FYARRO™ is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).

{ "type": "p", "children": [], "text": "FYARRO™ is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa)." }

The recommended dosage of FYARRO is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.

Table 1 lists the recommended dose reductions of FYARRO for adverse reactions.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 1. Recommended dose reductions of FYARRO for adverse reactions.</span> </caption> <colgroup> <col align="left" valign="bottom" width="34%"/> <col align="left" valign="bottom" width="66%"/> </colgroup> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Permanently discontinue FYARRO in patients who are unable to tolerate FYARRO after three dose reductions.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First First"> <td align="left" class="Lrule Rrule">Dose Reduction</td><td align="left" class="Rrule">Dose</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">First Dose Reduction</td><td align="left" class="Rrule">75 mg/m<span class="Sup">2</span> (25% reduction from 100 mg/m<span class="Sup">2</span>)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Second Dose Reduction</td><td align="left" class="Rrule">56 mg/m<span class="Sup">2</span> (25% reduction from 75 mg/m<span class="Sup">2</span>)</td> </tr> <tr class="Botrule Last Last"> <td align="left" class="Lrule Rrule">Third Dose Reduction<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="left" class="Rrule">45 mg/m<span class="Sup">2</span> (20% reduction from 56 mg/m<span class="Sup">2</span>)</td> </tr> </tbody> </table></div>

Table 2 lists the recommended dosage modifications of FYARRO for adverse reactions.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2. Recommended FYARRO Dosage Modifications for Adverse Reactions</span> </caption> <colgroup> <col align="left" valign="top" width="40%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="30%"/> </colgroup> <thead> <tr class="First First Last Last"> <th align="left" class="Botrule Lrule Rrule">Adverse Reaction</th><th align="left" class="Botrule Lrule Rrule">Severity<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></th><th align="left" class="Botrule Lrule Rrule">Dosage Modifications</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Severity based on Common Terminology Criteria for Adverse Events Version 4.03.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Stomatitis<br/> <span class="Italics">[see Warnings and Precautions (<a href="#S5.1">5.1</a>)]</span></td><td align="left" class="Botrule Rrule" valign="top">Grade 2 or 3</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until Grade ≤1.</li> <li>Restart at the same dose for first occurrence.</li> <li>If recurs, restart at reduced dose level.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Grade 4</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Permanently discontinue FYARRO.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Anemia<br/> <span class="Italics">[see Warnings and Precautions (<a href="#S5.2">5.2</a>)]</span></td><td align="left" class="Botrule Rrule" valign="top">Grade 2</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until Hb ≥8 g/dL.</li> <li>Restart at the same dose level.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Grade ≥3</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until Hb ≥8 g/dL.</li> <li>Restart at the same dose level.</li> <li>If recurs, resume at reduced dose level.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Thrombocytopenia<br/> <span class="Italics">[see Warnings and Precautions (<a href="#S5.2">5.2</a>)]</span></td><td align="left" class="Botrule Rrule" valign="top">Grade 2</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until platelet count &gt;100×10<span class="Sup">9</span>/L.</li> <li>Restart at the same dose level.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Grade ≥3</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until platelet count &gt;100×10<span class="Sup">9</span>/L.</li> <li>Restart at reduced dose level.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Neutropenia<br/> <span class="Italics">[see Warnings and Precautions (<a href="#S5.2">5.2</a>)]</span></td><td align="left" class="Botrule Rrule" valign="top">Grade 2 or 3</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until absolute neutrophil count ≥1.5×10<span class="Sup">9</span>/L.</li> <li>Restart at the same dose level.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Grade 4</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until absolute neutrophil count ≥1.5×10<span class="Sup">9</span>/L.</li> <li>Restart at reduced dose level.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Infections<br/> <span class="Italics">[see Warnings and Precautions (<a href="#S5.3">5.3</a>)]</span></td><td align="left" class="Botrule Rrule" valign="top">Grade 3</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until resolved.</li> <li>Restart at reduced dose level.</li> <li>If recurs, permanently discontinue FYARRO.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Grade 4</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until resolved.</li> <li>Restart at reduced dose level or permanently discontinue FYARRO.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Hypokalemia<br/> <span class="Italics">[see Warnings and Precautions (<a href="#S5.4">5.4</a>)]</span></td><td align="left" class="Botrule Rrule" valign="top">Grade 2</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until Grade ≤1.</li> <li>Restart at the same dose level.</li> <li>If recurs, restart at reduced dose level.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Grade ≥3</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until Grade ≤1.</li> <li>Restart at reduced dose level.</li> <li>If recurs, permanently discontinue FYARRO.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Hyperglycemia<br/> <span class="Italics">[see Warnings and Precautions (<a href="#S5.5">5.5</a>)]</span></td><td align="left" class="Botrule Rrule" valign="top">Grade ≥3</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until Grade ≤2.</li> <li>Restart at reduced dose level.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Interstitial Lung Disease / Non- Infectious Pneumonitis<br/> <span class="Italics">[see Warnings and Precautions (<a href="#S5.6">5.6</a>)]</span></td><td align="left" class="Botrule Rrule" valign="top">Grade 2</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO for up to 3 weeks until Grade ≤1.</li> <li>Restart at reduced dose level.</li> <li>If not resolved to Grade ≤1 within 3 weeks, permanently discontinue FYARRO.</li> <li>If recurs, permanently discontinue FYARRO.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Grade ≥3</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Permanently discontinue FYARRO.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Hemorrhage<br/> <span class="Italics">[see Warnings and Precautions (<a href="#S5.7">5.7</a>)]</span></td><td align="left" class="Botrule Rrule" valign="top">Grade 2 or 3</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until Grade ≤1.</li> <li>Resume at reduced dose.</li> <li>If recurs, permanently discontinue FYARRO.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Grade 4</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Permanently discontinue FYARRO.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Other Adverse Reactions<br/> <span class="Italics">[see Adverse Reactions (<a href="#S6.1">6.1</a>)]</span></td><td align="left" class="Botrule Rrule" valign="top">Grade 3</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Withhold FYARRO until Grade ≤1.</li> <li>Restart at the same dose level.</li> <li>If recurs, restart at reduced dose level.</li> </ul> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Grade 4</td><td align="left" class="Botrule Rrule"> <ul class="Disc"> <li>Permanently discontinue FYARRO.</li> </ul> </td> </tr> </tbody> </table></div>

Reduce the dosage of FYARRO to 56 mg/m2 when used concomitantly with a moderate or weak cytochrome P-450 3A4 (CYP3A4) inhibitor. Avoid concomitant use with drugs that are strong CYP3A4 and/or P-glycoprotein (P-gp) inhibitors and inducers and with grapefruit and grapefruit juice [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

The recommended dosage modification of FYARRO in patients with mild or moderate hepatic impairment is described in Table 3[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Closely monitor patients with hepatic impairment for increased toxicity. Avoid use in patients with severe hepatic impairment [see Use in Specific Populations (8.6)].

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3. Recommended FYARRO Dosage in Patients with Mild or Moderate Hepatic Impairment</span> </caption> <colgroup> <col align="left" valign="bottom" width="66%"/> <col align="left" valign="bottom" width="34%"/> </colgroup> <thead> <tr class="First First Last Last"> <th align="left" class="Botrule Lrule Rrule">Hepatic Impairment (based on NCI criteria)</th><th align="left" class="Botrule Lrule Rrule">Dosage</th> </tr> </thead> <tbody> <tr class="Botrule First First"> <td align="left" class="Lrule Rrule">Mild (total bilirubin ≤ULN, AST &gt;ULN or total bilirubin &gt;1 to 1.5×ULN, any AST)</td><td align="left" class="Rrule">75 mg/m<span class="Sup">2</span></td> </tr> <tr class="Botrule Last Last"> <td align="left" class="Lrule Rrule">Moderate (total bilirubin &gt;1.5 to 3.0×ULN, any AST)</td><td align="left" class="Rrule">56 mg/m<span class="Sup">2</span></td> </tr> </tbody> </table></div>

FYARRO is a hazardous drug. Follow applicable special handling and disposal procedures.1

FYARRO is supplied as a sterile lyophilized powder for reconstitution before use. READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION.

Preparation:

1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP.

2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL.

3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly on to the lyophilized powder, which has a cake-like appearance, as this will result in foaming.

4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized powder.

5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any powder occurs. Avoid shaking the vial to prevent the generation of foam.

6 .If foaming or clumping occurs, let suspension stand for at least 15 minutes until foam subsides. If foaming or clumping is present after one hour, do not use the reconstituted suspension.

Each mL of the reconstituted formulation will contain 5 mg sirolimus.

The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion.

7. Transfer the volume of FYARRO required for the calculated dose into an empty sterile PVC or polyolefin infusion bag for administration without further dilution.

The use of medical devices containing silicone oil as a lubricant (e.g., syringes and intravenous bags) to reconstitute and administer FYARRO may result in the formation of proteinaceous strands.

Visually inspect reconstituted FYARRO suspension in the infusion bag prior to administration. Discard reconstituted suspension if particulate matter, proteinaceous strands, or discoloration are observed.

Administration:

Administer the reconstituted FYARRO suspension intravenously over 30 minutes.

Unopened vials of FYARRO are stable until the date indicated on the package when stored between 2°C to 8°C (36°F to 46°F) in the original package. Neither freezing nor thawing adversely affects the stability of the product.

Stability of Reconstituted Suspension in the Vial

Reconstituted FYARRO in the vial should be used immediately but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 6 hours stored in the original carton to protect it from light. Discard any unused portion.

Stability of Reconstituted Suspension in the Infusion Bag

The suspension for infusion when prepared as recommended in an infusion bag should be used immediately but may be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from light for a maximum of 9 hours.

The total maximum combined refrigerated storage time of reconstituted FYARRO in the vial and in the infusion bag is 15 hours. This may be followed by storage in the infusion bag at ambient temperature (approximately 25°C) and lighting conditions for a maximum of 4 hours. Discard any unused portion.

For injectable suspension: white to yellow, sterile lyophilized powder containing 100 mg of sirolimus formulated as albumin-bound particles in single-dose vial for reconstitution.

{ "type": "p", "children": [], "text": "For injectable suspension: white to yellow, sterile lyophilized powder containing 100 mg of sirolimus formulated as albumin-bound particles in single-dose vial for reconstitution." }

FYARRO is contraindicated in patients with a history of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin [see Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": "FYARRO is contraindicated in patients with a history of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin [see Warnings and Precautions (5.8)]." }

Stomatitis, including mouth ulcers and oral mucositis, occurred in 79% of patients treated with FYARRO, including 18% Grade 3. Stomatitis was most often first reported within 8 weeks of treatment. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2), Adverse Reactions (6.1)]

FYARRO can cause myelosuppression including anemia, thrombocytopenia and neutropenia. Anemia occurred in 68% of patients; 6% were Grade 3. Thrombocytopenia and neutropenia occurred in 35% of patients each.

Obtain blood counts at baseline and every 2 months for the first year of treatment and every 3 months thereafter, or more frequently if clinically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

FYARRO can cause infections. Infections such as urinary tract infections (UTI), upper respiratory tract infections and sinusitis occurred in 59% of patients. Grade 3 infections occurred in 12% of patients, including a single case each of a UTI, pneumonia, skin, and abdominal infections. Monitor patients for infections, including opportunistic infections. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

FYARRO can cause hypokalemia. Hypokalemia occurred in 44% of patients, including 12% Grade 3 events. Monitor potassium levels prior to starting FYARRO and implement potassium supplementation as medically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

FYARRO can cause hyperglycemia. Hyperglycemia occurred in 12% of patients treated with FYARRO, all of which were Grade 3 events. Monitor fasting serum glucose prior to starting FYARRO. During treatment, monitor serum glucose every 3 months in non-diabetic patients, or as clinically indicated. Monitor serum glucose more frequently in diabetic patients. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

FYARRO can cause interstitial lung disease (ILD) / non-infectious pneumonitis. ILD / non-infectious pneumonitis occurred in 18% of patients treated with FYARRO, of which all were Grades 1 or 2. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2)].

FYARRO can cause serious and sometimes fatal hemorrhage. Hemorrhage occurred in 24% of patients treated with FYARRO, including Grade 3 and Grade 5 events in 2.9% of patients each [see Adverse Reactions (6.1)]. Monitor patients for signs and symptoms of hemorrhage. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration (2.2)].

FYARRO can cause hypersensitivity reactions [see Contraindications (4)].

Monitor patients closely for signs and symptoms of infusion reactions during and following each FYARRO infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor patients for at least 2 hours after the first infusion and as clinically needed for each subsequent infusion.

Reduce the rate, interrupt infusion, or permanently discontinue FYARRO based on severity and institute appropriate medical management as needed.

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], FYARRO can cause fetal harm when administered to a pregnant woman. In animal studies, mechanistic target of rapamycin kinase (mTOR) inhibitors caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant and to use effective contraception while using FYARRO and for 12 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

Azoospermia or oligospermia may be observed in patients treated with FYARRO [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. FYARRO is an anti-proliferative drug and affects rapidly dividing cells such as germ cells.

No studies in conjunction with immunization have been conducted with FYARRO. Immunization during FYARRO treatment may be ineffective. Update immunizations according to immunization guidelines prior to initiating FYARRO, if possible. Immunization with live vaccines is not recommended during treatment and avoid close contact with those who have received live vaccines while on FYARRO. The interval between live vaccinations and initiation of FYARRO should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies.

FYARRO contains human albumin, a derivative of human blood. Human albumin carries only a remote risk of transmission of viral diseases because of effective donor screening and product manufacturing processes. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been associated with albumin.

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.

The safety of FYARRO was assessed in a single-arm study (AMPECT). Thirty-four patients received FYARRO 100 mg/m2 on Days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. Among the 34 patients who received FYARRO, 16 (47%) were exposed for 6 months or longer and 7 (21%) were exposed for greater than 1 year.

The median age of patients who received FYARRO was 59.5 years (range 27 to 78 years), 82% were female and Eastern Cooperative Oncology Group (ECOG) Performance Status was 0 (76%) or 1 (24%). Race was 71% White, 9% Black, 9% Asian, 3% Hawaiian/Pacific Islander and 9% Other/Not Reported. Ethnicity was 82% not Hispanic or Latino, 15% Hispanic or Latino, and 3% Not Reported.

Serious adverse reactions occurred in 14 (41%) patients who received FYARRO. Serious adverse reactions in >5% of patients, including 4 (12%) patients with infection and 2 (6%) patients each with abdominal pain, dehydration, and upper gastrointestinal hemorrhage. Fatal adverse reactions occurred in 1 (2.9%) patient who received FYARRO and experienced upper gastrointestinal hemorrhage.

Permanent discontinuation of FYARRO due to an adverse reaction occurred in 3 (9%) patients. Adverse reactions which resulted in permanent discontinuation of FYARRO included pneumonitis, anemia, and noninfective cystitis.

Dosage interruptions of FYARRO due to an adverse reaction occurred in 22 (65%) patients. Adverse reactions which required dosage interruption in >5% of patients included stomatitis in 6 (18%) patients, pneumonitis in 5 (15%) patients, anemia in 3 (9%) patients, and dehydration, dermatitis acneiform, and thrombocytopenia in 2 (6%) patients each.

Dose reductions of FYARRO due to an adverse reaction occurred in 12 (35%) patients. Adverse reactions which required dose reductions in >5% of patients included stomatitis and pneumonitis in 3 (9%) patients each.

The most common adverse reactions (≥30%) were stomatitis in 27 (79%) patients, fatigue and rash in 23 (68%) patients each, infection in 20 (59%) patients, nausea and edema in 17 (50%) patients each, diarrhea, musculoskeletal pain and decreased weight in 16 (47%) patients each, decreased appetite in 15 (44%) patients, cough in 12 (35%) patients, and vomiting and dysgeusia in 11 (32%) patients each. The most common Grade 3 to 4 laboratory abnormalities (≥6%) were decreased lymphocytes in 7 (21%) patients, increased glucose and decreased potassium in 4 (12%) patients each, decreased phosphate in 3 (9%) patients, and decreased hemoglobin and increased lipase in 2 (6%) patients each.

Table 4 summarizes the adverse reactions in AMPECT.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4. Adverse Reactions ≥10% in Patients with PEComa Who Received FYARRO in AMPECT</span> </caption> <colgroup> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> </colgroup> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule"></th><th align="center" class="Botrule Lrule Rrule" colspan="2">FYARRO<br/>(N=34)</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule RRule">Adverse Reaction</th><th align="center" class="Botrule Lrule Rrule">All Grades<br/>(%)</th><th align="center" class="Botrule Lrule Rrule">Grade 3 to 4<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a> <br/>(%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>No Grade 4 reactions were reported</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>Includes stomatitis, aphthous ulcer, mouth ulceration, esophageal ulcer</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">‡</a> </dt> <dd>Includes diarrhea and enteritis</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">§</a> </dt> <dd>Includes abdominal pain, abdominal pain upper, and epigastric discomfort</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">¶</a> </dt> <dd>Includes face edema, generalized edema, edema, edema peripheral, and periorbital edema</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">#</a> </dt> <dd>Includes dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and skin exfoliation</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">Þ</a> </dt> <dd>Includes all reported infections, including but not limited to, upper respiratory tract infection, urinary tract infection, sinusitis , skin infection, folliculitis, nasopharyngitis, pharyngitis, pharyngitis streptococcal, pneumonia, vaginal infection</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">ß</a> </dt> <dd>Includes dysesthesia, hypoesthesia, neuropathy peripheral, paresthesia, and peripheral sensory neuropathy</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">à</a> </dt> <dd>Includes dizziness, dizziness postural, and vertigo</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">è</a> </dt> <dd>Includes arthralgia, back pain, musculoskeletal chest pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">ð</a> </dt> <dd>Includes cough, productive cough, and upper-airway cough syndrome</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">ø</a> </dt> <dd>Includes dyspnea and dyspnea exertional</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">ý</a> </dt> <dd>Includes epistaxis, hemorrhoidal hemorrhage, mouth hemorrhage, post procedural hemorrhage, and upper gastrointestinal hemorrhage. Includes one fatal adverse reaction of upper GI hemorrhage</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" colspan="3">Gastrointestinal</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Stomatitis<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a></td><td align="center" class="Botrule Rrule">79</td><td align="center" class="Botrule Rrule">18</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Nausea</td><td align="center" class="Botrule Rrule">50</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Diarrhea<a class="Sup" href="#footnote-5" name="footnote-reference-5">‡</a></td><td align="center" class="Botrule Rrule">47</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Vomiting</td><td align="center" class="Botrule Rrule">32</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Abdominal Pain<a class="Sup" href="#footnote-6" name="footnote-reference-6">§</a></td><td align="center" class="Botrule Rrule">29</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Constipation</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dry Mouth</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Hemorrhoids</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">General disorders</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Fatigue</td><td align="center" class="Botrule Rrule">68</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Edema<a class="Sup" href="#footnote-7" name="footnote-reference-7">¶</a></td><td align="center" class="Botrule Rrule">50</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Pyrexia</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Skin and subcutaneous tissue disorders</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Rash<a class="Sup" href="#footnote-8" name="footnote-reference-8">#</a></td><td align="center" class="Botrule Rrule">68</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Alopecia</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Pruritus</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dry Skin</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Nail disorder</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Infections</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Infections<a class="Sup" href="#footnote-9" name="footnote-reference-9">Þ</a></td><td align="center" class="Botrule Rrule">59</td><td align="center" class="Botrule Rrule">12</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Metabolism and nutrition</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased appetite</td><td align="center" class="Botrule Rrule">44</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dehydration</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Nervous system</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dysgeusia</td><td align="center" class="Botrule Rrule">32</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Headache</td><td align="center" class="Botrule Rrule">29</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Peripheral neuropathy<a class="Sup" href="#footnote-10" name="footnote-reference-10">ß</a></td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dizziness<a class="Sup" href="#footnote-11" name="footnote-reference-11">à</a></td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Investigations</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Weight decreased</td><td align="center" class="Botrule Rrule">47</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Musculoskeletal and connective tissue disorders</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Musculoskeletal pain<a class="Sup" href="#footnote-12" name="footnote-reference-12">è</a></td><td align="center" class="Botrule Rrule">47</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Respiratory, thoracic, and mediastinal disorders</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Cough<a class="Sup" href="#footnote-13" name="footnote-reference-13">ð</a></td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Pneumonitis</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Dyspnea<a class="Sup" href="#footnote-14" name="footnote-reference-14">ø</a></td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Vascular disorders</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Hypertension</td><td align="center" class="Botrule Rrule">29</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Hemorrhage<a class="Sup" href="#footnote-15" name="footnote-reference-15">ý</a></td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Psychiatric disorders</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Insomnia</td><td align="center" class="Botrule Rrule">21</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Eye disorders</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Vision blurred</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Sub">Grading according to NCI CTCAE Version 4.03</span></td> </tr> </tbody> </table></div>

