left\" class=\"Botrule Rrule\">\n<ul class=\"Circle\">\n<li>warm, red, or painful areas on your skin</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is ENVARSUS XR?</span>\n</p>\n<ul>\n<li>ENVARSUS XR is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney transplant.</li>\n<li>ENVARSUS XR is an extended-release tablet and is not the same as tacrolimus extended-release\ncapsules, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Your healthcare\nprovider should decide what medicine is right for you.</li>\n</ul>\n<p> It is not known if Envarsus XR is safe and effective in children.</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take ENVARSUS XR?</span>\n</p>\n<p>\n<span class=\"Bold\">Do not take ENVARSUS XR if you:</span>\n</p>\n<ul>\n<li>are allergic to tacrolimus or any of the ingredients in ENVARSUS XR. See the end of this Medication Guide for a complete <a href=\"#INGREDIENT01\">list of ingredients</a> in ENVARSUS XR.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I tell my doctor before taking ENVARSUS XR?</span>\n</p>\n<p>\n<span class=\"Bold\">Before you take ENVARSUS XR, tell your healthcare provider about all your medication conditions, including if you:</span>\n</p>\n<ul>\n<li>plan to receive any live vaccines. Ask your healthcare provider if you are not sure if your vaccine\nis a live vaccine.</li>\n<li>have or have had liver, kidney or heart problems.</li>\n<li>are pregnant or plan to become pregnant. ENVARSUS XR may harm your unborn baby. \n\t\t\t\t\t <ul class=\"Circle\">\n<li>If you are able to become pregnant, you should use effective birth control before and during\ntreatment with ENVARSUS XR. Talk to your healthcare provider about birth control methods\nthat may be right for you.</li>\n<li>Males who have female partners that are able to become pregnant should also use effective\nbirth control before and during treatment with ENVARSUS XR. Talk to your healthcare\nprovider before starting treatment with ENVARSUS XR about birth control methods that may\nbe right for you.</li>\n<li>There is a pregnancy registry for females who become pregnant and males who have fathered\na pregnancy during treatment with ENVARSUS XR. The purpose of this registry is to collect\ninformation about your health and of your baby. To enroll in this voluntary registry, call 1-877-\n955-6877 or register at <a href=\"https://www.transplantpregnancyregistry.org\">https://www.transplantpregnancyregistry.org</a>.</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. ENVARSUS XR passes into your breast milk. You and\nyour healthcare provider should decide if you will breastfeed while taking ENVARSUS XR</li>\n</ul>\n<p>\n<span class=\"Bold\"> Tell your healthcare provider about all the medicines you take,</span> including prescription and\nover-the-counter medicines, vitamins, natural, herbal or nutritional supplements.</p>\n<p>ENVARSUS XR may affect the way other medicines work, and other medicines may affect\nhow ENVARSUS XR works.</p>\n<p>\n<span class=\"Bold\">Especially tell your healthcare provider if you take:</span>\n</p>\n<ul>\n<li>sirolimus (RAPAMUNE):</li>\n<li>everolimus</li>\n<li>cyclosporine (GENGRAF, NEORAL, and SANDIMMUNE)</li>\n<li>medicines called aminoglycosides that are used to treat bacterial infections</li>\n<li>ganciclovir (CYTOVENE IV, VALCYTE)</li>\n<li>amphotericin B (ABELCET, AMBISOME)</li>\n<li>cisplatin</li>\n<li>antiviral medicines called nucleoside reverse transcriptase inhibitors</li>\n<li>antiviral medicines called protease inhibitors</li>\n<li>water pill (diuretic)</li>\n<li>medicine to treat high blood pressure</li>\n<li>erythromycin</li>\n<li>danazol</li>\n<li>ethyinyl estradiol</li>\n<li>cimetidine</li>\n<li>lansoprazole</li>\n<li>omeprazole</li>\n<li>azole antifungals</li>\n<li>imatinib</li>\n<li>nilotinib</li>\n<li>nelfinavir (VIRACEPT)</li>\n<li>telaprevir (INCIVEK)</li>\n<li>boceprevir)</li>\n<li>ritonavir (PAXLOVID, KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR)</li>\n<li>letermovir (PREVYMIS)</li>\n<li>ketoconazole</li>\n<li>itraconazole (ONMEL, SPORANOX)</li>\n<li>voriconazole (VFEND)</li>\n<li>posaconazole</li>\n<li>caspofungin (CANCIDAS)</li>\n<li>clarithromycin (BIAXIN, BIAXIN XL, PREVPAC)</li>\n<li>troleandomycin</li>\n<li>chloramphenicol</li>\n<li>nefazodone</li>\n<li>Schisandra sphenanthera extracts</li>\n<li>cobicistat</li>\n<li>rifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE)</li>\n<li>rifabutin (MYCOBUTIN)</li>\n<li>medicine to treat seizures (phenytoin, carbamazepine, phenobarbital</li>\n<li>St. John’s Wort</li>\n<li>amiodarone (NEXTERONE, PACERONE)</li>\n<li>cannabidiol (EPIDIOLEX)</li>\n<li>magnesium and aluminum hydroxide antacids</li>\n<li>metoclopramide</li>\n<li>methylprednisolone</li>\n<li>prednisone </li>\n</ul>\n<p>Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. ENVARSUS XR may affect the way other medicines work, and other medicines may affect how ENVARSUS XR works.