Table 5 summarizes the laboratory abnormalities in AMPECT.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 5. Laboratory Abnormalities ≥10% That Worsened from Baseline in Patients with PEComa who Received FYARRO in AMPECT</span> </caption> <colgroup> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="40%"/> </colgroup> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule"></th><th align="center" class="Botrule Lrule Rrule" colspan="2">FYARRO<a class="Sup" href="#footnote-16" name="footnote-reference-16">*</a> <br/>(N=34)</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule RRule">Laboratory Abnormality<a class="Sup" href="#footnote-17" name="footnote-reference-17">†</a></th><th align="center" class="Botrule Lrule Rrule">All Grades<br/>(%)</th><th align="center" class="Botrule Lrule Rrule">Grades 3 to 4<br/>(%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-16" name="footnote-16">*</a> </dt> <dd>The denominator used to calculate the rate varied from 33 to 34 based on the number of patients with a baseline value and at least one post-treatment value.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">†</a> </dt> <dd>Grading according to NCI CTCAE Version 4.03</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" colspan="3">Hematology</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased lymphocytes</td><td align="center" class="Botrule Rrule">82</td><td align="center" class="Botrule Rrule">21</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased hemoglobin</td><td align="center" class="Botrule Rrule">68</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased leukocytes</td><td align="center" class="Botrule Rrule">41</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased neutrophils</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased platelets</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">Chemistry</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Increased creatinine</td><td align="center" class="Botrule Rrule">82</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Increased triglycerides</td><td align="center" class="Botrule Rrule">52</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Increased cholesterol</td><td align="center" class="Botrule Rrule">48</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Increased alanine aminotransferase (ALT)</td><td align="center" class="Botrule Rrule">47</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased potassium</td><td align="center" class="Botrule Rrule">44</td><td align="center" class="Botrule Rrule">12</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased magnesium</td><td align="center" class="Botrule Rrule">42</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased albumin</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Increased aspartate transaminase (AST)</td><td align="center" class="Botrule Rrule">32</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Increased alkaline phosphatase</td><td align="center" class="Botrule Rrule">29</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased sodium</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">2.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased calcium</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased glucose</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Decreased phosphate</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Increased lipase</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Increased glucose</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">12</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">Increased sodium</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td> </tr> </tbody> </table></div>

Clinically relevant adverse reactions occurring in <10% of patients included enteritis, edema, pancytopenia, acute kidney injury, and acute coronary syndrome.

CYP3A4 and/or P-gp Inhibitors or Inducers

CYP3A4 and/or P-gp inhibitors may increase sirolimus concentrations, which may increase the risk of FYARRO adverse reactions. CYP3A4 and/or P-gp inducers may decrease sirolimus concentrations, which may reduce FYARRO effectiveness.

Risk Summary

Based on animal studies and the mechanism of action, FYARRO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Although there are no data on the use of FYARRO in pregnant women, there are limited data on the use of sirolimus during pregnancy. In animal studies, oral sirolimus was embryo/fetotoxic in rats [see Data] at sub-therapeutic doses. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for 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 2-4% and 15-20%, respectively.

Data

Animal Data

Reproductive studies in animals have not been performed with FYARRO. Studies with an oral formulation of sirolimus have shown that it crosses the placenta and is toxic to the conceptus.

In rat embryo-fetal development studies, pregnant rats were administered an oral formulation of sirolimus during the period of organogenesis (Gestational Day 6-15). Sirolimus produced embryo-fetal lethality at 0.5 mg/kg and reduced fetal weight at 1 mg/kg. The no observed adverse effect level (NOAEL) for fetal toxicity in rats was 0.1 mg/kg. Maternal toxicity (weight loss) was observed at 2 mg/kg. The NOAEL for maternal toxicity was 1 mg/kg.

In rabbit embryo-fetal development studies, pregnant rabbits were administered an oral formulation of sirolimus during the period of organogenesis (Gestational Day 6-18). There were no effects on embryo-fetal development at doses up to 0.05 mg/kg; however, at doses of 0.05 mg/kg and above, the ability to sustain a pregnancy was impaired (i.e., embryo-fetal abortion or early resorption). Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg.

In a pre- and post-natal development study in rats, pregnant females were dosed with an oral formation of sirolimus during gestation and lactation (Gestational Day 6 through Lactation Day 20). An increased incidence of dead pups occurred at 0.5 mg/kg, resulting in reduced live litter size. At 0.1 mg/kg, there were no adverse effects on offspring. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (e.g., morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest oral dose tested.

Risk Summary

There are no data on the presence of FYARRO in human milk or its effects on the breastfed child or on milk production.

It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action [see Clinical Pharmacology (12.1)]. Because of the potential for serious adverse reactions in breastfed infants from FYARRO, advise women not to breastfeed during treatment with FYARRO and for 2 weeks after the last dose.

FYARRO can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.9), Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating FYARRO.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with FYARRO and for 12 weeks after the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with FYARRO and for 12 weeks after the last dose.

Infertility

Although there are no data on the impact of FYARRO on fertility, based on available clinical findings with oral formulation of sirolimus and findings in animals, male and female fertility may be compromised by the treatment with FYARRO [see Warnings and Precautions (5.10), Nonclinical Toxicology (13.1)]. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of oral formulation of sirolimus. Azoospermia has been reported in males with the use of oral formulation sirolimus and has been reversible upon discontinuation in most cases.

The safety and efficacy of FYARRO in pediatric patients have not been established.

Of the 34 patients treated with FYARRO, 44% were 65 years of age and older, and 6% were 75 years of age and older. Clinical studies of FYARRO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

FYARRO is not recommended for use in patients with severe hepatic impairment. Reduce FYARRO dosage in patients with mild or moderate hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

FYARRO (sirolimus protein-bound particles for injectable suspension) (albumin-bound) is sirolimus formulated as albumin-bound nanoparticles. The active ingredient in FYARRO is sirolimus bound to albumin which exists in the nanoparticles in a non-crystalline, amorphous state.

{ "type": "p", "children": [], "text": "FYARRO (sirolimus protein-bound particles for injectable suspension) (albumin-bound) is sirolimus formulated as albumin-bound nanoparticles. The active ingredient in FYARRO is sirolimus bound to albumin which exists in the nanoparticles in a non-crystalline, amorphous state." }

Sirolimus is a mechanistic target of rapamycin kinase (mTOR) inhibitor. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus is [3S[3R*[S*(1R*,3S*,4S*)),6S*,7E,9S*,10S*,12S*,14R*,15E,17E,19E,21R*,23R*,26S*, 27S*,3 4aR*]]- 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy 3-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H- pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone. Its empirical formula is C51H79NO13, and the molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows:

{ "type": "p", "children": [], "text": "Sirolimus is a mechanistic target of rapamycin kinase (mTOR) inhibitor. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus is [3S[3R*[S*(1R*,3S*,4S*)),6S*,7E,9S*,10S*,12S*,14R*,15E,17E,19E,21R*,23R*,26S*, 27S*,3 4aR*]]- 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy 3-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H- pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone. Its empirical formula is C51H79NO13, and the molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows:" }

Sirolimus is a white to off-white crystalline powder and is insoluble in water but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.

{ "type": "p", "children": [], "text": "Sirolimus is a white to off-white crystalline powder and is insoluble in water but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile." }

FYARRO is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-dose vial contains 100 mg of sirolimus (bound to human albumin) and approximately 850 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate). Each milliliter (mL) of reconstituted suspension contains 5 mg sirolimus formulated as albumin-bound particles.

{ "type": "p", "children": [], "text": "FYARRO is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-dose vial contains 100 mg of sirolimus (bound to human albumin) and approximately 850 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate). Each milliliter (mL) of reconstituted suspension contains 5 mg sirolimus formulated as albumin-bound particles." }

Sirolimus in FYARRO is an inhibitor of mechanistic target of rapamycin kinase (mTOR, previously known as mammalian target of rapamycin). mTOR, a serine threonine kinase, is downstream of the PI3K/AKT pathway, controls key cellular processes such as cell survival, growth, and proliferation, and is commonly dysregulated in several human cancers. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus-FKBP-12 complex binds to and inhibits activation of the mechanistic target of rapamycin complex 1 (mTORC1). Inhibition of mTOR by sirolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and in vivo studies. In a nonclinical study in athymic mice bearing human tumor xenografts, intravenous administration of FYARRO resulted in higher tumor accumulation of sirolimus, inhibition of an mTOR target in the tumor, and tumor growth inhibition compared to administration of an oral formulation of sirolimus at the same weekly total dose.

Sirolimus exposure-response relationship has not been fully characterized.

Cardiac Electrophysiology

The effect of FYARRO on the QTc interval has not been adequately characterized.

Absorption

Following administration of FYARRO at the recommended dosage, the estimated mean (%CV) Cmax and AUC0-inf of sirolimus in patients with advanced solid tumors were 2590 ng/mL (30% CV) and 22100 ng∙h/mL (50% CV), respectively.

Distribution

The protein binding of sirolimus is >99%, primarily to serum albumin in vitro.

Elimination

The mean elimination half-life of sirolimus is approximately 59 hours (41% CV).

Metabolism

Sirolimus is metabolized by CYP3A4.

Excretion

Following a single radiolabeled sirolimus oral dose to human subjects, 91% and 2% of the radioactivity was recovered in feces and urine, respectively.

Specific Populations

There were no clinically significant differences in the pharmacokinetics of sirolimus based on age (18 to 78 years), sex, mild or moderate renal impairment (creatinine clearance 30 to 89 mL/min). The effect of race, severe renal impairment, and hepatic impairment on the pharmacokinetics of sirolimus is unknown.

Drug Interaction Studies

No studies evaluating the drug interaction potential of FYARRO have been conducted.

Sirolimus is a substrate for both CYP3A4 and P-gp.

No carcinogenicity, mutagenesis, or fertility studies were conducted with FYARRO.

Carcinogenicity studies have been conducted in mice and rats with an oral formulation of sirolimus. In an 86-week female mouse study, there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study, hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In a 104-week rat study, there were no significant findings.

Sirolimus was not genotoxic in an in vitro bacterial reverse mutation assay, a Chinese hamster ovary cell chromosomal aberration assay, a mouse lymphoma cell forward mutation assay, or an in vivo mouse micronucleus assay.

When female rats were treated by gavage with an oral formulation of sirolimus and mated to untreated males, female fertility was decreased at 0.5 mg/kg due to decreased implantation. In addition, reduced ovary and uterus weight were observed. The NOAEL for female rat fertility was 0.1 mg/kg.

When male rats were treated by gavage with an oral formulation of sirolimus and mated to untreated females, male fertility was decreased at 2 mg/kg. Atrophy of testes, epididymides, prostate, seminiferous tubules, and reduced sperm counts were observed. The NOAEL for male rat fertility was 0.5 mg/kg.

Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at 0.1 mg/kg.

The efficacy of FYARRO was assessed in AMPECT (NCT02494570), a multi-center, single-arm clinical trial in 31 patients with locally advanced unresectable or metastatic malignant PEComa. Patients were required to have measurable disease at baseline, centrally confirmed diagnosis by pathology of malignant PEComa, and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. Patients with lymphangioleiomyomatosis and prior treatment with a mTOR inhibitor were excluded. Patients received FYARRO at a dose of 100 mg/m2 on Days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity.

The efficacy population of 31 patients had the following demographic characteristics: median age 60 years (range 34 to 78), 81% Female, 74% White, 10% Black, and 81% ECOG PS of 0. Five (16%) patients had locally advanced disease and 26 (84%) had metastatic disease. Ninety-four percent of patients had prior surgery,19% had prior radiation therapy, and 13% had prior systemic therapy.

The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review (BICR) using RECIST v.1.1.

The efficacy results are summarized in Table 6.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 6. Efficacy Results in AMPECT</span> </caption> <colgroup> <col align="left" valign="bottom" width="60%"/> <col align="left" valign="bottom" width="40%"/> </colgroup> <thead> <tr class="Botrule First First Last Last"> <th align="left" class="Lrule Rrule">Efficacy Endpoints</th><th align="left" class="Rrule">FYARRO<br/>(N=31)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-18" name="footnote-18">*</a> </dt> <dd>All responses were initially partial responses. Two patients with partial response converted to complete response during the follow up-period.</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">†</a> </dt> <dd>Denotes ongoing responses</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First First"> <td align="left" class="Lrule Rrule"><span class="Bold">Overall Response Rate</span> (95% CI)<a class="Sup" href="#footnote-18" name="footnote-reference-18">*</a></td><td align="left" class="Rrule">39% (22%, 58%)</td> </tr> <tr class="Botrule"> <th align="left" class="Lrule Rrule">Duration of Response (DOR)</th><th align="left" class="Rrule">(N=12)</th> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Median (95% CI) in months</td><td align="left" class="Rrule">NR (6.5, NE)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Range in months</td><td align="left" class="Rrule">5.6, 55.5<a class="Sup" href="#footnote-19" name="footnote-reference-19">†</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">% with duration ≥6 months</td><td align="left" class="Rrule">92%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">% with duration ≥12 months</td><td align="left" class="Rrule">67%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">% with duration ≥24 months</td><td align="left" class="Rrule">58%</td> </tr> <tr class="Botrule Last Last"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Sub">CI = Confidence Interval; NR = Not Reached; NE = Not Estimable</span></td> </tr> </tbody> </table></div>

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

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FYARRO (sirolimus protein-bound particles for injectable suspension) (albumin-bound) is a white to yellow, sterile lyophilized powder supplied as:

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NDC 80803-153-50, 100 mg of sirolimus in a single-dose vial. Each carton contains 1 vial.

{ "type": "p", "children": [], "text": "NDC 80803-153-50, 100 mg of sirolimus in a single-dose vial. Each carton contains 1 vial." }

Store the vials in the original cartons at 2° to 8°C [USP Refrigerated Temperature] (36° to 46°F).

{ "type": "p", "children": [], "text": "Store the vials in the original cartons at 2° to 8°C [USP Refrigerated Temperature] (36° to 46°F)." }

Retain in the original package to protect from light.

{ "type": "p", "children": [], "text": "Retain in the original package to protect from light." }

FYARRO is a hazardous drug. Follow applicable special handling and disposal procedures.1

{ "type": "p", "children": [], "text": "FYARRO is a hazardous drug. Follow applicable special handling and disposal procedures.1\n" }

Stomatitis

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

Advise patients of the risk of stomatitis [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of stomatitis [see Warnings and Precautions (5.1)]." }

Myelosuppression

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

Advise patients of the risk of myelosuppression and the need to monitor blood counts periodically during therapy [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of myelosuppression and the need to monitor blood counts periodically during therapy [see Warnings and Precautions (5.2)]." }

Infections

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

Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infection to their healthcare provider [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infection to their healthcare provider [see Warnings and Precautions (5.3)]." }

Hypokalemia

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

Advise patients of the risk of hypokalemia and the need to monitor potassium periodically during therapy [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of hypokalemia and the need to monitor potassium periodically during therapy [see Warnings and Precautions (5.4)]." }

Hyperglycemia

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

Advise patients of the risk of hyperglycemia and the need to monitor glucose periodically during therapy [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of hyperglycemia and the need to monitor glucose periodically during therapy [see Warnings and Precautions (5.5)]." }

Interstitial Lung Disease / Non-Infectious Pneumonitis

{ "type": "p", "children": [], "text": "\nInterstitial Lung Disease / Non-Infectious Pneumonitis\n" }

Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions (5.6)]." }

Hemorrhage

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

Advise patients of the risk of hemorrhage. Instruct patients to report signs of bleeding, and to seek immediate medical attention for signs or symptoms of severe bleeding [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of hemorrhage. Instruct patients to report signs of bleeding, and to seek immediate medical attention for signs or symptoms of severe bleeding [see Warnings and Precautions (5.7)]." }

Hypersensitivity Reactions

{ "type": "p", "children": [], "text": "\nHypersensitivity Reactions\n" }

Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications (4), Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications (4), Warnings and Precautions (5.8)]." }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.9)]. Advise females of reproductive potential to use effective contraception during treatment and for 12 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.9)]. Advise females of reproductive potential to use effective contraception during treatment and for 12 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)]." }

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 12 weeks after the last dose [see Warnings and Precautions (5.9), Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise males with female partners of reproductive potential to use effective contraception during treatment and for 12 weeks after the last dose [see Warnings and Precautions (5.9), Use in Specific Populations (8.3)]." }

Infertility

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

Advise males and females of reproductive potential of the potential risk for impaired fertility [see Warnings and Precautions (5.10), Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise males and females of reproductive potential of the potential risk for impaired fertility [see Warnings and Precautions (5.10), Use in Specific Populations (8.3)]." }

Immunizations

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

Advise patients that vaccinations may be less effective while being treated with FYARRO. Advise patients to avoid the use of live vaccines, and close contact with those who have received live vaccines, while on FYARRO [see Warnings and Precautions (5.11)].

{ "type": "p", "children": [], "text": "Advise patients that vaccinations may be less effective while being treated with FYARRO. Advise patients to avoid the use of live vaccines, and close contact with those who have received live vaccines, while on FYARRO [see Warnings and Precautions (5.11)]." }

Lactation

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

Advise women not to breastfeed during treatment with FYARRO and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise women not to breastfeed during treatment with FYARRO and for 2 weeks after the last dose [see Use in Specific Populations (8.2)]." }

Drug Interactions

{ "type": "p", "children": [], "text": "\nDrug Interactions\n" }

Advise patients to inform their healthcare provider about all concomitant medications, including prescription medicine, over the counter drugs, vitamins, and herbal products [see Drug Interactions (7)]. Inform patients to avoid grapefruit and grapefruit juice while taking FYARRO.

{ "type": "p", "children": [], "text": "Advise patients to inform their healthcare provider about all concomitant medications, including prescription medicine, over the counter drugs, vitamins, and herbal products [see Drug Interactions (7)]. Inform patients to avoid grapefruit and grapefruit juice while taking FYARRO." }

This product's label may have been updated. For current full prescribing information, please visit www.aadibio.com.

{ "type": "p", "children": [], "text": "This product's label may have been updated. For current full prescribing information, please visit www.aadibio.com." }

Manufactured for Aadi Bioscience, Inc., Pacific Palisades, CA 90272.

{ "type": "p", "children": [], "text": "Manufactured for Aadi Bioscience, Inc., Pacific Palisades, CA 90272." }

FYARRO is a trademark of Aadi Bioscience, Inc.

{ "type": "p", "children": [], "text": "FYARRO is a trademark of Aadi Bioscience, Inc." }

Patent: www.aadibio.com/patents/

{ "type": "p", "children": [], "text": "Patent: www.aadibio.com/patents/" }

NDC 80803-153-50        Rx OnlyFyarro™ sirolimus protein-boundparticles for injectablesuspension (albumin-bound)100 mg per vialFor intravenous infusionSingle-dose vialDiscard any unused portion.

{ "type": "p", "children": [], "text": "NDC 80803-153-50        Rx OnlyFyarro™\nsirolimus protein-boundparticles for injectablesuspension (albumin-bound)100 mg per vialFor intravenous infusionSingle-dose vialDiscard any unused portion." }

Sirolimus is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants.

In patients at low- to moderate-immunologic risk, it is recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [see Dosage and Administration (2.2)].

In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level >80%]), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation [see Dosage and Administration (2.3), Clinical Studies (14.3)].

Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine >4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies [see Clinical Studies (14.2)].

In patients at high-immunologic risk, the safety and efficacy of sirolimus used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient [see Clinical Studies (14.3)].

In pediatric patients, the safety and efficacy of sirolimus have not been established in patients <13 years old, or in pediatric (<18 years) renal transplant patients considered at high-immunologic risk [see Adverse Reactions (6.5), Clinical Studies (14.6)].

The safety and efficacy of de novo use of sirolimus without cyclosporine have not been established in renal transplant patients [see Warnings and Precautions (5.12)].

The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established [see Clinical Studies (14.4)].

Sirolimus is indicated for the treatment of patients with lymphangioleiomyomatosis (LAM).

The initial dose of sirolimus should be administered as soon as possible after transplantation. It is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [see Drug Interactions (7.2)].

Frequent sirolimus dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dose adjustments can be based on simple proportion: new sirolimus dose = current dose × (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: sirolimus loading dose = 3 × (new maintenance dose - current maintenance dose). The maximum sirolimus dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

Two milligrams (2 mg) of sirolimus oral solution have been demonstrated to be clinically equivalent to 2 mg sirolimus tablets; hence, at this dose these two formulations are interchangeable. However, it is not known if higher doses of sirolimus oral solution are clinically equivalent to higher doses of sirolimus tablets on a mg-to-mg basis [see Clinical Pharmacology (12.3)].

Sirolimus and Cyclosporine Combination Therapy

For de novo renal transplant patients, it is recommended that sirolimus tablets be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of sirolimus equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range [see Dosage and Administration (2.5)].

Sirolimus Following Cyclosporine Withdrawal

At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the sirolimus dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range [see Dosage and Administration (2.5)]. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased [see Clinical Pharmacology (12.3)].

In patients with high-immunologic risk, it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation [see Clinical Studies (14.3)]. The safety and efficacy of this combination in high-immunologic risk patients has not been studied beyond the first 12 months. Therefore, after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient.

For patients receiving sirolimus with cyclosporine, sirolimus therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of sirolimus should thereafter be adjusted [see Dosage and Administration (2.5)].

The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations [see Dosage and Administration (2.5)]. Prednisone should be administered at a minimum of 5 mg/day.

Antibody induction therapy may be used.

For patients with lymphangioleiomyomatosis, the initial Sirolimus dose should be 2 mg/day. Sirolimus whole blood trough concentrations should be measured in 10–20 days, with dosage adjustment to maintain concentrations between 5–15 ng/mL [see Dosage and Administration (2.5)].

In most patients, dose adjustments can be based on simple proportion: new Sirolimus dose = current dose × (target concentration/current concentration). Frequent Sirolimus dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or under dosing because sirolimus has a long half-life. Once Sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. Once a stable dose is achieved, therapeutic drug monitoring should be performed at least every three months.

Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients ≥13 years who weigh less than 40 kg, in patients with hepatic impairment, when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [see Warnings and Precautions (5.20, 5.21), Drug Interactions (7)].

Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters.

When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range [see Clinical Studies (14), Clinical Pharmacology (12.3)]. Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL.

The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable [see Warnings and Precautions (5.17), Clinical Pharmacology (12.3)]. Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Therefore, communication should be maintained with the laboratory performing the assay. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see References (15)].

The initial dosage in patients ≥13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m2/day. The loading dose should be 3 mg/m2.

It is recommended that the maintenance dose of sirolimus be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. It is not necessary to modify the sirolimus loading dose [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Dosage adjustment is not needed in patients with impaired renal function [see Use in Specific Populations (8.7)].

Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus [see Warnings and Precautions (5.4)]." }

Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. The rates of lymphoma/lymphoproliferative disease observed in Studies 1 and 2 were 0.7–3.2% (for sirolimus -treated patients) versus 0.6–0.8% (azathioprine and placebo control) [see Adverse Reactions (6.1) and (6.2)]. Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended. The use of sirolimus has been associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss and hepatic artery thrombosis (HAT).

In a study in de novo liver transplant patients, the use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss (22% in combination versus 9% on tacrolimus alone). Many of these patients had evidence of infection at or near the time of death.

In this and another study in de novo liver transplant patients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT (7% in combination versus 2% in the control arm); most cases of HAT occurred within 30 days post-transplantation, and most led to graft loss or death.

In a clinical study in stable liver transplant patients 6–144 months post-liver transplantation and receiving a CNI-based regimen, an increased number of deaths was observed in the group converted to a sirolimus-based regimen compared to the group who was continued on a CNI-based regimen, although the difference was not statistically significant (3.8% versus 1.4%) [see Clinical Studies (14.5)].

Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen.

The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended.

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the administration of sirolimus [see Adverse Reactions (6.7)].

Sirolimus has been associated with the development of angioedema. The concomitant use of sirolimus with other drugs known to cause angioedema, such as angiotensin converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema. Elevated sirolimus levels (with/without concomitant ACE inhibitors) may also potentiate angioedema [see Drug Interactions (7.2)]. In some cases, the angioedema has resolved upon discontinuation or dose reduction of sirolimus.

There have been reports of impaired or delayed wound healing in patients receiving sirolimus, including lymphocele and wound dehiscence [see Adverse Reactions (6.1)]. Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in patients treated with sirolimus [see Adverse Reactions (6.1)]. Appropriate measures should be considered to minimize such complications. Patients with a body mass index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature.

There have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion, ascites, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving sirolimus.

Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with sirolimus compared with azathioprine or placebo controls in Studies 1 and 2 [see Adverse Reactions (6.1)]. There were increased incidences of hypercholesterolemia (43–46%) and/or hypertriglyceridemia (45–57%) in patients receiving sirolimus compared with placebo controls (each 23%). The risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including sirolimus.

Any patient who is administered sirolimus should be monitored for hyperlipidemia. If detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines.

In clinical trials of patients receiving sirolimus plus cyclosporine or sirolimus after cyclosporine withdrawal, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels. The concomitant administration of sirolimus and HMG-CoA reductase inhibitors resulted in adverse reactions such as CPK elevations (3%), myalgia (6.7%) and rhabdomyolysis (<1%). In these trials, the number of patients was too small and duration of follow-up too short to evaluate the long-term impact of sirolimus on cardiovascular mortality.

During sirolimus therapy with or without cyclosporine, patients should be monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents.

Renal function should be closely monitored during the co-administration of sirolimus with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function. Patients treated with cyclosporine and sirolimus were noted to have higher serum creatinine levels and lower glomerular filtration rates compared with patients treated with cyclosporine and placebo or azathioprine controls (Studies 1 and 2). The rate of decline in renal function in these studies was greater in patients receiving sirolimus and cyclosporine compared with control therapies.

Appropriate adjustment of the immunosuppressive regimen, including discontinuation of sirolimus and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels. In patients at low- to moderate-immunologic risk, continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when the benefits outweigh the risks of this combination for the individual patients. Caution should be exercised when using agents (e.g., aminoglycosides and amphotericin B) that are known to have a deleterious effect on renal function.

In patients with delayed graft function, sirolimus may delay recovery of renal function.

Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors (CNI) to sirolimus in maintenance renal transplant patients 6–120 months post-transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to sirolimus compared with CNI continuation [see Clinical Studies (14.4), Adverse Reactions (6.4)]. Patients with the greatest amount of urinary protein excretion prior to sirolimus conversion were those whose protein excretion increased the most after conversion. New onset nephrosis (nephrotic syndrome) was also reported as a treatment-emergent adverse reaction in 2.2% of the sirolimus conversion group patients in comparison to 0.4% in the CNI continuation group of patients. Nephrotic range proteinuria (defined as urinary protein to creatinine ratio >3.5) was also reported in 9.2% in the sirolimus conversion group of patients in comparison to 3.7% in the CNI continuation group of patients. In some patients, reduction in the degree of urinary protein excretion was observed for individual patients following discontinuation of sirolimus. The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established.

Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus-associated nephropathy, which has been observed in renal transplant patients receiving immunosuppressants, including sirolimus. This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss [see Adverse Reactions (6.7)]. Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy.

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients treated with immunosuppressants, including sirolimus. PML commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Consideration should be given to reducing the amount of immunosuppression in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.

Cases of interstitial lung disease [ILD] (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including sirolimus. In some cases, the ILD was reported with pulmonary hypertension (including pulmonary arterial hypertension [PAH]) as a secondary event. In some cases, the ILD has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the trough sirolimus concentration increases [see Adverse Reactions (6.7)].

The safety and efficacy of de novo use of sirolimus without cyclosporine is not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with sirolimus, mycophenolate mofetil (MMF), steroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of sirolimus without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial.

The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) [see Adverse Reactions (6.7)].

Cases of Pneumocystis carinii pneumonia have been reported in transplant patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for 1 year following transplantation.

Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], sirolimus can cause fetal harm when administered to a pregnant woman. In animal studies, sirolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using sirolimus and for 12 weeks after ending treatment [see Use in Specific Populations (8.1)].

Azoospermia or oligospermia may be observed [see Adverse Reactions (6.7), Nonclinical Toxicology (13.1)]. Sirolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells.

Currently in clinical practice, sirolimus whole blood concentrations are being measured by various chromatographic and immunoassay methodologies. Patient sample concentration values from different assays may not be interchangeable [see Dosage and Administration (2.5)].

Patients on immunosuppressive therapy are at increased risk for skin cancer. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Adverse Reactions (6.1, 6.2, 6.7)].

The use of live vaccines should be avoided during treatment with sirolimus; live vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid. Immunosuppressants may affect response to vaccination. Therefore, during treatment with sirolimus, vaccination may be less effective.

Avoid concomitant use of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) [see Drug Interactions (7.2)].

When cannabidiol and sirolimus are co-administered, closely monitor for an increase in sirolimus blood levels and for adverse reactions suggestive of sirolimus toxicity. A dose reduction of sirolimus should be considered as needed when sirolimus is co-administered with cannabidiol [see Dosage and Administration (2.5), Drug Interactions (7.5)].

The safety and efficacy of sirolimus oral solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials [see Clinical Studies (14.1)]. The safety profiles in the two studies were similar.

The incidence of adverse reactions in the randomized, double-blind, multicenter, placebo-controlled trial (Study 2) in which 219 renal transplant patients received sirolimus oral solution 2 mg/day, 208 received sirolimus oral solution 5 mg/day, and 124 received placebo is presented in Table 1 below. The study population had a mean age of 46 years (range 15 to 71 years), the distribution was 67% male, and the composition by race was: White (78%), Black (11%), Asian (3%), Hispanic (2%), and Other (5%). All patients were treated with cyclosporine and corticosteroids. Data (≥ 12 months post-transplant) presented in the following table show the adverse reactions that occurred in at least one of the sirolimus treatment groups with an incidence of ≥20%.

The safety profile of the tablet did not differ from that of the oral solution formulation [see Clinical Studies (14.1)].

In general, adverse reactions related to the administration of sirolimus were dependent on dose/concentration. Although a daily maintenance dose of 5 mg, with a loading dose of 15 mg, was shown to be safe and effective, no efficacy advantage over the 2 mg dose could be established for renal transplant patients. Patients receiving 2 mg of sirolimus oral solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of sirolimus oral solution per day.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 1: ADVERSE REACTIONS OCCURRING AT A FREQUENCY OF ≥20% IN AT LEAST ONE OF THE SIROLIMUS TREATMENT GROUPS IN A STUDY OF PROPHYLAXIS OF ORGAN REJECTION FOLLOWING RENAL TRANSPLANTATION (%) AT ≥ 12 MONTHS POST-TRANSPLANTATION (STUDY 2)<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span> </caption> <col width="46%"/> <col width="18%"/> <col width="18%"/> <col width="18%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"></td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First">––– Sirolimus Oral Solution––– </p> </td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"></td><td align="center" valign="top"> <p class="First">2 mg/day</p> </td><td align="center" valign="top"> <p class="First">5 mg/day</p> </td><td align="center" valign="top"> <p class="First">Placebo</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Adverse Reaction </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(n = 218)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(n = 208)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(n = 124)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Peripheral edema</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">54</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">58</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">48</p> </td> </tr> <tr> <td valign="top"> <p class="First">Hypertriglyceridemia</p> </td><td align="center" valign="top"> <p class="First">45</p> </td><td align="center" valign="top"> <p class="First">57</p> </td><td align="center" valign="top"> <p class="First">23</p> </td> </tr> <tr> <td valign="top"> <p class="First">Hypertension</p> </td><td align="center" valign="top"> <p class="First">45</p> </td><td align="center" valign="top"> <p class="First">49</p> </td><td align="center" valign="top"> <p class="First">48</p> </td> </tr> <tr> <td valign="top"> <p class="First">Hypercholesterolemia</p> </td><td align="center" valign="top"> <p class="First">43</p> </td><td align="center" valign="top"> <p class="First">46</p> </td><td align="center" valign="top"> <p class="First">23</p> </td> </tr> <tr> <td valign="top"> <p class="First">Creatinine increased</p> </td><td align="center" valign="top"> <p class="First">39</p> </td><td align="center" valign="top"> <p class="First">40</p> </td><td align="center" valign="top"> <p class="First">38</p> </td> </tr> <tr> <td valign="top"> <p class="First">Constipation</p> </td><td align="center" valign="top"> <p class="First">36</p> </td><td align="center" valign="top"> <p class="First">38</p> </td><td align="center" valign="top"> <p class="First">31</p> </td> </tr> <tr> <td valign="top"> <p class="First">Abdominal pain</p> </td><td align="center" valign="top"> <p class="First">29</p> </td><td align="center" valign="top"> <p class="First">36</p> </td><td align="center" valign="top"> <p class="First">30</p> </td> </tr> <tr> <td valign="top"> <p class="First">Diarrhea</p> </td><td align="center" valign="top"> <p class="First">25</p> </td><td align="center" valign="top"> <p class="First">35</p> </td><td align="center" valign="top"> <p class="First">27</p> </td> </tr> <tr> <td valign="top"> <p class="First">Headache</p> </td><td align="center" valign="top"> <p class="First">34</p> </td><td align="center" valign="top"> <p class="First">34</p> </td><td align="center" valign="top"> <p class="First">31</p> </td> </tr> <tr> <td valign="top"> <p class="First">Fever</p> </td><td align="center" valign="top"> <p class="First">23</p> </td><td align="center" valign="top"> <p class="First">34</p> </td><td align="center" valign="top"> <p class="First">35</p> </td> </tr> <tr> <td valign="top"> <p class="First">Urinary tract infection</p> </td><td align="center" valign="top"> <p class="First">26</p> </td><td align="center" valign="top"> <p class="First">33</p> </td><td align="center" valign="top"> <p class="First">26</p> </td> </tr> <tr> <td valign="top"> <p class="First">Anemia</p> </td><td align="center" valign="top"> <p class="First">23</p> </td><td align="center" valign="top"> <p class="First">33</p> </td><td align="center" valign="top"> <p class="First">21</p> </td> </tr> <tr> <td valign="top"> <p class="First">Nausea</p> </td><td align="center" valign="top"> <p class="First">25</p> </td><td align="center" valign="top"> <p class="First">31</p> </td><td align="center" valign="top"> <p class="First">29</p> </td> </tr> <tr> <td valign="top"> <p class="First">Arthralgia</p> </td><td align="center" valign="top"> <p class="First">25</p> </td><td align="center" valign="top"> <p class="First">31</p> </td><td align="center" valign="top"> <p class="First">18</p> </td> </tr> <tr> <td valign="top"> <p class="First">Thrombocytopenia</p> </td><td align="center" valign="top"> <p class="First">14</p> </td><td align="center" valign="top"> <p class="First">30</p> </td><td align="center" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td valign="top"> <p class="First">Pain</p> </td><td align="center" valign="top"> <p class="First">33</p> </td><td align="center" valign="top"> <p class="First">29</p> </td><td align="center" valign="top"> <p class="First">25</p> </td> </tr> <tr> <td valign="top"> <p class="First">Acne</p> </td><td align="center" valign="top"> <p class="First">22</p> </td><td align="center" valign="top"> <p class="First">22</p> </td><td align="center" valign="top"> <p class="First">19</p> </td> </tr> <tr> <td valign="top"> <p class="First">Rash</p> </td><td align="center" valign="top"> <p class="First">10</p> </td><td align="center" valign="top"> <p class="First">20</p> </td><td align="center" valign="top"> <p class="First">6</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Edema</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">18</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">15</p> </td> </tr> </tbody> </table></div>

The following adverse reactions were reported less frequently (≥3%, but <20%)

Less frequently (<3%) occurring adverse reactions included: lymphoma/post-transplant lymphoproliferative disorder, mycobacterial infections (including M. tuberculosis), pancreatitis, cytomegalovirus (CMV), and Epstein-Barr virus.

Increased Serum Cholesterol and Triglycerides

The use of sirolimus in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment.

In Studies 1 and 2, in de novo renal transplant patients who began the study with fasting, total serum cholesterol <200 mg/dL or fasting, total serum triglycerides <200 mg/dL, there was an increased incidence of hypercholesterolemia (fasting serum cholesterol >240 mg/dL) or hypertriglyceridemia (fasting serum triglycerides >500 mg/dL), respectively, in patients receiving both sirolimus 2 mg and sirolimus 5 mg compared with azathioprine and placebo controls.

Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42–52% of patients enrolled in the sirolimus arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm. In other sirolimus renal transplant studies, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels [see Warnings and Precautions (5.7)].

Abnormal Healing

Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia, and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary).

Malignancies

Table 2 below summarizes the incidence of malignancies in the two controlled trials (Studies 1 and 2) for the prevention of acute rejection [see Clinical Studies (14.1)].