</p>\n<p>Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take ENVARSUS XR?</span>\n</p>\n<ul>\n<li>Take ENVARSUS XR exactly as your healthcare provider tells you to take it.</li>\n<li>Your healthcare provider may change your dose of ENVARSUS XR if needed. <span class=\"Bold\">Do not</span> stop taking or\nchange your dose of ENVARSUS XR without talking to your healthcare provider.</li>\n<li>Take ENVARSUS XR 1-time daily with fluid (preferably water) on an empty stomach, at least 1 hour\nbefore or at least 2 hours after a meal, at the same time each day (preferably in the morning). Taking ENVARSUS XR at the same time each day helps to keep the amount of ENVARSUS XR in your body at a steady level.</li>\n<li>Take ENVARSUS XR tablets whole. <span class=\"Bold\">Do not</span> chew, divide, crush, or dissolve ENVARSUS XR tablets\nbefore swallowing. If you cannot swallow ENVARSUS XR tablets whole, tell your healthcare provider.</li>\n<li>If you miss your dose of ENVARSUS XR, it should be taken as soon as possible, but no longer than 15\nhours after missing your dose. If the time after missing your dose is more than 15 hours, the missed dose\nshould be skipped and the next dose should be taken the following morning at your regularly scheduled\ntime. <span class=\"Bold\">Do not</span> take 2 doses at the same time.</li>\n<li>If you take too much ENVARSUS XR, call your healthcare provider or go to the nearest hospital\nemergency room right away.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking ENVARSUS XR?</span>\n</p>\n<ul>\n<li>Live vaccines such as the flu vaccine through your nose, measles, mumps, rubella, polio by mouth, BCG (TB vaccine), yellow fever, chicken pox (varicella), or typhoid.</li>\n<li>Exposure to sunlight and UV light such as tanning machines. Wear protective clothing and use a sunscreen.</li>\n<li>You should not eat grapefruit or drink grapefruit juice while taking ENVARSUS XR.</li>\n<li>You should not drink alcohol while taking ENVARSUS XR.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of ENVARSUS XR?</span>\n</p>\n<p>\n<span class=\"Bold\">ENVARSUS XR may cause serious side effects, including:</span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">See “What the most important information I should know about ENVARSUS XR?”</span>\n</li>\n<li>\n<span class=\"Bold\">problems from medication errors such as graft rejection and other serious reactions.</span> People who take ENVARSUS XR have sometimes been given the wrong medicine because some medicines have the same ingredient (tacrolimus) as ENVARSUS XR. <span class=\"Bold\">Check your ENVARSUS XR when you get a new prescription to make sure you have received the right medicine.</span>\n<ul>\n<li>Call your healthcare provider right away if you think you were given the wrong medicine.</li>\n<li>Ask your healthcare provider or pharmacist if you are not sure what ENVARSUS XR should look like.</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">high blood sugar (diabetes)</span>. High blood sugar is a serious, but common side effect of ENVARSUS XR. Your healthcare provider may do certain tests to check for diabetes while\nyou take ENVARSUS XR. Call your healthcare provider right away if you have:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\">\n<ul class=\"Circle\">\n<li>frequent urination</li>\n<li>confusion</li>\n<li>fruity smell on your breath</li>\n</ul>\n</td><td align=\"left\">\n<ul class=\"Circle\">\n<li>increased thirst or hunger</li>\n<li>drowsiness</li>\n<li>nausea, vomiting, or stomach pain</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Circle\">\n<li>blurred vision</li>\n<li>loss of appetite</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<ul>\n<li>\n<span class=\"Bold\">kidney problems</span>. Kidney problems are serious, but common side effects of ENVARSUS XR. Your healthcare provider may do certain tests to check for kidney function while you take ENVARSUS XR.</li>\n<li>\n<span class=\"Bold\">nervous system problems</span>. Nervous system problems are a serious, but common side effect of ENVARSUS XR. Call your healthcare provider right away if you get any of these symptoms while taking ENVARSUS XR:</li>\n<li>\n<span class=\"Bold\">high levels of potassium in your blood</span>. High levels of potassium in your blood are a serious, but common side effect of ENVARSUS XR. Your healthcare provider may do certain tests to check your potassium level while you take ENVARSUS XR.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\">\n<ul class=\"Circle\">\n<li>confusion</li>\n<li>numbness and tingling</li>\n<li>vision changes</li>\n</ul>\n</td><td align=\"left\">\n<ul class=\"Circle\">\n<li>coma</li>\n<li>headache</li>\n<li>muscle tremors</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Circle\">\n<li>seizures</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<ul>\n<li>\n<span class=\"Bold\">high blood pressure</span>. High blood pressure is a serious, but common side effect of ENVARSUS XR. Your healthcare provider will monitor your blood pressure while you take ENVARSUS XR.</li>\n<li>\n<span class=\"Bold\">changes in the electrical activity of your heart (QT prolongation).</span> Your healthcare provider may do certain tests to check your heart function while you take ENVARSUS XR.\n </li>\n<li>\n<span class=\"Bold\">severe low blood cell count (anemia)</span>. Your healthcare provider may stop your treatment with ENVARSUS XR if you develop a severe low blood cell count.\n </li>\n<li>\n<span class=\"Bold\">blood clotting problems: </span> Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, or when you develop certain infections, the risk of developing these symptoms may increase.\n </li>\n</ul>\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of ENVARSUS XR in people who received a kidney transplant are:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>diarrhea</li>\n<li>low red blood cell count (anemia)</li>\n</ul>\n</td><td align=\"left\">\n<ul class=\"Disc\">\n<li>urinary tract infection</li>\n<li>constipation</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Disc\">\n<li>swelling in the arms, hands, or legs (peripheral edema)</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of ENVARSUS XR in people who are switching from immediate-release tacrolimus to ENVARSUS XR are </span> diarrhea and high blood creatinine.</p>\n<p>These are not all the possible side effects of ENVARSUS XR. For more information, ask your healthcare\nprovider or pharmacist.<br/>\n<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at\n1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store ENVARSUS XR?</span>\n</p>\n<ul>\n<li>Store ENVARSUS XR at room temperature between 68 ºF to 77 ºF (20 °C to 25 ºC).</li>\n<li>Safely throw away medicine that is out of date or no longer needed.</li>\n</ul>\n<p class=\"Bold\">Keep ENVARSUS XR and all medicines out of reach of children.</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of ENVARSUS XR.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ENVARSUS XR for a condition for which it was not prescribed. Do not give ENVARSUS XR to other people, even if they have the same symptoms that you have. It may harm them.</p>\n<br/>\n<p>This Medication Guide summarizes the most important information about ENVARSUS XR. If you would like\nmore information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for\ninformation about ENVARSUS XR that is written for health professionals.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in ENVARSUS XR?</span>\n</p>\n<p>\n<a name=\"INGREDIENT01\"></a><span class=\"Bold\">Active ingredient:</span> tacrolimus USP.<br/>\n<span class=\"Bold\">Inactive ingredients:</span> hypromellose USP, lactose monohydrate NF, polyethylene glycol NF, poloxamer NF, magnesium stearate NF, tartaric acid NF, butylated hydroxytoluene NF, and dimethicone NF.</p>\n<br/>\n<p>Manufactured by: <span class=\"Bold\">Rottendorf Pharma GmbH,</span> 59320 Ennigerloh, North Rhine-Westphalia, Germany <br/>\n Manufactured for: <span class=\"Bold\">Veloxis Pharmaceuticals, Inc.,</span> Cary, North Carolina 27518, United States <br/>\n\t\t\t\tFor more information, go to www.ENVARSUSXR.com or call 1-844-Veloxis (1-844-835-6947).\n\t\t\t\t</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