At 24 months (Study 1) and 36 months (Study 2) post-transplant, there were no significant differences among treatment groups.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 2: INCIDENCE (%) OF MALIGNANCIES IN STUDY 1 (24 MONTHS) AND STUDY 2 (36 MONTHS) POST-TRANSPLANT<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-3" name="footnote-reference-3">†</a></span> </caption> <col width="37%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <col width="16%"/> <col width="11%"/> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">‡</a> </dt> <dd>Patients may be counted in more than one category.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"></td><td align="center" class="Toprule" colspan="2" valign="bottom"> <p class="First">Sirolimus Oral Solution<br/>2 mg/day</p> </td><td align="center" class="Toprule" colspan="2" valign="bottom"> <p class="First">Sirolimus Oral Solution<br/>5 mg/day</p> </td><td align="center" class="Toprule" valign="bottom"> <p class="First">Azathioprine<br/>2–3 mg/kg/day</p> </td><td align="center" class="Toprule" valign="bottom"> <p class="First">Placebo</p> </td> </tr> <tr> <td class="Botrule" valign="bottom"> <p class="First">Malignancy </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Study 1<br/>(n = 284)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Study 2<br/>(n = 227)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Study 1<br/>(n = 274)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Study 2<br/>(n = 219)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Study 1<br/>(n = 161)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Study 2<br/>(n = 130)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Lymphoma/lymphoproliferative disease</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">0.7</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">1.8</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">1.1</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">3.2</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">0.6</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">0.8</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold"> <br/>Skin Carcinoma</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Any Squamous Cell<a class="Sup" href="#footnote-4" name="footnote-reference-4">‡</a> </p> </td><td align="center" valign="top"> <p class="First">0.4</p> </td><td align="center" valign="top"> <p class="First">2.7</p> </td><td align="center" valign="top"> <p class="First">2.2</p> </td><td align="center" valign="top"> <p class="First">0.9</p> </td><td align="center" valign="top"> <p class="First">3.8</p> </td><td align="center" valign="top"> <p class="First">3.0</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Any Basal Cell<a class="Sup" href="#footnote-4">‡</a> </p> </td><td align="center" valign="top"> <p class="First">0.7</p> </td><td align="center" valign="top"> <p class="First">2.2</p> </td><td align="center" valign="top"> <p class="First">1.5</p> </td><td align="center" valign="top"> <p class="First">1.8</p> </td><td align="center" valign="top"> <p class="First">2.5</p> </td><td align="center" valign="top"> <p class="First">5.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Melanoma</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.4</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">1.4</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Miscellaneous/Not Specified</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.8</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold"> <br/>Total</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold"> <br/>1.1</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold"> <br/>4.4</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold"> <br/>3.3</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold"> <br/>4.1</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold"> <br/>4.3</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold"> <br/>7.7</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Other Malignancy</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">1.1</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">2.2</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">1.5</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">1.4</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">0.6</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">2.3</span> </p> </td> </tr> </tbody> </table></div>

The incidence of adverse reactions was determined through 36 months in a randomized, multicenter, controlled trial (Study 3) in which 215 renal transplant patients received sirolimus as a maintenance regimen following cyclosporine withdrawal, and 215 patients received sirolimus with cyclosporine therapy [see Clinical Studies (14.2)]. All patients were treated with corticosteroids. The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2 mg sirolimus groups in Studies 1 and 2.

Following randomization (at 3 months), patients who had cyclosporine eliminated from their therapy experienced higher incidences of the following adverse reactions: abnormal liver function tests (including increased AST/SGOT and increased ALT/SGPT), hypokalemia, thrombocytopenia, and abnormal healing. Conversely, the incidence of the following adverse events was higher in patients who remained on cyclosporine than those who had cyclosporine withdrawn from therapy: hypertension, cyclosporine toxicity, increased creatinine, abnormal kidney function, toxic nephropathy, edema, hyperkalemia, hyperuricemia, and gum hyperplasia. Mean systolic and diastolic blood pressure improved significantly following cyclosporine withdrawal.

Malignancies

The incidence of malignancies in Study 3 [see Clinical Studies (14.2)] is presented in Table 3.

In Study 3, the incidence of lymphoma/lymphoproliferative disease was similar in all treatment groups. The overall incidence of malignancy was higher in patients receiving sirolimus plus cyclosporine compared with patients who had cyclosporine withdrawn. Conclusions regarding these differences in the incidence of malignancy could not be made because Study 3 was not designed to consider malignancy risk factors or systematically screen subjects for malignancy. In addition, more patients in the sirolimus with cyclosporine group had a pre-transplantation history of skin carcinoma.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 3: INCIDENCE (%) OF MALIGNANCIES IN STUDY 3 (CYCLOSPORINE WITHDRAWAL STUDY) AT 36 MONTHS POST-TRANSPLANT<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a></span> </caption> <col width="40%"/> <col width="21%"/> <col width="19%"/> <col width="19%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">‡</a> </dt> <dd>Patients may be counted in more than one category.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First">Malignancy</p> </td><td align="center" class="Botrule Toprule" valign="bottom"> <p class="First">Nonrandomized<br/>(n = 95)</p> </td><td align="center" class="Botrule Toprule" valign="bottom"> <p class="First">Sirolimus with Cyclosporine Therapy<br/>(n = 215)</p> </td><td align="center" class="Botrule Toprule" valign="bottom"> <p class="First">Sirolimus Following Cyclosporine Withdrawal<br/>(n = 215)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Lymphoma/lymphoproliferative disease</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">1.1</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">1.4</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">0.5</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold"> <br/>Skin Carcinoma</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Any Squamous Cell<a class="Sup" href="#footnote-7" name="footnote-reference-7">‡</a> </p> </td><td align="center" valign="top"> <p class="First">3.2</p> </td><td align="center" valign="top"> <p class="First">3.3</p> </td><td align="center" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Any Basal Cell<a class="Sup" href="#footnote-7">‡</a> </p> </td><td align="center" valign="top"> <p class="First">3.2</p> </td><td align="center" valign="top"> <p class="First">6.5</p> </td><td align="center" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Melanoma</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.5</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Miscellaneous/Not Specified</p> </td><td align="center" valign="top"> <p class="First">1.1</p> </td><td align="center" valign="top"> <p class="First">0.9</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold"> <br/>Total</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold"> <br/>4.2</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold"> <br/>7.9</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold"> <br/>3.7</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Other Malignancy</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">3.2</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">3.3</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">1.9</span> </p> </td> </tr> </tbody> </table></div>

Safety was assessed in 224 patients who received at least one dose of sirolimus with cyclosporine [see Clinical Studies (14.3)]. Overall, the incidence and nature of adverse reactions was similar to those seen in previous combination studies with sirolimus. The incidence of malignancy was 1.3% at 12 months.

The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant population have not been established [see Clinical Studies (14.4)]. In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (initial target sirolimus concentrations of 12–20 ng/mL, and then 8–20 ng/mL, by chromatographic assay) in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n = 87) with a baseline glomerular filtration rate of less than 40 mL/min. There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this stratum of the sirolimus treatment arm.

The subset of patients with a baseline glomerular filtration rate of less than 40 mL/min had 2 years of follow-up after randomization. In this population, the rate of pneumonia was 25.9% (15/58) versus 13.8% (4/29), graft loss (excluding death with functioning graft loss) was 22.4% (13/58) versus 31.0% (9/29), and death was 15.5% (9/58) versus 3.4% (1/29) in the sirolimus conversion group and CNI continuation group, respectively.

In the subset of patients with a baseline glomerular filtration rate of greater than 40 mL/min, there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the sirolimus conversion arm.

Overall in this study, a 5-fold increase in the reports of tuberculosis among sirolimus 2.0% (11/551) and comparator 0.4% (1/273) treatment groups was observed with 2:1 randomization scheme.

In a second study evaluating the safety and efficacy of conversion from tacrolimus to sirolimus 3 to 5 months post-kidney transplant, a higher rate of adverse events, discontinuations due to adverse events, acute rejection, and new onset diabetes mellitus was observed following conversion to sirolimus. There was also no benefit with respect to renal function and a greater incidence of proteinuria was observed after conversion to sirolimus [(see Clinical Studies (14.4)].

Safety was assessed in a controlled clinical trial in pediatric (<18 years of age) renal transplant patients considered at high-immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy [see Clinical Studies (14.6)]. The use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with a higher incidence of deterioration of renal function (creatinine increased) compared to calcineurin inhibitor-based therapy, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections.

Safety was assessed in a controlled trial involving 89 patients with lymphangioleiomyomatosis, 46 of whom were treated with sirolimus [see Clinical Studies (14.7)]. The adverse drug reactions observed in this trial were consistent with the known safety profile for renal transplant patients receiving sirolimus, with the addition of weight decreased which was reported at a greater incidence with sirolimus when compared to placebo. Adverse reactions occurring at a frequency of ≥20% in the sirolimus treatment group and greater than placebo include stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.

The following adverse reactions have been identified during post-approval use of sirolimus in transplant patients. 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.

Cyclosporine, a substrate and inhibitor of CYP3A4 and P-gp, was demonstrated to increase sirolimus concentrations when co-administered with sirolimus. In order to diminish the effect of this interaction with cyclosporine, it is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). If cyclosporine is withdrawn from combination therapy with sirolimus, higher doses of sirolimus are needed to maintain the recommended sirolimus trough concentration ranges [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp. Alternative agents with lesser interaction potential with sirolimus should be considered [see Warnings and Precautions (5.20), Clinical Pharmacology (12.3)].

Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with sirolimus [see Clinical Pharmacology (12.3)].

Exercise caution when using sirolimus with drugs or agents that are modulators of CYP3A4 and P-gp. The dosage of sirolimus and/or the co-administered drug may need to be adjusted [see Clinical Pharmacology (12.3)].

The blood levels of sirolimus may increase upon concomitant use with cannabidiol. When cannabidiol and sirolimus are co-administered, closely monitor for an increase in sirolimus blood levels and for adverse reactions suggestive of sirolimus toxicity. A dose reduction of sirolimus should be considered as needed when sirolimus is co-administered with cannabidiol [see Dosage and Administration (2.5), Warnings and Precautions (5.21)].

Risk Summary

Based on animal studies and the mechanism of action, sirolimus can cause fetal harm when administered to a pregnant woman [see Data, Clinical Pharmacology (12.1)]. There are limited data on the use of sirolimus during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal studies, sirolimus was embryo/fetotoxic in rats at sub-therapeutic doses [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for 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 2–4% and 15–20%, respectively.

Data

Animal Data

Sirolimus crossed the placenta and was toxic to the conceptus.

In rat embryo-fetal development studies, pregnant rats were administered sirolimus orally during the period of organogenesis (Gestational Day 6–15). Sirolimus produced embryo-fetal lethality at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) and reduced fetal weight at 1 mg/kg (5-fold the clinical dose of 2 mg). The no observed adverse effect level (NOAEL) for fetal toxicity in rats was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg). Maternal toxicity (weight loss) was observed at 2 mg/kg (10-fold the clinical dose of 2 mg). The NOAEL for maternal toxicity was 1 mg/kg. In combination with cyclosporine, rats had increased embryo-fetal mortality compared with sirolimus alone.

In rabbit embryo-fetal development studies, pregnant rabbits were administered sirolimus orally during the period of organogenesis (Gestational Day 6–18). There were no effects on embryo-fetal development at doses up to 0.05 mg/kg (0.5-fold the clinical dose of 2 mg, on a body surface area basis); however, at doses of 0.05 mg/kg and above, the ability to sustain a successful pregnancy was impaired (i.e., embryo-fetal abortion or early resorption). Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg (0.25-fold the clinical dose of 2 mg).

In a pre- and post-natal development study in rats, pregnant females were dosed during gestation and lactation (Gestational Day 6 through Lactation Day 20). An increased incidence of dead pups, resulting in reduced live litter size, occurred at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg/kg on a body surface area basis). At 0.1 mg/kg (0.5-fold the clinical dose of 2 mg), there were no adverse effects on offspring. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest dose tested.

Risk Summary

It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action [see Clinical Pharmacology (12.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sirolimus and any potential adverse effects on the breastfed child from sirolimus.

Contraception

Females should not be pregnant or become pregnant while receiving sirolimus. Advise females of reproductive potential that animal studies have been shown sirolimus to be harmful to the developing fetus. Females of reproductive potential are recommended to use highly effective contraceptive method. Effective contraception must be initiated before sirolimus therapy, during sirolimus therapy, and for 12 weeks after sirolimus therapy has been stopped [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)].

Infertility

Based on clinical findings and findings in animals, male and female fertility may be compromised by the treatment with sirolimus [see Adverse Reactions (6.7), Nonclinical Toxicology (13.1)]. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of sirolimus. Azoospermia has been reported in males with the use of sirolimus and has been reversible upon discontinuation of sirolimus in most cases.

Renal Transplant

The safety and efficacy of sirolimus in pediatric patients <13 years have not been established.

The safety and efficacy of sirolimus oral solution and sirolimus tablets have been established for prophylaxis of organ rejection in renal transplantation in children ≥13 years judged to be at low- to moderate-immunologic risk. Use of sirolimus oral solution and sirolimus tablets in this subpopulation of children ≥13 years is supported by evidence from adequate and well-controlled trials of sirolimus oral solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients [see Clinical Pharmacology (12.3)].

Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (<18 years of age) renal transplant patients judged to be at high-immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of sirolimus oral solution or tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival [see Clinical Studies (14.6)].

Lymphangioleiomyomatosis

The safety and efficacy of Sirolimus in pediatric patients <18 years have not been established.

Clinical studies of sirolimus oral solution or tablets did not include sufficient numbers of patients ≥65 years to determine whether they respond differently from younger patients. Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary. Differences in responses between the elderly and younger patients have not been identified. 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, or cardiac function, and of concomitant disease or other drug therapy.

The maintenance dose of sirolimus should be reduced in patients with hepatic impairment [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)].

Dosage adjustment is not required in patients with renal impairment [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)].

Reports of overdose with sirolimus have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section [see Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "Reports of overdose with sirolimus have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section [see Adverse Reactions (6)]." }

General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD50 was greater than 800 mg/kg.

{ "type": "p", "children": [], "text": "General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD50 was greater than 800 mg/kg." }

Sirolimus is an mTOR inhibitor immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone. Its molecular formula is C51H79NO13 and its molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows.

{ "type": "p", "children": [], "text": "Sirolimus is an mTOR inhibitor immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone. Its molecular formula is C51H79NO13 and its molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows." }

Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.

{ "type": "p", "children": [], "text": "Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile." }

Sirolimus is available as a tan, triangular-shaped tablet containing 0.5 mg sirolimus, as a white, triangular-shaped tablet containing 1 mg sirolimus, and as a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus.

{ "type": "p", "children": [], "text": "Sirolimus is available as a tan, triangular-shaped tablet containing 0.5 mg sirolimus, as a white, triangular-shaped tablet containing 1 mg sirolimus, and as a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus." }

The inactive ingredients in sirolimus tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl-alpha tocopherol, and other ingredients. The 0.5 mg and 2 mg dosage strengths also contain yellow iron (ferric) oxide and brown iron (ferric) oxide.

{ "type": "p", "children": [], "text": "The inactive ingredients in sirolimus tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl-alpha tocopherol, and other ingredients. The 0.5 mg and 2 mg dosage strengths also contain yellow iron (ferric) oxide and brown iron (ferric) oxide." }

Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.

Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability.

Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats. In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific.

In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.

Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.

Orally-administered sirolimus, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of organ rejection in low-to moderate-immunologic risk renal transplant patients at 6 months following transplantation compared with either azathioprine or placebo [see Clinical Studies (14.1)]. There was no demonstrable efficacy advantage of a daily maintenance dose of 5 mg with a loading dose of 15 mg over a daily maintenance dose of 2 mg with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range [see Dosage and Administration (2.5)].

Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients.

The pharmacokinetic parameters of sirolimus in low- to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in Table 4.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 4: MEAN ± SD STEADY STATE SIROLIMUS PHARMACOKINETIC PARAMETERS IN LOW- TO MODERATE-IMMUNOLOGIC RISK ADULT RENAL TRANSPLANT PATIENTS FOLLOWING SIROLIMUS 2 MG DAILY<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-9" name="footnote-reference-9">†</a></span> </caption> <col width="49%"/> <col width="26%"/> <col width="26%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>In presence of cyclosporine administered 4 hours before sirolimus dosing.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">†</a> </dt> <dd>Based on data collected at months 1 and 3 post-transplantation.</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">‡</a> </dt> <dd>Average C<span class="Sub">min</span> over 6 months.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"></td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First">Multiple Dose (daily dose)</p> </td> </tr> <tr> <td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">Solution</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Tablets</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">C<span class="Sub">max</span> (ng/mL)</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">14.4 ± 5.3</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">15.0 ± 4.9</p> </td> </tr> <tr> <td valign="top"> <p class="First">t<span class="Sub">max</span> (hr)</p> </td><td align="center" valign="top"> <p class="First">2.1 ± 0.8</p> </td><td align="center" valign="top"> <p class="First">3.5 ± 2.4</p> </td> </tr> <tr> <td valign="top"> <p class="First">AUC (ng∙h/mL)</p> </td><td align="center" valign="top"> <p class="First">194 ± 78</p> </td><td align="center" valign="top"> <p class="First">230 ± 67</p> </td> </tr> <tr> <td valign="top"> <p class="First">C<span class="Sub">min</span> (ng/mL)<a class="Sup" href="#footnote-10" name="footnote-reference-10">‡</a> </p> </td><td align="center" valign="top"> <p class="First">7.1 ± 3.5</p> </td><td align="center" valign="top"> <p class="First">7.6 ± 3.1</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">CL/F (mL/h/kg)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">173 ± 50</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">139 ± 63</p> </td> </tr> </tbody> </table></div>

Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUCτ,ss. Upon repeated, twice-daily administration without an initial loading dose in a multiple-dose study, the average trough concentration of sirolimus increases approximately 2- to 3-fold over the initial 6 days of therapy, at which time steady-state is reached. A loading dose of 3 times the maintenance dose will provide near steady-state concentrations within 1 day in most patients [see Dosage and Administration (2.3, 2.5), Warning and Precautions (5.17)].

Absorption

Following administration of sirolimus oral solution, the mean times to peak concentration (tmax) of sirolimus are approximately 1 hour and 2 hours in healthy subjects and renal transplant patients, respectively. The systemic availability of sirolimus is low, and was estimated to be approximately 14% after the administration of sirolimus oral solution. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of sirolimus oral solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m2.

Food Effects

To minimize variability in sirolimus concentrations, both sirolimus oral solution and tablets should be taken consistently with or without food [see Dosage and Administration (2)]. In healthy subjects, a high-fat meal (861.8 kcal, 54.9% kcal from fat) increased the mean total exposure (AUC) of sirolimus by 23 to 35%, compared with fasting. The effect of food on the mean sirolimus Cmax was inconsistent depending on the sirolimus dosage form evaluated.

Distribution

The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (Vss/F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins, mainly serum albumin (97%), α1-acid glycoprotein, and lipoproteins.

Metabolism

Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations [see Warnings and Precautions (5.20) and Drug Interactions (7)]. Sirolimus is extensively metabolized by O-demethylation and/or hydroxylation. Seven (7) major metabolites, including hydroxy, demethyl, and hydroxydemethyl, are identifiable in whole blood. Some of these metabolites are also detectable in plasma, fecal, and urine samples. Sirolimus is the major component in human whole blood and contributes to more than 90% of the immunosuppressive activity.

Excretion

After a single dose of [14C] sirolimus oral solution in healthy volunteers, the majority (91%) of radioactivity was recovered from the feces, and only a minor amount (2.2%) was excreted in urine. The mean ± SD terminal elimination half-life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours.

Sirolimus Concentrations (Chromatographic Equivalent) Observed in Phase 3 Clinical Studies

The following sirolimus concentrations (chromatographic equivalent) were observed in phase 3 clinical studies for prophylaxis of organ rejection in de novo renal transplant patients [see Clinical Studies (14)].

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 5: SIROLIMUS WHOLE BLOOD TROUGH CONCENTRATIONS OBSERVED IN RENAL TRANSPLANT PATIENTS ENROLLED IN PHASE 3 STUDIES</span> </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-11" name="footnote-11">*</a> </dt> <dd>Months 4 through 12</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">†</a> </dt> <dd>Up to Week 2; observed CsA C<span class="Sub">min</span> was 217 (56 – 432) ng/mL</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">‡</a> </dt> <dd>Week 2 to Week 26; observed CsA C<span class="Sub">min</span> range was 174 (71 – 288) ng/mL </dd> <dt> <a href="#footnote-reference-14" name="footnote-14">§</a> </dt> <dd>Week 26 to Week 52; observed CsA C<span class="Sub">min</span> was 136 (54.5 – 218) ng/mL</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule" rowspan="2" valign="bottom"> <p class="First">Patient Population (Study number)</p> </td><td align="center" class="Toprule" rowspan="2" valign="middle"> <p class="First">Treatment</p> </td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First">Year 1</p> </td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First">Year 3</p> </td> </tr> <tr> <td align="center" class="Botrule" valign="top"> <p class="First">Mean<br/>(ng/mL)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">10<span class="Sup">th</span> – 90<span class="Sup">th</span> percentiles<br/>(ng/mL)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Mean<br/>(ng/mL)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">10<span class="Sup">th</span> – 90<span class="Sup">th</span> percentiles<br/>(ng/mL)</p> </td> </tr> <tr> <td class="Botrule Toprule" rowspan="2" valign="top"> <p class="First">Low-to-moderate risk<br/>(Studies 1 &amp; 2)</p> </td><td class="Botrule Toprule" valign="top"> <p class="First">Sirolimus<br/>(2 mg/day) + CsA</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">7.2</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">3.6 – 11</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">–</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">–</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Sirolimus<br/>(5 mg/day) + CsA</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8 – 22</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">–</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">–</p> </td> </tr> <tr> <td class="Botrule" rowspan="2" valign="top"> <p class="First">Low-to-moderate risk<br/>(Study 3)</p> </td><td class="Botrule" valign="top"> <p class="First">Sirolimus + CsA</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8.6</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">5 – 13<a class="Sup" href="#footnote-11" name="footnote-reference-11">*</a> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">9.1</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">5.4 – 14</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Sirolimus alone</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14 – 22<a class="Sup" href="#footnote-11">*</a> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">11 – 22</p> </td> </tr> <tr> <td rowspan="2" valign="top"> <p class="First">High risk<br/>(Study 4)</p> </td><td valign="top"> <p class="First">Sirolimus + CsA</p> </td><td align="center" valign="top"> <p class="First">15.7</p> </td><td align="center" valign="top"> <p class="First">5.4 – 27.3<a class="Sup" href="#footnote-12" name="footnote-reference-12">†</a> </p> </td><td align="center" valign="top"> <p class="First">–</p> </td><td align="center" valign="top"> <p class="First">–</p> </td> </tr> <tr> <td valign="top"></td><td align="center" valign="top"> <p class="First">11.8</p> </td><td align="center" valign="top"> <p class="First">6.2 – 16.9<a class="Sup" href="#footnote-13" name="footnote-reference-13">‡</a> </p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr class="Last"> <td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">11.5</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">6.3 – 17.3<a class="Sup" href="#footnote-14" name="footnote-reference-14">§</a> </p> </td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td> </tr> </tbody> </table></div>

The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state required approximately 6 weeks. Following cyclosporine withdrawal, larger sirolimus doses were required due to the absence of the inhibition of sirolimus metabolism and transport by cyclosporine and to achieve higher target sirolimus trough concentrations during concentration-controlled administration [see Dosage and Administration (2.1), Drug Interactions (7.1)].

Lymphangioleiomyomatosis

In a clinical trial of patients with lymphangioleiomyomatosis, the median whole blood sirolimus trough concentration after 3 weeks of receiving sirolimus tablets at a dose of 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to 9.0 ng/mL; n = 37).

Pharmacokinetics in Specific Populations

Hepatic Impairment

Sirolimus was administered as a single, oral dose to subjects with normal hepatic function and to patients with Child-Pugh classification A (mild), B (moderate), or C (severe) hepatic impairment. Compared with the values in the normal hepatic function group, the patients with mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, with no statistically significant differences in mean Cmax. As the severity of hepatic impairment increased, there were steady increases in mean sirolimus t1/2, and decreases in the mean sirolimus clearance normalized for body weight (CL/F/kg).

The maintenance dose of sirolimus should be reduced by approximately one third in patients with mild to moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment [see Dosage and Administration (2.5)]. It is not necessary to modify the sirolimus loading dose in patients with mild, moderate, and severe hepatic impairment. Therapeutic drug monitoring is necessary in all patients with hepatic impairment [see Dosage and Administration (2.7)].

Renal Impairment

The effect of renal impairment on the pharmacokinetics of sirolimus is not known. However, there is minimal (2.2%) renal excretion of the drug or its metabolites in healthy volunteers. The loading and the maintenance doses of sirolimus need not be adjusted in patients with renal impairment [see Dosage and Administration (2.6)].

Pediatric Renal Transplant Patients

Sirolimus pharmacokinetic data were collected in concentration-controlled trials of pediatric renal transplant patients who were also receiving cyclosporine and corticosteroids. The target ranges for trough concentrations were either 10–20 ng/mL for the 21 children receiving tablets, or 5–15 ng/mL for the one child receiving oral solution. The children aged 6–11 years (n = 8) received mean ± SD doses of 1.75 ± 0.71 mg/day (0.064 ± 0.018 mg/kg, 1.65 ± 0.43 mg/m2). The children aged 12–18 years (n = 14) received mean ± SD doses of 2.79 ± 1.25 mg/day (0.053 ± 0.0150 mg/kg, 1.86 ± 0.61 mg/m2). At the time of sirolimus blood sampling for pharmacokinetic evaluation, the majority (80%) of these pediatric patients received the sirolimus dose at 16 hours after the once-daily cyclosporine dose. See Table 6 below.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 6: SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC RENAL TRANSPLANT PATIENTS (MULTIPLE-DOSE CONCENTRATION CONTROL)<a class="Sup" href="#footnote-15" name="footnote-reference-15">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-16" name="footnote-reference-16">†</a></span> </caption> <col width="7%"/> <col width="6%"/> <col width="11%"/> <col width="13%"/> <col width="9%"/> <col width="13%"/> <col width="14%"/> <col width="14%"/> <col width="13%"/> <tfoot> <tr> <td align="left" colspan="9"> <dl class="Footnote"> <dt> <a href="#footnote-reference-15" name="footnote-15">*</a> </dt> <dd>Sirolimus co-administered with cyclosporine oral solution [MODIFIED] (e.g., Neoral<span class="Sup">®</span> Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral<span class="Sup">®</span> Soft Gelatin Capsules).</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">†</a> </dt> <dd>As measured by Liquid Chromatographic/Tandem Mass Spectrometric Method (LC/MS/MS)</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">‡</a> </dt> <dd>Oral-dose clearance adjusted by either body weight (kg) or body surface area (m<span class="Sup">2</span>).</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule" valign="bottom"> <p class="First">Age</p> </td><td align="center" class="Toprule" valign="bottom"> <p class="First">n</p> </td><td align="center" class="Toprule" valign="bottom"> <p class="First">Body weight</p> </td><td align="center" class="Toprule" valign="bottom"> <p class="First">C<span class="Sub">max,ss</span> </p> </td><td align="center" class="Toprule" valign="bottom"> <p class="First">t<span class="Sub">max,ss</span> </p> </td><td align="center" class="Toprule" valign="bottom"> <p class="First">C<span class="Sub">min,ss</span> </p> </td><td align="center" class="Toprule" valign="bottom"> <p class="First">AUC<span class="Sub">т,ss</span> </p> </td><td align="center" class="Toprule" valign="bottom"> <p class="First">CL/F<a class="Sup" href="#footnote-17" name="footnote-reference-17">‡</a> </p> </td><td align="center" class="Toprule" valign="bottom"> <p class="First">CL/F<a class="Sup" href="#footnote-17">‡</a> </p> </td> </tr> <tr> <td align="center" class="Botrule" valign="top"> <p class="First">(y)</p> </td><td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">(kg)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(ng/mL)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(h)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(ng/mL)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(ng∙h/mL)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(mL/h/kg)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(L/h/m<span class="Sup">2</span>)</p> </td> </tr> <tr> <td align="center" class="Toprule" valign="top"> <p class="First">6–11</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">27 ± 10</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">22.1 ± 8.9</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">5.88 ± 4.05</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">10.6 ± 4.3</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">356 ± 127</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">214 ± 129</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">5.4 ± 2.8</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule" valign="top"> <p class="First">12–18</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">52 ± 15</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">34.5 ± 12.2</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">2.7 ± 1.5</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14.7 ± 8.6</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">466 ± 236</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">136 ± 57</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">4.7 ± 1.9</p> </td> </tr> </tbody> </table></div>

Table 7 below summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically impaired renal function.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 7: SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC PATIENTS WITH END-STAGE KIDNEY DISEASE MAINTAINED ON HEMODIALYSIS OR PERITONEAL DIALYSIS (1, 3, 9, 15 mg/m<span class="Sup">2</span> SINGLE DOSE)<a class="Sup" href="#footnote-18" name="footnote-reference-18">*</a></span> </caption> <col width="24%"/> <col width="7%"/> <col width="20%"/> <col width="14%"/> <col width="35%"/> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-18" name="footnote-18">*</a> </dt> <dd>All subjects received sirolimus oral solution.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="top"> <p class="First">Age Group (y)</p> </td><td class="Botrule Toprule" valign="top"> <p class="First">n</p> </td><td class="Botrule Toprule" valign="top"> <p class="First">t<span class="Sub">max</span> (h)</p> </td><td class="Botrule Toprule" valign="top"> <p class="First">t<span class="Sub">1/2</span> (h)</p> </td><td class="Botrule Toprule" valign="top"> <p class="First">CL/F/WT (mL/h/kg)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">5–11</p> </td><td class="Toprule" valign="top"> <p class="First">9</p> </td><td class="Toprule" valign="top"> <p class="First">1.1 ± 0.5</p> </td><td class="Toprule" valign="top"> <p class="First">71 ± 40</p> </td><td class="Toprule" valign="top"> <p class="First">580 ± 450</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">12–18</p> </td><td class="Botrule" valign="top"> <p class="First">11</p> </td><td class="Botrule" valign="top"> <p class="First">0.79 ± 0.17</p> </td><td class="Botrule" valign="top"> <p class="First">55 ± 18</p> </td><td class="Botrule" valign="top"> <p class="First">450 ± 232</p> </td> </tr> </tbody> </table></div>

Geriatric

Clinical studies of sirolimus did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. After the administration of sirolimus oral solution or tablets, sirolimus trough concentration data in renal transplant patients >65 years of age were similar to those in the adult population 18 to 65 years of age.

Gender

Sirolimus clearance in males was 12% lower than that in females; male subjects had a significantly longer t1/2 than did female subjects (72.3 hours versus 61.3 hours). Dose adjustments based on gender are not recommended.

Race

In the phase 3 trials for the prophylaxis of organ rejection following renal transplantation using sirolimus solution or tablets and cyclosporine oral solution [MODIFIED] (e.g., Neoral® Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral® Soft Gelatin Capsules) [see Clinical Studies (14)], there were no significant differences in mean trough sirolimus concentrations over time between Black (n = 190) and non-Black (n = 852) patients during the first 6 months after transplantation.

Drug-Drug Interactions

Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below.

Cyclosporine: Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). Sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased [see Dosage and Administration (2.2), Drug Interactions (7.1)].

In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus tablets either simultaneously or 4 hours after a 300-mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, mean Cmax and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimus Cmax and AUC were both increased by only 33% compared with administration of sirolimus alone.

In a single dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus oral solution either simultaneously or 4 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean Cmax and AUC of sirolimus, following simultaneous administration were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus Cmax and AUC were increased by only 37% and 80%, respectively, compared with administration of sirolimus alone.

In a single-dose cross-over drug-drug interaction study, 33 healthy volunteers received 5 mg sirolimus oral solution alone, 2 hours before, and 2 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). When given 2 hours before Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus Cmax and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean Cmax and AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone.

Mean cyclosporine Cmax and AUC were not significantly affected when sirolimus oral solution was given simultaneously or when administered 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after Neoral® in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were needed to maintain target cyclosporine concentration.

In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5, 1.5, and 3 mg/m2/day was administered simultaneously with Sandimmune® Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (% CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune® Oral Solution (cyclosporine oral solution) administration. However, the % CV was higher (range 85.9% – 165%) than those from previous studies.

Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary [see Drug Interactions (7.4)]. The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem.

Erythromycin: Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and erythromycin is not recommended [see Warnings and Precautions (5.20), Drug Interactions (7.2)]. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 800 mg q 8h of erythromycin as erythromycin ethylsuccinate tablets at steady state to 24 healthy volunteers significantly affected the bioavailability of sirolimus and erythromycin. Sirolimus Cmax and AUC were increased 4.4- and 4.2-fold respectively and tmax was increased by 0.4 hr. Erythromycin Cmax and AUC were increased 1.6- and 1.7-fold, respectively, and tmax was increased by 0.3 hr.

Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and ketoconazole is not recommended [see Warnings and Precautions (5.20), Drug Interactions (7.2)]. Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of sirolimus oral solution, as reflected by increases in sirolimus Cmax, tmax, and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal t½ of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations.

Rifampin: Rifampin is a strong inducer of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and rifampin is not recommended. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered [see Warnings and Precautions (5.20), Drug Interactions (7.2)]. Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20-mg dose of sirolimus oral solution, greatly decreased sirolimus AUC and Cmax by about 82% and 71%, respectively.

Verapamil: Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary; [see Drug Interactions (7.4)]. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady state to 25 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus Cmax and AUC were increased 2.3- and 2.2-fold, respectively, without substantial change in tmax. The Cmax and AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and tmax was decreased by 1.2 hr.

Drugs Which May Be Co-administered Without Dose Adjustment

Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. Sirolimus and these drugs may be co-administered without dose adjustments.

Other Drug-Drug Interactions

Co-administration of sirolimus with other known strong inhibitors of CYP3A4 and/or P-gp (such as voriconazole, itraconazole, telithromycin, or clarithromycin) or other known strong inducers of CYP3A4 and/or P-gp (such as rifabutin) is not recommended [see Warnings and Precautions (5.20), Drug Interactions (7.2)]. In patients in whom strong inhibitors or inducers of CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 should be considered.

Care should be exercised when drugs or other substances that are substrates and/or inhibitors or inducers of CYP3A4 are administered concomitantly with sirolimus. Other drugs that have the potential to increase sirolimus blood concentrations include (but are not limited to):

Other drugs that have the potential to decrease sirolimus concentrations include (but are not limited to):

Other Drug-Food Interactions

Grapefruit juice reduces CYP3A4-mediated drug metabolism. Grapefruit juice must not be taken with sirolimus [see Drug Interactions (7.3)].

Drug-Herb Interactions

St. John's Wort (Hypericum perforatum) induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. John's Wort in patients receiving sirolimus could result in reduced sirolimus concentrations [see Drug Interactions (7.4)].

Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings.

Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.

When female rats were treated by oral gavage with sirolimus and mated to untreated males, female fertility was decreased at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) due to decreased implantation. In addition, reduced ovary and uterus weight were observed. The NOAEL for female rat fertility was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg).

When male rats were treated by oral gavage with sirolimus and mated to untreated females, male fertility was decreased at 2 mg/kg (9.7-fold the clinical dose of 2 mg, on a body surface area basis). Atrophy of testes, epididymides, prostate, seminiferous tubules, and reduced sperm counts were observed. The NOAEL for male rat fertility was 0.5 mg/kg (2.5-fold the clinical dose of 2 mg).

Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at 0.1 mg/kg (1-fold the clinical dose of 2 mg, on a body surface area basis).

Sirolimus Oral Solution

The safety and efficacy of sirolimus oral solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials. These studies compared two dose levels of sirolimus oral solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids. Study 1 was conducted in the United States at 38 sites. Seven hundred nineteen (719) patients were enrolled in this trial and randomized following transplantation; 284 were randomized to receive sirolimus oral solution 2 mg/day; 274 were randomized to receive sirolimus oral solution 5 mg/day, and 161 to receive azathioprine 2–3 mg/kg/day. Study 2 was conducted in Australia, Canada, Europe, and the United States, at a total of 34 sites. Five hundred seventy-six (576) patients were enrolled in this trial and randomized before transplantation; 227 were randomized to receive sirolimus oral solution 2 mg/day; 219 were randomized to receive sirolimus oral solution 5 mg/day, and 130 to receive placebo. In both studies, the use of antilymphocyte antibody induction therapy was prohibited. In both studies, the primary efficacy endpoint was the rate of efficacy failure in the first 6 months after transplantation. Efficacy failure was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft loss, or death.

The tables below summarize the results of the primary efficacy analyses from these trials. Sirolimus oral solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of efficacy failure (statistically significant at the <0.025 level; nominal significance level adjusted for multiple [2] dose comparisons) at 6 months following transplantation compared with both azathioprine and placebo.

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 8: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 24 MONTHS FOR STUDY 1<a class="Sup" href="#footnote-19" name="footnote-reference-19">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-20" name="footnote-reference-20">†</a></span> </caption> <col width="32%"/> <col width="17%"/> <col width="17%"/> <col width="19%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-19" name="footnote-19">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-20" name="footnote-20">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-21" name="footnote-21">‡</a> </dt> <dd>Primary endpoint.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First">Parameter</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Oral Solution<br/>2 mg/day<br/>(n = 284)</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Oral Solution<br/>5 mg/day<br/>(n = 274)</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Azathioprine<br/>2–3 mg/kg/day<br/>(n = 161)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Efficacy failure at 6 months</span><a class="Sup" href="#footnote-21" name="footnote-reference-21">‡</a> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First">18.7</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">16.8</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">32.3</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Italics"> <br/>Components of efficacy failure</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Biopsy-proven acute rejection</p> </td><td align="center" valign="top"> <p class="First">16.5</p> </td><td align="center" valign="top"> <p class="First">11.3</p> </td><td align="center" valign="top"> <p class="First">29.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Graft loss</p> </td><td align="center" valign="top"> <p class="First">1.1</p> </td><td align="center" valign="top"> <p class="First">2.9</p> </td><td align="center" valign="top"> <p class="First">2.5</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Death</p> </td><td align="center" valign="top"> <p class="First">0.7</p> </td><td align="center" valign="top"> <p class="First">1.8</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Lost to follow-up</p> </td><td align="center" valign="top"> <p class="First">0.4</p> </td><td align="center" valign="top"> <p class="First">0.7</p> </td><td align="center" valign="top"> <p class="First">0.6</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold"> <br/>Efficacy failure at 24 months</span> </p> </td><td align="center" valign="top"> <p class="First"> <br/>32.8</p> </td><td align="center" valign="top"> <p class="First"> <br/>25.9</p> </td><td align="center" valign="top"> <p class="First"> <br/>36.0</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Italics"> <br/>Components of efficacy failure</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Biopsy-proven acute rejection</p> </td><td align="center" valign="top"> <p class="First">23.6</p> </td><td align="center" valign="top"> <p class="First">17.5</p> </td><td align="center" valign="top"> <p class="First">32.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Graft loss</p> </td><td align="center" valign="top"> <p class="First">3.9</p> </td><td align="center" valign="top"> <p class="First">4.7</p> </td><td align="center" valign="top"> <p class="First">3.1</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Death</p> </td><td align="center" valign="top"> <p class="First">4.2</p> </td><td align="center" valign="top"> <p class="First">3.3</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Lost to follow-up</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1.1</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.4</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.6</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 9: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 36 MONTHS FOR STUDY 2<a class="Sup" href="#footnote-22" name="footnote-reference-22">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-23" name="footnote-reference-23">†</a></span> </caption> <col width="32%"/> <col width="18%"/> <col width="18%"/> <col width="17%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-22" name="footnote-22">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-23" name="footnote-23">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-24" name="footnote-24">‡</a> </dt> <dd>Primary endpoint.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First">Parameter</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Oral Solution<br/>2 mg/day<br/>(n = 227)</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Oral Solution<br/>5 mg/day<br/>(n = 219)</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Placebo<br/>(n = 130)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Efficacy failure at 6 months</span><a class="Sup" href="#footnote-24" name="footnote-reference-24">‡</a> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First">30.0</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">25.6</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">47.7</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Italics"> <br/>Components of efficacy failure</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Biopsy-proven acute rejection</p> </td><td align="center" valign="top"> <p class="First">24.7</p> </td><td align="center" valign="top"> <p class="First">19.2</p> </td><td align="center" valign="top"> <p class="First">41.5</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Graft loss</p> </td><td align="center" valign="top"> <p class="First">3.1</p> </td><td align="center" valign="top"> <p class="First">3.7</p> </td><td align="center" valign="top"> <p class="First">3.9</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Death</p> </td><td align="center" valign="top"> <p class="First">2.2</p> </td><td align="center" valign="top"> <p class="First">2.7</p> </td><td align="center" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Lost to follow-up</p> </td><td align="center" valign="top"> <p class="First">0</p> </td><td align="center" valign="top"> <p class="First">0</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold"> <br/>Efficacy failure at 36 months</span> </p> </td><td align="center" valign="top"> <p class="First"> <br/>44.1</p> </td><td align="center" valign="top"> <p class="First"> <br/>41.6</p> </td><td align="center" valign="top"> <p class="First"> <br/>54.6</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Italics"> <br/>Components of efficacy failure</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Biopsy-proven acute rejection</p> </td><td align="center" valign="top"> <p class="First">32.2</p> </td><td align="center" valign="top"> <p class="First">27.4</p> </td><td align="center" valign="top"> <p class="First">43.9</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Graft loss</p> </td><td align="center" valign="top"> <p class="First">6.2</p> </td><td align="center" valign="top"> <p class="First">7.3</p> </td><td align="center" valign="top"> <p class="First">4.6</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Death</p> </td><td align="center" valign="top"> <p class="First">5.7</p> </td><td align="center" valign="top"> <p class="First">5.9</p> </td><td align="center" valign="top"> <p class="First">5.4</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Lost to follow-up</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.9</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.8</p> </td> </tr> </tbody> </table></div>

Patient and graft survival at 1 year were co-primary endpoints. The following table shows graft and patient survival at 1 and 2 years in Study 1, and 1 and 3 years in Study 2. The graft and patient survival rates were similar in patients treated with sirolimus and comparator-treated patients.