PRINCIPAL DISPLAY PANEL - Envarsus 0.75 mg 30 Count Carton Label

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL - Envarsus 0.75 mg 30 Count Carton Label\n\n\n" }

NDC 68992-3075-3

{ "type": "p", "children": [], "text": "NDC 68992-3075-3" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

0.75 mg

{ "type": "p", "children": [], "text": "\n0.75 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

Dosage: See Package Insert for dosage information.

{ "type": "p", "children": [], "text": "Dosage: See Package Insert for dosage information." }

Always dispense with a Medication Guide

{ "type": "p", "children": [], "text": "Always dispense with a Medication Guide" }

For oral use only

{ "type": "p", "children": [], "text": "For oral use only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

30 Tablets

{ "type": "p", "children": [], "text": "\n30 Tablets \n" }

PRINCIPAL DISPLAY PANEL - Envarsus 0.75 mg 30 Count Bottle Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 0.75 mg 30 Count Bottle Label\n\n\n" }

NDC 68992-3075-3

{ "type": "p", "children": [], "text": "NDC 68992-3075-3" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

0.75 mg

{ "type": "p", "children": [], "text": "\n0.75 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Always Dispense With a Medication Guide

{ "type": "p", "children": [], "text": "Always Dispense With a Medication Guide" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

30 Tablets          Rx only

{ "type": "p", "children": [], "text": "\n30 Tablets          Rx only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

PRINCIPAL DISPLAY PANEL - Envarsus 0.75 mg 100 Count Carton Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 0.75 mg 100 Count Carton Label\n\n\n" }

NDC 68992-3075-1

{ "type": "p", "children": [], "text": "NDC 68992-3075-1" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

0.75 mg

{ "type": "p", "children": [], "text": "\n0.75 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

Dosage: See Package Insert for dosage information.

{ "type": "p", "children": [], "text": "Dosage: See Package Insert for dosage information." }

Always dispense with a Medication Guide

{ "type": "p", "children": [], "text": "Always dispense with a Medication Guide" }

For oral use only

{ "type": "p", "children": [], "text": "For oral use only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

100 Tablets

{ "type": "p", "children": [], "text": "\n100 Tablets \n" }

PRINCIPAL DISPLAY PANEL - Envarsus 0.75 mg 100 Count Bottle Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 0.75 mg 100 Count Bottle Label\n\n\n" }

NDC 68992-3075-1

{ "type": "p", "children": [], "text": "NDC 68992-3075-1" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

0.75 mg

{ "type": "p", "children": [], "text": "\n0.75 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Always Dispense With a Medication Guide

{ "type": "p", "children": [], "text": "Always Dispense With a Medication Guide" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

100 Tablets          Rx only

{ "type": "p", "children": [], "text": "\n100 Tablets          Rx only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

PRINCIPAL DISPLAY PANEL - Envarsus 1 mg 30 Count Carton Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 1 mg 30 Count Carton Label\n\n\n" }

NDC 68992-3010-3

{ "type": "p", "children": [], "text": "NDC 68992-3010-3" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

1 mg

{ "type": "p", "children": [], "text": "\n1 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

Dosage: See Package Insert for dosage information.

{ "type": "p", "children": [], "text": "Dosage: See Package Insert for dosage information." }

Always dispense with a Medication Guide

{ "type": "p", "children": [], "text": "Always dispense with a Medication Guide" }

For oral use only

{ "type": "p", "children": [], "text": "For oral use only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

30 Tablets

{ "type": "p", "children": [], "text": "\n30 Tablets \n" }

PRINCIPAL DISPLAY PANEL - Envarsus 1 mg 30 Count Bottle Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 1 mg 30 Count Bottle Label\n\n\n" }

NDC 68992-3010-3

{ "type": "p", "children": [], "text": "NDC 68992-3010-3" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

1 mg

{ "type": "p", "children": [], "text": "\n1 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Always Dispense With a Medication Guide

{ "type": "p", "children": [], "text": "Always Dispense With a Medication Guide" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

30 Tablets          Rx only

{ "type": "p", "children": [], "text": "\n30 Tablets          Rx only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

PRINCIPAL DISPLAY PANEL - Envarsus 1 mg 100 Count Carton Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 1 mg 100 Count Carton Label\n\n\n" }

NDC 68992-3010-1

{ "type": "p", "children": [], "text": "NDC 68992-3010-1" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

1 mg

{ "type": "p", "children": [], "text": "\n1 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

Dosage: See Package Insert for dosage information.