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 10: GRAFT AND PATIENT SURVIVAL (%) FOR STUDY 1 (12 AND 24 MONTHS) AND STUDY 2 (12 AND 36 MONTHS)<a class="Sup" href="#footnote-25" name="footnote-reference-25">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-26" name="footnote-reference-26">†</a></span> </caption> <col width="18%"/> <col width="17%"/> <col width="17%"/> <col width="18%"/> <col width="16%"/> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-25" name="footnote-25">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-26" name="footnote-26">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First">  Parameter</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Oral Solution<br/>2 mg/day</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Oral Solution<br/>5 mg/day</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Azathioprine<br/>2–3 mg/kg/day</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Placebo</p> </td> </tr> <tr> <td class="Botrule Toprule" valign="top"> <p class="First">Study 1</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">(n = 284)</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">(n = 274)</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">(n = 161)</p> </td><td class="Botrule Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Graft survival</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">94.7</p> </td><td align="center" valign="top"> <p class="First">92.7</p> </td><td align="center" valign="top"> <p class="First">93.8</p> </td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 24</p> </td><td align="center" valign="top"> <p class="First">85.2</p> </td><td align="center" valign="top"> <p class="First">89.1</p> </td><td align="center" valign="top"> <p class="First">90.1</p> </td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Patient survival</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">97.2</p> </td><td align="center" valign="top"> <p class="First">96.0</p> </td><td align="center" valign="top"> <p class="First">98.1</p> </td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 24</p> </td><td align="center" valign="top"> <p class="First">92.6</p> </td><td align="center" valign="top"> <p class="First">94.9</p> </td><td align="center" valign="top"> <p class="First">96.3</p> </td><td valign="top"></td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Study 2</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(n = 227)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(n = 219)</p> </td><td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">(n = 130)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Graft survival</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">89.9</p> </td><td align="center" valign="top"> <p class="First">90.9</p> </td><td valign="top"></td><td align="center" valign="top"> <p class="First">87.7</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Month 36</p> </td><td align="center" valign="top"> <p class="First">81.1</p> </td><td align="center" valign="top"> <p class="First">79.9</p> </td><td valign="top"></td><td align="center" valign="top"> <p class="First">80.8</p> </td> </tr> <tr> <td valign="top"> <p class="First">Patient survival</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">96.5</p> </td><td align="center" valign="top"> <p class="First">95.0</p> </td><td valign="top"></td><td align="center" valign="top"> <p class="First">94.6</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Month 36</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">90.3</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">89.5</p> </td><td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">90.8</p> </td> </tr> </tbody> </table></div>

The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with sirolimus compared with the control groups included a reduction in all grades of rejection.

In Study 1, which was prospectively stratified by race within center, efficacy failure was similar for sirolimus oral solution 2 mg/day and lower for sirolimus oral solution 5 mg/day compared with azathioprine in Black patients. In Study 2, which was not prospectively stratified by race, efficacy failure was similar for both sirolimus oral solution doses compared with placebo in Black patients. The decision to use the higher dose of sirolimus oral solution in Black patients must be weighed against the increased risk of dose-dependent adverse events that were observed with the sirolimus oral solution 5-mg dose [see Adverse Reactions (6.1)].

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 11: PERCENTAGE OF EFFICACY FAILURE BY RACE AT 6 MONTHS<a class="Sup" href="#footnote-27" name="footnote-reference-27">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-28" name="footnote-reference-28">†</a></span> </caption> <col width="18%"/> <col width="17%"/> <col width="17%"/> <col width="18%"/> <col width="16%"/> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-27" name="footnote-27">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-28" name="footnote-28">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First">  Parameter</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Oral Solution<br/>2 mg/day</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Oral Solution<br/>5 mg/day</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Azathioprine<br/>2–3 mg/kg/day</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Placebo</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Study 1</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Black (n = 166)</p> </td><td align="center" valign="top"> <p class="First">34.9 (n = 63)</p> </td><td align="center" valign="top"> <p class="First">18.0 (n = 61)</p> </td><td align="center" valign="top"> <p class="First">33.3 (n = 42)</p> </td><td valign="top"></td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">  Non-Black<br/>  (n = 553)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14.0 (n = 221)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">16.4 (n = 213)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">31.9 (n = 119)</p> </td><td class="Botrule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Study 2</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Black (n = 66)</p> </td><td align="center" valign="top"> <p class="First">30.8 (n = 26)</p> </td><td align="center" valign="top"> <p class="First">33.7 (n = 27)</p> </td><td valign="top"></td><td align="center" valign="top"> <p class="First">38.5 (n = 13)</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Non-Black<br/>  (n = 510)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">29.9 (n = 201)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">24.5 (n = 192)</p> </td><td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">48.7 (n = 117)</p> </td> </tr> </tbody> </table></div>

Mean glomerular filtration rates (GFR) post-transplant were calculated by using the Nankivell equation at 12 and 24 months for Study 1, and 12 and 36 months for Study 2. Mean GFR was lower in patients treated with cyclosporine and sirolimus oral solution compared with those treated with cyclosporine and the respective azathioprine or placebo control.

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 12: OVERALL CALCULATED GLOMERULAR FILTRATION RATES (Mean ± SEM, cc/min) BY NANKIVELL EQUATION POST-TRANSPLANT<a class="Sup" href="#footnote-29" name="footnote-reference-29">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-30" name="footnote-reference-30">†</a></span> </caption> <col width="17%"/> <col width="17%"/> <col width="17%"/> <col width="18%"/> <col width="16%"/> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-29" name="footnote-29">*</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-30" name="footnote-30">†</a> </dt> <dd>Patients who had a graft loss were included in the analysis with GFR set to 0.0.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First">Parameter</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Oral Solution<br/>2 mg/day</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Oral Solution<br/>5 mg/day</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Azathioprine<br/>2–3 mg/kg/day</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Placebo</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Study 1</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">57.4 ± 1.3<br/>(n = 269)</p> </td><td align="center" valign="top"> <p class="First">54.6 ± 1.3<br/>(n = 248)</p> </td><td align="center" valign="top"> <p class="First">64.1 ± 1.6)<br/>(n = 149)</p> </td><td valign="top"></td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">  Month 24</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">58.4 ± 1.5<br/>(n = 221)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">52.6 ± 1.5<br/>(n = 222)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">62.4 ± 1.9<br/>(n = 132)</p> </td><td class="Botrule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Study 2</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">52.4 ± 1.5<br/>(n = 211)</p> </td><td align="center" valign="top"> <p class="First">51.5 ± 1.5<br/>(n = 199)</p> </td><td valign="top"></td><td align="center" valign="top"> <p class="First">58.0 ± 2.1<br/>(n = 117)</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Month 36</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">48.1 ± 1.8<br/>(n = 183)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">46.1 ± 2.0<br/>(n = 177)</p> </td><td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">53.4 ± 2.7<br/>(n = 102)</p> </td> </tr> </tbody> </table></div>

Within each treatment group in Studies 1 and 2, mean GFR at one-year post-transplant was lower in patients who experienced at least one episode of biopsy-proven acute rejection, compared with those who did not.

Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels [see Warnings and Precautions (5.8)].

Sirolimus Tablets

The safety and efficacy of sirolimus oral solution and sirolimus tablets for the prevention of organ rejection following renal transplantation were demonstrated to be clinically equivalent in a randomized, multicenter, controlled trial [see Clinical Pharmacology (12.3)].

The safety and efficacy of sirolimus as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months after renal transplantation. Study 3 was a randomized, multicenter, controlled trial conducted at 57 centers in Australia, Canada, and Europe. Five hundred twenty-five (525) patients were enrolled. All patients in this study received the tablet formulation. This study compared patients who were administered sirolimus, cyclosporine, and corticosteroids continuously with patients who received this same standardized therapy for the first 3 months after transplantation (pre-randomization period) followed by the withdrawal of cyclosporine. During cyclosporine withdrawal, the sirolimus dosages were adjusted to achieve targeted sirolimus whole blood trough concentration ranges (16 to 24 ng/mL until month 12, then 12 to 20 ng/mL thereafter, expressed as chromatographic assay values). At 3 months, 430 patients were equally randomized to either continue sirolimus with cyclosporine therapy or to receive sirolimus as a maintenance regimen following cyclosporine withdrawal.

Eligibility for randomization included no Banff Grade 3 acute rejection or vascular rejection episode in the 4 weeks before random assignment, serum creatinine ≤4.5 mg/dL, and adequate renal function to support cyclosporine withdrawal (in the opinion of the investigator). The primary efficacy endpoint was graft survival at 12 months after transplantation. Secondary efficacy endpoints were the rate of biopsy-confirmed acute rejection, patient survival, incidence of efficacy failure (defined as the first occurrence of either biopsy-proven acute rejection, graft loss, or death), and treatment failure (defined as the first occurrence of either discontinuation, acute rejection, graft loss, or death).

The following table summarizes the resulting graft and patient survival at 12, 24, and 36 months for this trial. At 12, 24, and 36 months, graft and patient survival were similar for both groups.

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 13: GRAFT AND PATIENT SURVIVAL (%): STUDY 3<a class="Sup" href="#footnote-31" name="footnote-reference-31">*</a></span> </caption> <col width="28%"/> <col width="29%"/> <col width="28%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-31" name="footnote-31">*</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-32" name="footnote-32">†</a> </dt> <dd>Primary efficacy endpoint.</dd> <dt> <a href="#footnote-reference-33" name="footnote-33">‡</a> </dt> <dd>Survival including loss to follow-up as an event.</dd> <dt> <a href="#footnote-reference-34" name="footnote-34">§</a> </dt> <dd>Initial planned duration of the study. </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First">Parameter</p> </td><td align="center" class="Botrule Toprule" valign="bottom"> <p class="First">Sirolimus with Cyclosporine Therapy<br/>(n = 215)</p> </td><td align="center" class="Botrule Toprule" valign="bottom"> <p class="First">Sirolimus Following Cyclosporine Withdrawal<br/>(n = 215)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Graft Survival</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Month 12<a class="Sup" href="#footnote-32" name="footnote-reference-32">†</a> </p> </td><td align="center" valign="top"> <p class="First">95.3<a class="Sup" href="#footnote-33" name="footnote-reference-33">‡</a> </p> </td><td align="center" valign="top"> <p class="First">97.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">Month 24</p> </td><td align="center" valign="top"> <p class="First">91.6</p> </td><td align="center" valign="top"> <p class="First">94.0</p> </td> </tr> <tr> <td valign="top"> <p class="First">Month 36<a class="Sup" href="#footnote-34" name="footnote-reference-34">§</a> </p> </td><td align="center" valign="top"> <p class="First">87.0</p> </td><td align="center" valign="top"> <p class="First">91.6</p> </td> </tr> <tr> <td valign="top"> <p class="First">Patient Survival</p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Month 12</p> </td><td align="center" valign="top"> <p class="First">97.2</p> </td><td align="center" valign="top"> <p class="First">98.1</p> </td> </tr> <tr> <td valign="top"> <p class="First">Month 24</p> </td><td align="center" valign="top"> <p class="First">94.4</p> </td><td align="center" valign="top"> <p class="First">95.8</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Month 36<a class="Sup" href="#footnote-34">§</a> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">91.6</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">94.0</p> </td> </tr> </tbody> </table></div>

The following table summarizes the results of first biopsy-proven acute rejection at 12 and 36 months. There was a significant difference in first biopsy-proven rejection rates between the two groups after randomization and through 12 months. Most of the post-randomization acute rejections occurred in the first 3 months following randomization.

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 14: INCIDENCE OF FIRST BIOPSY-PROVEN ACUTE REJECTION (%) BY TREATMENT GROUP AT 36 MONTHS: STUDY 3<a class="Sup" href="#footnote-35" name="footnote-reference-35">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-36" name="footnote-reference-36">†</a></span> </caption> <col width="40%"/> <col width="22%"/> <col width="22%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-35" name="footnote-35">*</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-36" name="footnote-36">†</a> </dt> <dd>All patients received corticosteroids.</dd> <dt> <a href="#footnote-reference-37" name="footnote-37">‡</a> </dt> <dd>Randomization occurred at 3 months ± 2 weeks.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First">Period</p> </td><td align="center" class="Botrule Toprule" valign="bottom"> <p class="First">Sirolimus with Cyclosporine Therapy<br/>(n = 215)</p> </td><td align="center" class="Botrule Toprule" valign="bottom"> <p class="First">Sirolimus Following Cyclosporine Withdrawal<br/>(n = 215)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Pre-randomization<a class="Sup" href="#footnote-37" name="footnote-reference-37">‡</a> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First">9.3</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">10.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">Post-randomization through 12 months<a class="Sup" href="#footnote-37">‡</a> </p> </td><td align="center" valign="top"> <p class="First">4.2</p> </td><td align="center" valign="top"> <p class="First">9.8</p> </td> </tr> <tr> <td valign="top"> <p class="First">Post-randomization from 12 to 36 months</p> </td><td align="center" valign="top"> <p class="First">1.4</p> </td><td align="center" valign="top"> <p class="First">0.5</p> </td> </tr> <tr> <td valign="top"> <p class="First">Post-randomization through 36 months</p> </td><td align="center" valign="top"> <p class="First">5.6</p> </td><td align="center" valign="top"> <p class="First">10.2</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Total at 36 months</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14.9</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">20.5</p> </td> </tr> </tbody> </table></div>

Patients receiving renal allografts with ≥4 HLA mismatches experienced significantly higher rates of acute rejection following randomization to the cyclosporine withdrawal group, compared with patients who continued cyclosporine (15.3% versus 3.0%). Patients receiving renal allografts with ≤3 HLA mismatches demonstrated similar rates of acute rejection between treatment groups (6.8% versus 7.7%) following randomization.

The following table summarizes the mean calculated GFR in Study 3 (cyclosporine withdrawal study).

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 15: CALCULATED GLOMERULAR FILTRATION RATES (mL/min) BY NANKIVELL EQUATION AT 12, 24, AND 36 MONTHS POST-TRANSPLANT: STUDY 3<a class="Sup" href="#footnote-38" name="footnote-reference-38">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-39" name="footnote-reference-39">†</a><span class="Sup">,</span><a class="Sup" href="#footnote-40" name="footnote-reference-40">‡</a></span> </caption> <col width="28%"/> <col width="29%"/> <col width="28%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-38" name="footnote-38">*</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-39" name="footnote-39">†</a> </dt> <dd>Patients who had a graft loss were included in the analysis and had their GFR set to 0.0.</dd> <dt> <a href="#footnote-reference-40" name="footnote-40">‡</a> </dt> <dd>All patients received corticosteroids.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First">Parameter</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus with Cyclosporine Therapy</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus Following Cyclosporine Withdrawal</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Month 12</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Mean ± SEM</p> </td><td align="center" valign="top"> <p class="First">53.2 ± 1.5<br/>(n = 208)</p> </td><td align="center" valign="top"> <p class="First">59.3 ± 1.5<br/>(n = 203)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Month 24</p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Mean ± SEM</p> </td><td align="center" valign="top"> <p class="First">48.4 ± 1.7<br/>(n = 203)</p> </td><td align="center" valign="top"> <p class="First">58.4 ± 1.6<br/>(n = 201)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Month 36</p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Mean ± SEM</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">47.0 ± 1.8<br/>(n = 196)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">58.5 ± 1.9<br/>(n = 199)</p> </td> </tr> </tbody> </table></div>

The mean GFR at 12, 24, and 36 months, calculated by the Nankivell equation, was significantly higher for patients receiving sirolimus as a maintenance regimen following cyclosporine withdrawal than for those in the sirolimus with cyclosporine therapy group. Patients who had an acute rejection prior to randomization had a significantly higher GFR following cyclosporine withdrawal compared to those in the sirolimus with cyclosporine group. There was no significant difference in GFR between groups for patients who experienced acute rejection post-randomization.

Although the initial protocol was designed for 36 months, there was a subsequent amendment to extend this study. The results for the cyclosporine withdrawal group at months 48 and 60 were consistent with the results at month 36. Fifty-two percent (112/215) of the patients in the sirolimus with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR.

Sirolimus was studied in a one-year, clinical trial in high risk patients (Study 4) who were defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reasons and/or patients with high panel-reactive antibodies (PRA; peak PRA level >80%). Patients received concentration-controlled sirolimus and cyclosporine (MODIFIED), and corticosteroids per local practice. The sirolimus dose was adjusted to achieve target whole blood trough sirolimus concentrations of 10–15 ng/mL (chromatographic method) throughout the 12-month study period. The cyclosporine dose was adjusted to achieve target whole blood trough concentrations of 200–300 ng/mL through week 2, 150–200 ng/mL from week 2 to week 26, and 100–150 ng/mL from week 26 to week 52 [see Clinical Pharmacology (12.3)] for the observed trough concentrations ranges. Antibody induction was allowed per protocol as prospectively defined at each transplant center, and was used in 88.4% of patients. The study was conducted at 35 centers in the United States. A total of 224 patients received a transplant and at least one dose of sirolimus and cyclosporine and was comprised of 77.2% Black patients, 24.1% repeat renal transplant recipients, and 13.5% patients with high PRA. Efficacy was assessed with the following endpoints, measured at 12 months: efficacy failure (defined as the first occurrence of biopsy-confirmed acute rejection, graft loss, or death), first occurrence of graft loss or death, and renal function as measured by the calculated GFR using the Nankivell formula. The table below summarizes the result of these endpoints.

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 16: EFFICACY FAILURE, GRAFT LOSS OR DEATH AND CALCULATED GLOMERULAR FUNCTION RATES (mL/min) BY NANKIVELL EQUATION AT 12 MONTHS POST-TRANSPLANT: STUDY 4</span> </caption> <col width="42%"/> <col width="43%"/> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-41" name="footnote-41">*</a> </dt> <dd>Calculated glomerular filtration rate by Nankivell equation.</dd> <dt> <a href="#footnote-reference-42" name="footnote-42">†</a> </dt> <dd>Patients who had graft loss were included in this analysis with GFR set to 0.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First">  Parameter</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">Sirolimus with Cyclosporine, Corticosteroids<br/>(n = 224)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Efficacy Failure (%)</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">23.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">Graft Loss or Death (%)</p> </td><td align="center" valign="top"> <p class="First">9.8</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Renal Function (mean ± SEM)<a class="Sup" href="#footnote-41" name="footnote-reference-41">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-42" name="footnote-reference-42">†</a> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">52.6 ± 1.6<br/>(n = 222)</p> </td> </tr> </tbody> </table></div>

Patient survival at 12 months was 94.6%. The incidence of biopsy-confirmed acute rejection was 17.4% and the majority of the episodes of acute rejection were mild in severity.

Conversion from calcineurin inhibitors (CNI) to sirolimus was assessed in maintenance renal transplant patients 6 months to 10 years post-transplant (Study 5). This study was a randomized, multicenter, controlled trial conducted at 111 centers globally, including US and Europe, and was intended to show that renal function was improved by conversion from CNI to sirolimus. Eight hundred thirty (830) patients were enrolled and stratified by baseline calculated glomerular filtration rate (GFR, 20–40 mL/min versus greater than 40 mL/min). In this trial there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the sirolimus conversion arm. In addition, enrollment of patients with baseline calculated GFR less than 40 mL/min was discontinued due to a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death [see Adverse Reactions (6.4)].

This study compared renal transplant patients (6–120 months after transplantation) who were converted from calcineurin inhibitors to sirolimus, with patients who continued to receive calcineurin inhibitors. Concomitant immunosuppressive medications included mycophenolate mofetil (MMF), azathioprine (AZA), and corticosteroids. sirolimus was initiated with a single loading dose of 12–20 mg, after which dosing was adjusted to achieve a target sirolimus whole blood trough concentration of 8–20 ng/mL (chromatographic method). The efficacy endpoint was calculated GFR at 12 months post-randomization. Additional endpoints included biopsy-confirmed acute rejection, graft loss, and death. Findings in the patient stratum with baseline calculated GFR greater than 40 mL/min (sirolimus conversion, n = 497; CNI continuation, n = 246) are summarized below. There was no clinically or statistically significant improvement in Nankivell GFR compared to baseline.

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 17: RENAL FUNCTION IN STABLE RENAL TRANSPLANT PATIENTS IN PATIENTS WITH BASELINE GFR &gt;40 mL/min THE SIROLIMUS CONVERSION STUDY (STUDY 5)</span> </caption> <col width="21%"/> <col width="21%"/> <col width="22%"/> <col width="21%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Parameter</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">Sirolimus Conversion<br/>N=496</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">CNI Continuation<br/>N=245</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">Difference (95% CI)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">GFR mL/min (Nankivell) at 1 year</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">59.0</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">57.7</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">1.3 (-1.1, 3.7)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">GFR mL/min (Nankivell) at 2 year</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">53.7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">52.1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.6 (-1.4, 4.6)</p> </td> </tr> </tbody> </table></div>

The rates of acute rejection, graft loss, and death were similar at 1 and 2 years. Treatment-emergent adverse events occurred more frequently during the first 6 months after sirolimus conversion. The rates of pneumonia were significantly higher for the sirolimus conversion group.

While the mean and median values for urinary protein to creatinine ratio were similar between treatment groups at baseline, significantly higher mean and median levels of urinary protein excretion were seen in the sirolimus conversion arm at 1 year and at 2 years, as shown in the table below [see Warnings and Precautions (5.9)]. In addition, when compared to patients who continued to receive calcineurin inhibitors, a higher percentage of patients had urinary protein to creatinine ratios >1 at 1 and 2 years after sirolimus conversion. This difference was seen in both patients who had a urinary protein to creatinine ratio ≤1 and those who had a protein to creatinine ratio >1 at baseline. More patients in the sirolimus conversion group developed nephrotic range proteinuria, as defined by a urinary protein to creatinine ratio >3.5 (46/482 [9.5%] versus 9/239 [3.8%]), even when the patients with baseline nephrotic range proteinuria were excluded. The rate of nephrotic range proteinuria was significantly higher in the sirolimus conversion group compared to the calcineurin inhibitor continuation group with baseline urinary protein to creatinine ratio >1 (13/29 versus 1/14), excluding patients with baseline nephrotic range proteinuria.

<div class="scrollingtable"><table width="75%"> <caption> <span>TABLE 18: MEAN AND MEDIAN VALUES FOR URINARY PROTEIN TO CREATININE RATIO (mg/mg) BETWEEN TREATMENT GROUPS AT BASELINE, 1 AND 2 YEARS IN THE STRATUM WITH BASELINE CALCULATED GFR &gt;40 mL/min</span> </caption> <col width="13%"/> <col width="8%"/> <col width="11%"/> <col width="12%"/> <col width="9%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Study period</p> </td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"> <p class="First">Sirolimus Conversion</p> </td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="top"> <p class="First">CNI Continuation</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">N</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Mean ± SD</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Median</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">N</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Mean ± SD</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Median</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">p-value</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Baseline</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">410</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">0.35 ± 0.76</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">0.13</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">207</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">0.28 ± 0.61</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">0.11</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">0.381</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 year</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">423</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.88 ± 1.61</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.31</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">203</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.37 ± 0.88</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">&lt;0.001</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 years</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">373</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.86 ± 1.48</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.32</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">190</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.47 ± 0.98</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">&lt;0.001</p> </td> </tr> </tbody> </table></div>

The above information should be taken into account when considering conversion from calcineurin inhibitors to sirolimus in stable renal transplant patients due to the lack of evidence showing that renal function improves following conversion, and the finding of a greater increment in urinary protein excretion, and an increased incidence of treatment-emergent nephrotic range proteinuria following conversion to sirolimus. This was particularly true among patients with existing abnormal urinary protein excretion prior to conversion.

In an open-label, randomized, comparative, multicenter study where kidney transplant patients were either converted from tacrolimus to sirolimus 3 to 5 months post-transplant (sirolimus group) or remained on tacrolimus, there was no significant difference in renal function at 2 years post-transplant. Overall, 44/131 (33.6%) discontinued treatment in the sirolimus group versus 12/123 (9.8%) in the tacrolimus group. More patients reported adverse events 130/131 (99.2%) versus 112/123 (91.1%) and more patients reported discontinuations from the treatment due to adverse events 28/131 (21.4%) versus 4/123 (3.3%) in the sirolimus group compared to the tacrolimus group.

The incidence of biopsy-confirmed acute rejection was higher for patients in the sirolimus group 11/131 (8.4%) compared to the tacrolimus group 2/123 (1.6%) through 2 years post-transplant. The rate of new-onset diabetes mellitus post-randomization, defined as 30 days or longer of continuous or at least 25 days non-stop (without gap) use of any diabetic treatment after randomization, a fasting glucose ≥126 mg/dL or a non-fasting glucose ≥200 mg/dL, was higher in the sirolimus group 15/82 (18.3%) compared to the tacrolimus group 4/72 (5.6%). A greater incidence of proteinuria, was seen in the sirolimus group 19/131 (14.5%) versus 2/123 (1.6%) in the tacrolimus group.

Conversion from a CNI-based regimen to a sirolimus-based regimen was assessed in stable liver transplant patients 6–144 months post-transplant. The clinical study was a 2:1 randomized, multi-center, controlled trial conducted at 82 centers globally, including the US and Europe, and was intended to show that renal function was improved by conversion from a CNI to sirolimus without adversely impacting efficacy or safety. A total of 607 patients were enrolled.

The study failed to demonstrate superiority of conversion to a sirolimus-based regimen compared to continuation of a CNI-based regimen in baseline-adjusted GFR, as estimated by Cockcroft-Gault, at 12 months (62 mL/min in the sirolimus conversion group and 63 mL/min in the CNI continuation group). The study also failed to demonstrate non-inferiority, with respect to the composite endpoint consisting of graft loss and death (including patients with missing survival data) in the sirolimus conversion group compared to the CNI continuation group (6.6% versus 5.6%). The number of deaths in the sirolimus conversion group (15/393, 3.8%) was higher than in the CNI continuation group (3/214, 1.4%), although the difference was not statistically significant. The rates of premature study discontinuation (primarily due to adverse events or lack of efficacy), adverse events overall (infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the sirolimus conversion group compared to the CNI continuation group.

Sirolimus was evaluated in a 36-month, open-label, randomized, controlled clinical trial at 14 North American centers in pediatric (aged 3 to <18 years) renal transplant patients considered to be at high-immunologic risk for developing chronic allograft nephropathy, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. Seventy-eight (78) subjects were randomized in a 2:1 ratio to sirolimus (sirolimus target concentrations of 5 to 15 ng/mL, by chromatographic assay, n = 53) in combination with a calcineurin inhibitor and corticosteroids or to continue calcineurin-inhibitor-based immunosuppressive therapy (n = 25). The primary endpoint of the study was efficacy failure as defined by the first occurrence of biopsy-confirmed acute rejection, graft loss, or death, and the trial was designed to show superiority of sirolimus added to a calcineurin-inhibitor-based immunosuppressive regimen compared to a calcineurin-inhibitor-based regimen. The cumulative incidence of efficacy failure up to 36 months was 45.3% in the sirolimus group compared to 44.0% in the control group, and did not demonstrate superiority. There was one death in each group. The use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections [see Warnings and Precautions (5.8)]. This study does not support the addition of sirolimus to calcineurin-inhibitor-based immunosuppressive therapy in this subpopulation of pediatric renal transplant patients.

The safety and efficacy of sirolimus for treatment of lymphangioleiomyomatosis (LAM) were assessed in a randomized, double-blind, multicenter, controlled trial. This study compared sirolimus (dose-adjusted to maintain blood trough concentrations between 5–15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observation period. Eighty-nine (89) patients were enrolled; 43 patients were randomized to receive placebo and 46 patients to receive sirolimus. The primary endpoint was the difference between the groups in the rate of change (slope) per month in forced expiratory volume in 1 second (FEV1). During the treatment period, the FEV1 slope was -12±2 mL per month in the placebo group and 1±2 mL per month in the sirolimus group (treatment difference = 13 mL (95% CI: 7, 18). The absolute between-group difference in the mean change in FEV1 during the 12-month treatment period was 153 mL, or approximately 11% of the mean FEV1 at enrollment. Similar improvements were seen for forced vital capacity (FVC). After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group (see Figure 1).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="100%"/> <tbody class="Headless"> <tr> <td align="center" valign="top"> <p class="First"> <span class="Bold">FIGURE 1: CHANGE IN FORCED EXPIRATORY VOLUME IN 1 SECOND (FEV1) DURING THE TREATMENT AND OBSERVATION PHASES OF THE STUDY IN LAM PATIENTS</span> </p> </td> </tr> <tr> <td valign="top"><a name="id3886"></a><img alt="Figure 1" src="/dailymed/image.cfm?name=sirolimus-02.jpg&amp;setid=5908cd1a-fc5a-462f-99ed-1d8983e253c9"/></td> </tr> </tbody> </table></div>

The rate of change over 12 months of vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor which has been shown to be elevated in patients with LAM, was significantly different in the sirolimus-treated group (-88.0 ± 16.6 pg/mL/month) compared to placebo (-2.42 ± 17.2 pg/mL/month) with a treatment difference of -86 pg/mL/month (95% CI: -133, -39). The absolute between-group difference in the mean change in VEGF-D during the 12-month treatment period was -1017.2, or approximately 50% of the mean VEGF-D at enrollment.

Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see Dosage and Administration (2.5)].

{ "type": "p", "children": [], "text": "\nClinical Therapeutics, Volume 22, Supplement B, April 2000 [see Dosage and Administration (2.5)]." }

Sirolimus Tablets are available as follows:

Sirolimus Tablets should be stored at 20°C to 25°C [USP Controlled Room Temperature] (68°F to 77°F). Dispense in a tight, light-resistant container as defined in the USP.

Patients should be given complete dosage instructions [see FDA-Approved Medication Guide].

Advise patients that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor because of the increased risk for skin cancer [see Warnings and Precautions (5.18)].

Advise female patients of reproductive potential to avoid becoming pregnant throughout treatment and for 12 weeks after sirolimus therapy has stopped. Sirolimus can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to her fetus. Before making a decision to breastfeed, inform the patient that the effects of breastfeeding in infants while taking this drug are unknown, but there is potential for serious adverse effects [see Warnings and Precautions (5.15), Use in Specific Populations (8.1, 8.2, 8.3)].

Inform male and female patients that sirolimus may impair fertility [see Warnings and Precautions (5.16), Adverse Reactions (6.7), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