{ "type": "p", "children": [], "text": "Dosage: See Package Insert for dosage information." }

Always dispense with a Medication Guide

{ "type": "p", "children": [], "text": "Always dispense with a Medication Guide" }

For oral use only

{ "type": "p", "children": [], "text": "For oral use only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

100 Tablets

{ "type": "p", "children": [], "text": "\n100 Tablets \n" }

PRINCIPAL DISPLAY PANEL - Envarsus 1 mg 100 Count Bottle Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 1 mg 100 Count Bottle Label\n\n\n" }

NDC 68992-3010-1

{ "type": "p", "children": [], "text": "NDC 68992-3010-1" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

1 mg

{ "type": "p", "children": [], "text": "\n1 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Always Dispense With a Medication Guide

{ "type": "p", "children": [], "text": "Always Dispense With a Medication Guide" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

100 Tablets          Rx only

{ "type": "p", "children": [], "text": "\n100 Tablets          Rx only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

PRINCIPAL DISPLAY PANEL - Envarsus 4 mg 30 Count Carton Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 4 mg 30 Count Carton Label\n\n\n" }

NDC 68992-3040-3

{ "type": "p", "children": [], "text": "NDC 68992-3040-3" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

4 mg

{ "type": "p", "children": [], "text": "\n4 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

Dosage: See Package Insert for dosage information.

{ "type": "p", "children": [], "text": "Dosage: See Package Insert for dosage information." }

Always dispense with a Medication Guide

{ "type": "p", "children": [], "text": "Always dispense with a Medication Guide" }

For oral use only

{ "type": "p", "children": [], "text": "For oral use only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

30 Tablets

{ "type": "p", "children": [], "text": "\n30 Tablets \n" }

PRINCIPAL DISPLAY PANEL - Envarsus 4 mg 30 Count Bottle Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 4 mg 30 Count Bottle Label\n\n\n" }

NDC 68992-3040-3

{ "type": "p", "children": [], "text": "NDC 68992-3040-3" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

4 mg

{ "type": "p", "children": [], "text": "\n4 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Always Dispense With a Medication Guide

{ "type": "p", "children": [], "text": "Always Dispense With a Medication Guide" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

30 Tablets          Rx only

{ "type": "p", "children": [], "text": "\n30 Tablets          Rx only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

PRINCIPAL DISPLAY PANEL - Envarsus 4 mg 100 Count Carton Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 4 mg 100 Count Carton Label\n\n\n" }

NDC 68992-3040-1

{ "type": "p", "children": [], "text": "NDC 68992-3040-1" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

4 mg

{ "type": "p", "children": [], "text": "\n4 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

Dosage: See Package Insert for dosage information.

{ "type": "p", "children": [], "text": "Dosage: See Package Insert for dosage information." }

Always dispense with a Medication Guide

{ "type": "p", "children": [], "text": "Always dispense with a Medication Guide" }

For oral use only

{ "type": "p", "children": [], "text": "For oral use only" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }

100 Tablets

{ "type": "p", "children": [], "text": "\n100 Tablets \n" }

PRINCIPAL DISPLAY PANEL - Envarsus 4 mg 100 Count Bottle Label

{ "type": "p", "children": [], "text": "\n\n\nPRINCIPAL DISPLAY PANEL - Envarsus 4 mg 100 Count Bottle Label\n\n\n" }

NDC 68992-3040-1

{ "type": "p", "children": [], "text": "NDC 68992-3040-1" }

Envarsus XR®

{ "type": "p", "children": [], "text": "\nEnvarsus XR®\n" }

(tacrolimus extended-release tablets)

{ "type": "p", "children": [], "text": "\n(tacrolimus extended-release tablets)\n" }

4 mg

{ "type": "p", "children": [], "text": "\n4 mg\n" }

ONCE-DAILY

{ "type": "p", "children": [], "text": "\nONCE-DAILY\n" }

Always Dispense With a Medication Guide

{ "type": "p", "children": [], "text": "Always Dispense With a Medication Guide" }

Swallow tablet whole.

{ "type": "p", "children": [], "text": "\nSwallow tablet whole.\n" }

Do not chew, divide, or crush tablet.

{ "type": "p", "children": [], "text": "\nDo not chew, divide, or crush tablet.\n" }

100 Tablets

{ "type": "p", "children": [], "text": "\n100 Tablets \n" }

Veloxis PHARMACEUTICALS

{ "type": "p", "children": [], "text": "\nVeloxis PHARMACEUTICALS\n" }