LAB-0620-13.0

{ "type": "p", "children": [], "text": "LAB-0620-13.0" }

<div class="scrollingtable"><table width="100%"> <col width="5%"/> <col width="48%"/> <col width="48%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">This Medication Guide has been approved by the U.S. Food and Drug Administration.     Revised Nov 2024</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">MEDICATION GUIDE</span> <br/>Sirolimus Tablets</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <a name="refmostimportantinfo"></a><span class="Bold">What is the most important information I should know about sirolimus?</span> </p> <p>Sirolimus can cause serious side effects, including:</p> <p> <span class="Bold">1. Increased risk of getting infections.</span> Serious infections can happen including infections caused by viruses, bacteria, and fungi (yeast). Your doctor may put you on medicine to help prevent some of these infections.</p> <p>Call your doctor right away if you have symptoms of infection including fever or chills while taking sirolimus.</p> <p> <span class="Bold">2. Increased risk of getting certain cancers.</span> People who take sirolimus have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Talk with your doctor about your risk for cancer.</p> <p> <span class="Bold">Sirolimus has not been shown to be safe and effective in people who have had liver or lung transplants. Serious complications and death may happen in people who take sirolimus after a liver or lung transplant.</span> You should not take <span class="Bold">sirolimus</span> if you have had a liver or lung transplant without talking with your doctor.</p> <p> <span class="Bold">See the section "<a href="#refpossiblesideeffects">What are the possible side effects of sirolimus?</a>" for information about other side effects of sirolimus.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">What is sirolimus?</span> </p> <p>Sirolimus is a prescription medicine used to prevent rejection (anti-rejection medicine) in people 13 years of age and older who have received a kidney transplant. Rejection is when your body's immune system recognizes the new organ as a "foreign" threat and attacks it.</p> <p>Sirolimus is used with other medicines called cyclosporine (Gengraf, Neoral, Sandimmune), and corticosteroids. Your doctor will decide:</p> <dl> <dt>•</dt> <dd>if sirolimus is right for you, and</dd> <dt>•</dt> <dd>how to best use it with cyclosporine and corticosteroids after your transplant.</dd> </dl> <p>It is not known if sirolimus is safe and effective in children under 13 years of age.</p> <p>Sirolimus is a prescription medicine also used to treat lymphangioleiomyomatosis (LAM). LAM is a rare progressive lung disease that affects predominantly women of childbearing age.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Who should not take sirolimus?</span> </p> <p>Do not take sirolimus if you are allergic to sirolimus or any of the other ingredients in sirolimus. See the end of this leaflet for a complete list of ingredients in sirolimus.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <a name="refwhatshoulditellmydoctor"></a><span class="Bold">What should I tell my doctor before taking sirolimus?</span> </p> <dl> <dt>•</dt> <dd>have liver problems</dd> <dt>•</dt> <dd>have skin cancer or it runs in your family</dd> <dt>•</dt> <dd>have high cholesterol or triglycerides (fat in your blood)</dd> <dt>•</dt> <dd>are pregnant or are a female who can become pregnant. Sirolimus can harm your unborn baby. You should not become pregnant during treatment with sirolimus and for 12 weeks after ending treatment with sirolimus. In order to avoid pregnancy, a female who can get pregnant should use effective birth control during treatment and for 12 weeks after your final dose of sirolimus. Talk with your doctor about what birth control method is right for you during this time. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with sirolimus or within 12 weeks after your final dose of sirolimus.</dd> <dt>•</dt> <dd>It is not known whether sirolimus passes into breast milk; however, there is a risk of serious side effects in breastfed infants. You and your doctor should decide about the best way to feed your baby if you take sirolimus.</dd> </dl> <p> <span class="Bold">Tell your doctor about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins and herbal supplements. Using sirolimus with certain medicines may affect each other causing serious side effects.</p> <p>Sirolimus may affect the way other medicines work, and other medicines may affect how sirolimus works.</p> <p>Especially tell your doctor if you take:</p> <dl> <dt>•</dt> <dd>a medicine to lower your cholesterol or triglycerides</dd> <dt>•</dt> <dd>cyclosporine (including Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf) or other medicines that suppress the immune system</dd> <dt>•</dt> <dd>an antibiotic</dd> <dt>•</dt> <dd>an antifungal medicine</dd> <dt>•</dt> <dd>a medicine for high blood pressure or heart problems</dd> <dt>•</dt> <dd>an anti-seizure medicine</dd> <dt>•</dt> <dd>medicines used to treat stomach acid, ulcers, or other gastrointestinal problems</dd> <dt>•</dt> <dd>bromocriptine mesylate (Parlodel, Cycloset)</dd> <dt>•</dt> <dd>danazol</dd> <dt>•</dt> <dd>letermovir (Prevymis)</dd> <dt>•</dt> <dd>medicines to treat HIV or hepatitis C</dd> <dt>•</dt> <dd>St. John's Wort</dd> <dt>•</dt> <dd>cannabidiol (Epidiolex)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">How should I take sirolimus?</span> </p> <dl> <dt>•</dt> <dd>Read the Instructions for Use that comes with your sirolimus for information about the right way to take sirolimus tablets.</dd> <dt>•</dt> <dd>Take sirolimus exactly as your doctor tells you to take it.</dd> <dt>•</dt> <dd>Your doctor will tell you how much sirolimus to take and when to take it. Do not change your dose of sirolimus unless your doctor tells you to.</dd> <dt>•</dt> <dd>If you also take cyclosporine (Gengraf, Neoral, Sandimmune), you should take your sirolimus and cyclosporine about 4 hours apart.</dd> <dt>•</dt> <dd>Do not stop taking sirolimus or your other anti-rejection medicines unless your doctor tells you to.</dd> <dt>•</dt> <dd>Your doctor will check the levels of sirolimus in your blood. Your doctor may change your dose of sirolimus depending on your blood test results.</dd> <dt>•</dt> <dd>Sirolimus is taken by mouth 1 time each day.</dd> <dt>•</dt> <dd>Do not crush, chew, or split sirolimus tablets. Tell your doctor if you cannot swallow sirolimus tablets. Your doctor can prescribe sirolimus as a solution.</dd> <dt>•</dt> <dd>Take each dose of sirolimus the same way, either with or without food. Food can affect the amount of medicine that gets into your bloodstream. Taking each dose of sirolimus the same way helps keep your blood levels of sirolimus more stable. Do not take sirolimus with grapefruit juice.</dd> <dt>•</dt> <dd>If you have taken more medicine than you were told, contact a doctor or go to the nearest hospital emergency department right away.</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 sirolimus?</span> </p> <dl> <dt>•</dt> <dd>Avoid receiving live vaccines while taking sirolimus. Some vaccines may not work as well while you are taking sirolimus.</dd> <dt>•</dt> <dd>Limit your time in sunlight and UV light. Cover your skin with clothing and use a broad spectrum sunscreen with a high protection factor because of the increased risk for skin cancer with sirolimus.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <a name="refpossiblesideeffects"></a><span class="Bold">What are the possible side effects of sirolimus?</span> </p> <p> <span class="Bold">Sirolimus may cause serious side effects, including:</span> </p> <dl> <dt>•</dt> <dd>See <span class="Bold">"<a href="#refmostimportantinfo">What is the most important information I should know about sirolimus?</a>"</span> </dd> <dt>•</dt> <dd> <span class="Bold">Serious allergic reactions. Tell your doctor or get medical help right away</span> if you get any of following symptoms of an allergic reaction:</dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>•</dt> <dd>swelling of your face, eyes, or mouth</dd> <dt>•</dt> <dd>trouble breathing or wheezing</dd> <dt>•</dt> <dd>throat tightness</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>•</dt> <dd>chest pain or tightness</dd> <dt>•</dt> <dd>feeling dizzy or faint</dd> <dt>•</dt> <dd>rash or peeling of your skin</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Swelling (edema).</span> Fluid may collect in your hands and feet and in various tissues of your body, including in the sac around your heart or lungs. Call your doctor if you have trouble breathing.</dd> <dt>•</dt> <dd> <span class="Bold">Poor wound healing.</span> Sirolimus may cause your wounds to heal slowly or not heal well. Tell your doctor if you have any redness or drainage, your wound does not heal, or the wound opens up.</dd> <dt>•</dt> <dd> <span class="Bold">Increased levels of cholesterol and triglycerides (lipids or fat) in your blood.</span> Your doctor should do blood tests to check your lipids during treatment with sirolimus. Your doctor may prescribe treatment with diet, exercise, or medicine if your lipid levels are too high. During treatment with sirolimus, your blood levels of cholesterol and triglycerides may remain high even if you follow your prescribed treatment plan.</dd> <dt>•</dt> <dd> <span class="Bold">Effects on kidney function.</span> When sirolimus is taken with cyclosporine (Gengraf, Neoral, Sandimmune), the function of your transplanted kidney may be affected. Your doctor should regularly do tests to check your kidney function while you are taking sirolimus with cyclosporine (Gengraf, Neoral, Sandimmune).</dd> <dt>•</dt> <dd> <span class="Bold">Increased protein in your urine.</span> Your doctor may regularly test your urine protein.</dd> <dt>•</dt> <dd> <span class="Bold">Increased risk for viral infections.</span> <dl> <dt>•</dt> <dd>Certain viruses can live in your body and cause active infections when your immune system is weak. BK virus can affect how your kidney works and cause your transplanted kidney to fail.</dd> <dt>•</dt> <dd>A certain virus can cause a rare serious brain infection called Progressive Multifocal Leukoencephalopathy (PML). PML usually causes death or severe disability. Call your doctor right away if you notice any new or worsening medical problems such as:<dl> <dt>•</dt> <dd>confusion</dd> <dt>•</dt> <dd>sudden change in thinking, walking, strength on one side of your body</dd> <dt>•</dt> <dd>other problems that have lasted over several days</dd> </dl> </dd> </dl> </dd> <dt>•</dt> <dd> <span class="Bold">Lung or breathing problems.</span> This can sometimes lead to death. Tell your doctor if you have a new or worsening cough, shortness of breath, difficulty breathing or any new breathing problems. Your doctor may need to stop sirolimus or lower your dose.</dd> <dt>•</dt> <dd> <span class="Bold">Blood clotting problems.</span> When sirolimus is taken with cyclosporine or tacrolimus, you may develop a blood clotting problem. Tell your doctor if you get any unexplained bleeding or bruising.</dd> <dt>•</dt> <dd> <span class="Bold">Possible harm to your unborn baby.</span> Sirolimus can harm your unborn baby. You should not become pregnant during treatment with sirolimus and for 12 weeks after ending treatment with sirolimus. See <span class="Bold">"<a href="#refwhatshoulditellmydoctor">What should I tell my doctor before taking sirolimus?</a>".</span> </dd> </dl> <p class="First"> <span class="Bold">The most common side effects of sirolimus in people with renal transplant include:</span> </p> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>•</dt> <dd>high blood pressure</dd> <dt>•</dt> <dd>pain (including stomach and joint pain)</dd> <dt>•</dt> <dd>diarrhea</dd> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>fever</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>•</dt> <dd>urinary tract infection</dd> <dt>•</dt> <dd>low red blood cell count (anemia)</dd> <dt>•</dt> <dd>nausea</dd> <dt>•</dt> <dd>low platelet count (cells that help blood to clot)</dd> <dt>•</dt> <dd>high blood sugar (diabetes)</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 sirolimus in people with LAM include: </span> </p> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>•</dt> <dd>mouth sores</dd> <dt>•</dt> <dd>diarrhea</dd> <dt>•</dt> <dd>stomach pain</dd> <dt>•</dt> <dd>nausea</dd> <dt>•</dt> <dd>sore throat</dd> <dt>•</dt> <dd>acne</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>•</dt> <dd>chest pain</dd> <dt>•</dt> <dd>upper respiratory tract infection</dd> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>dizziness</dd> <dt>•</dt> <dd>sore muscles</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Other side effects that may occur with sirolimus:</span> </p> <dl> <dt>•</dt> <dd>Sirolimus may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.</dd> <dt>•</dt> <dd>Sirolimus may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First">Tell your doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all of the possible side effects of sirolimus. For more information ask your doctor or pharmacist.</p> <p> <span class="Bold">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">How should I store sirolimus?</span> </p> <p> <span class="Bold">Sirolimus tablets:</span> </p> <dl> <dt>•</dt> <dd>Store sirolimus tablets at room temperature between 68°F to 77°F (20°C to 25°C).</dd> <dt>•</dt> <dd>Bottles: Keep the bottle of sirolimus tablets tightly closed.</dd> </dl> <p>Do not use sirolimus after the expiration date. The expiration date refers to the last day of that month.</p> <p>Safely throw away medicine that is out of date or no longer needed.</p> <p> <span class="Bold">Keep sirolimus 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 sirolimus.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use sirolimus for a condition for which it was not prescribed. Do not give sirolimus to other people even if they have the same symptoms that you have. It may harm them.</p> <p>This Medication Guide summarizes the most important information about sirolimus. If you would like more information talk to your doctor. You can ask your pharmacist or doctor for information about sirolimus that is written for health professionals.</p> <p>For more information about sirolimus call 1-877-446-3679.</p> </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 sirolimus?</span> </p> <p>Active ingredients: sirolimus</p> <p>Inactive ingredients: sirolimus tablets: sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, <span class="Italics">dl</span>-alpha tocopherol, and other ingredients. The 0.5 mg and 2 mg dosage strengths also contain yellow iron (ferric) oxide and brown iron (ferric) oxide.</p> <a name="id4251"></a><img alt="Logo" src="/dailymed/image.cfm?name=sirolimus-04.jpg&amp;setid=5908cd1a-fc5a-462f-99ed-1d8983e253c9"/><p>For sirolimus oral tablets:</p> <p>LAB-0621-8.0</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"5%\"/>\n<col width=\"48%\"/>\n<col width=\"48%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"3\" valign=\"top\">This Medication Guide has been approved by the U.S. Food and Drug Administration.     Revised Nov 2024</td>\n</tr>\n</tfoot>\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\">MEDICATION GUIDE</span>\n<br/>Sirolimus Tablets</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<a name=\"refmostimportantinfo\"></a><span class=\"Bold\">What is the most important information I should know about sirolimus?</span>\n</p>\n<p>Sirolimus can cause serious side effects, including:</p>\n<p>\n<span class=\"Bold\">1. Increased risk of getting infections.</span> Serious infections can happen including infections caused by viruses, bacteria, and fungi (yeast). Your doctor may put you on medicine to help prevent some of these infections.</p>\n<p>Call your doctor right away if you have symptoms of infection including fever or chills while taking sirolimus.</p>\n<p>\n<span class=\"Bold\">2. Increased risk of getting certain cancers.</span> People who take sirolimus have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Talk with your doctor about your risk for cancer.</p>\n<p>\n<span class=\"Bold\">Sirolimus has not been shown to be safe and effective in people who have had liver or lung transplants. Serious complications and death may happen in people who take sirolimus after a liver or lung transplant.</span> You should not take <span class=\"Bold\">sirolimus</span> if you have had a liver or lung transplant without talking with your doctor.</p>\n<p>\n<span class=\"Bold\">See the section \"<a href=\"#refpossiblesideeffects\">What are the possible side effects of sirolimus?</a>\" for information about other side effects of sirolimus.</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\">What is sirolimus?</span>\n</p>\n<p>Sirolimus is a prescription medicine used to prevent rejection (anti-rejection medicine) in people 13 years of age and older who have received a kidney transplant. Rejection is when your body's immune system recognizes the new organ as a \"foreign\" threat and attacks it.</p>\n<p>Sirolimus is used with other medicines called cyclosporine (Gengraf, Neoral, Sandimmune), and corticosteroids. Your doctor will decide:</p>\n<dl>\n<dt>•</dt>\n<dd>if sirolimus is right for you, and</dd>\n<dt>•</dt>\n<dd>how to best use it with cyclosporine and corticosteroids after your transplant.</dd>\n</dl>\n<p>It is not known if sirolimus is safe and effective in children under 13 years of age.</p>\n<p>Sirolimus is a prescription medicine also used to treat lymphangioleiomyomatosis (LAM). LAM is a rare progressive lung disease that affects predominantly women of childbearing age.</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\">Who should not take sirolimus?</span>\n</p>\n<p>Do not take sirolimus if you are allergic to sirolimus or any of the other ingredients in sirolimus. See the end of this leaflet for a complete list of ingredients in sirolimus.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<a name=\"refwhatshoulditellmydoctor\"></a><span class=\"Bold\">What should I tell my doctor before taking sirolimus?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have liver problems</dd>\n<dt>•</dt>\n<dd>have skin cancer or it runs in your family</dd>\n<dt>•</dt>\n<dd>have high cholesterol or triglycerides (fat in your blood)</dd>\n<dt>•</dt>\n<dd>are pregnant or are a female who can become pregnant. Sirolimus can harm your unborn baby. You should not become pregnant during treatment with sirolimus and for 12 weeks after ending treatment with sirolimus. In order to avoid pregnancy, a female who can get pregnant should use effective birth control during treatment and for 12 weeks after your final dose of sirolimus. Talk with your doctor about what birth control method is right for you during this time. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with sirolimus or within 12 weeks after your final dose of sirolimus.</dd>\n<dt>•</dt>\n<dd>It is not known whether sirolimus passes into breast milk; however, there is a risk of serious side effects in breastfed infants. You and your doctor should decide about the best way to feed your baby if you take sirolimus.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your doctor about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins and herbal supplements. Using sirolimus with certain medicines may affect each other causing serious side effects.</p>\n<p>Sirolimus may affect the way other medicines work, and other medicines may affect how sirolimus works.</p>\n<p>Especially tell your doctor if you take:</p>\n<dl>\n<dt>•</dt>\n<dd>a medicine to lower your cholesterol or triglycerides</dd>\n<dt>•</dt>\n<dd>cyclosporine (including Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf) or other medicines that suppress the immune system</dd>\n<dt>•</dt>\n<dd>an antibiotic</dd>\n<dt>•</dt>\n<dd>an antifungal medicine</dd>\n<dt>•</dt>\n<dd>a medicine for high blood pressure or heart problems</dd>\n<dt>•</dt>\n<dd>an anti-seizure medicine</dd>\n<dt>•</dt>\n<dd>medicines used to treat stomach acid, ulcers, or other gastrointestinal problems</dd>\n<dt>•</dt>\n<dd>bromocriptine mesylate (Parlodel, Cycloset)</dd>\n<dt>•</dt>\n<dd>danazol</dd>\n<dt>•</dt>\n<dd>letermovir (Prevymis)</dd>\n<dt>•</dt>\n<dd>medicines to treat HIV or hepatitis C</dd>\n<dt>•</dt>\n<dd>St. John's Wort</dd>\n<dt>•</dt>\n<dd>cannabidiol (Epidiolex)</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\">How should I take sirolimus?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Read the Instructions for Use that comes with your sirolimus for information about the right way to take sirolimus tablets.</dd>\n<dt>•</dt>\n<dd>Take sirolimus exactly as your doctor tells you to take it.</dd>\n<dt>•</dt>\n<dd>Your doctor will tell you how much sirolimus to take and when to take it. Do not change your dose of sirolimus unless your doctor tells you to.</dd>\n<dt>•</dt>\n<dd>If you also take cyclosporine (Gengraf, Neoral, Sandimmune), you should take your sirolimus and cyclosporine about 4 hours apart.</dd>\n<dt>•</dt>\n<dd>Do not stop taking sirolimus or your other anti-rejection medicines unless your doctor tells you to.</dd>\n<dt>•</dt>\n<dd>Your doctor will check the levels of sirolimus in your blood. Your doctor may change your dose of sirolimus depending on your blood test results.</dd>\n<dt>•</dt>\n<dd>Sirolimus is taken by mouth 1 time each day.</dd>\n<dt>•</dt>\n<dd>Do not crush, chew, or split sirolimus tablets. Tell your doctor if you cannot swallow sirolimus tablets. Your doctor can prescribe sirolimus as a solution.</dd>\n<dt>•</dt>\n<dd>Take each dose of sirolimus the same way, either with or without food. Food can affect the amount of medicine that gets into your bloodstream. Taking each dose of sirolimus the same way helps keep your blood levels of sirolimus more stable. Do not take sirolimus with grapefruit juice.</dd>\n<dt>•</dt>\n<dd>If you have taken more medicine than you were told, contact a doctor or go to the nearest hospital emergency department right away.</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 sirolimus?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Avoid receiving live vaccines while taking sirolimus. Some vaccines may not work as well while you are taking sirolimus.</dd>\n<dt>•</dt>\n<dd>Limit your time in sunlight and UV light. Cover your skin with clothing and use a broad spectrum sunscreen with a high protection factor because of the increased risk for skin cancer with sirolimus.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<a name=\"refpossiblesideeffects\"></a><span class=\"Bold\">What are the possible side effects of sirolimus?</span>\n</p>\n<p>\n<span class=\"Bold\">Sirolimus may cause serious side effects, including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>See <span class=\"Bold\">\"<a href=\"#refmostimportantinfo\">What is the most important information I should know about sirolimus?</a>\"</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Serious allergic reactions. Tell your doctor or get medical help right away</span> if you get any of following symptoms of an allergic reaction:</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\"></td><td valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>swelling of your face, eyes, or mouth</dd>\n<dt>•</dt>\n<dd>trouble breathing or wheezing</dd>\n<dt>•</dt>\n<dd>throat tightness</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>chest pain or tightness</dd>\n<dt>•</dt>\n<dd>feeling dizzy or faint</dd>\n<dt>•</dt>\n<dd>rash or peeling of your skin</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\">Swelling (edema).</span> Fluid may collect in your hands and feet and in various tissues of your body, including in the sac around your heart or lungs. Call your doctor if you have trouble breathing.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Poor wound healing.</span> Sirolimus may cause your wounds to heal slowly or not heal well. Tell your doctor if you have any redness or drainage, your wound does not heal, or the wound opens up.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased levels of cholesterol and triglycerides (lipids or fat) in your blood.</span> Your doctor should do blood tests to check your lipids during treatment with sirolimus. Your doctor may prescribe treatment with diet, exercise, or medicine if your lipid levels are too high. During treatment with sirolimus, your blood levels of cholesterol and triglycerides may remain high even if you follow your prescribed treatment plan.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Effects on kidney function.</span> When sirolimus is taken with cyclosporine (Gengraf, Neoral, Sandimmune), the function of your transplanted kidney may be affected. Your doctor should regularly do tests to check your kidney function while you are taking sirolimus with cyclosporine (Gengraf, Neoral, Sandimmune).</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased protein in your urine.</span> Your doctor may regularly test your urine protein.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased risk for viral infections.</span>\n<dl>\n<dt>•</dt>\n<dd>Certain viruses can live in your body and cause active infections when your immune system is weak. BK virus can affect how your kidney works and cause your transplanted kidney to fail.</dd>\n<dt>•</dt>\n<dd>A certain virus can cause a rare serious brain infection called Progressive Multifocal Leukoencephalopathy (PML). PML usually causes death or severe disability. Call your doctor right away if you notice any new or worsening medical problems such as:<dl>\n<dt>•</dt>\n<dd>confusion</dd>\n<dt>•</dt>\n<dd>sudden change in thinking, walking, strength on one side of your body</dd>\n<dt>•</dt>\n<dd>other problems that have lasted over several days</dd>\n</dl>\n</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Lung or breathing problems.</span> This can sometimes lead to death. Tell your doctor if you have a new or worsening cough, shortness of breath, difficulty breathing or any new breathing problems. Your doctor may need to stop sirolimus or lower your dose.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Blood clotting problems.</span> When sirolimus is taken with cyclosporine or tacrolimus, you may develop a blood clotting problem. Tell your doctor if you get any unexplained bleeding or bruising.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Possible harm to your unborn baby.</span> Sirolimus can harm your unborn baby. You should not become pregnant during treatment with sirolimus and for 12 weeks after ending treatment with sirolimus. See <span class=\"Bold\">\"<a href=\"#refwhatshoulditellmydoctor\">What should I tell my doctor before taking sirolimus?</a>\".</span>\n</dd>\n</dl>\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of sirolimus in people with renal transplant include:</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>high blood pressure</dd>\n<dt>•</dt>\n<dd>pain (including stomach and joint pain)</dd>\n<dt>•</dt>\n<dd>diarrhea</dd>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>fever</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>urinary tract infection</dd>\n<dt>•</dt>\n<dd>low red blood cell count (anemia)</dd>\n<dt>•</dt>\n<dd>nausea</dd>\n<dt>•</dt>\n<dd>low platelet count (cells that help blood to clot)</dd>\n<dt>•</dt>\n<dd>high blood sugar (diabetes)</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 sirolimus in people with LAM include: </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>mouth sores</dd>\n<dt>•</dt>\n<dd>diarrhea</dd>\n<dt>•</dt>\n<dd>stomach pain</dd>\n<dt>•</dt>\n<dd>nausea</dd>\n<dt>•</dt>\n<dd>sore throat</dd>\n<dt>•</dt>\n<dd>acne</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>chest pain</dd>\n<dt>•</dt>\n<dd>upper respiratory tract infection</dd>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>dizziness</dd>\n<dt>•</dt>\n<dd>sore muscles</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\">Other side effects that may occur with sirolimus:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Sirolimus may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.</dd>\n<dt>•</dt>\n<dd>Sirolimus may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern 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\">Tell your doctor if you have any side effect that bothers you or that does not go away.</p>\n<p>These are not all of the possible side effects of sirolimus. For more information ask your doctor or pharmacist.</p>\n<p>\n<span class=\"Bold\">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</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\">How should I store sirolimus?</span>\n</p>\n<p>\n<span class=\"Bold\">Sirolimus tablets:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store sirolimus tablets at room temperature between 68°F to 77°F (20°C to 25°C).</dd>\n<dt>•</dt>\n<dd>Bottles: Keep the bottle of sirolimus tablets tightly closed.</dd>\n</dl>\n<p>Do not use sirolimus after the expiration date. The expiration date refers to the last day of that month.</p>\n<p>Safely throw away medicine that is out of date or no longer needed.</p>\n<p>\n<span class=\"Bold\">Keep sirolimus 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 sirolimus.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use sirolimus for a condition for which it was not prescribed. Do not give sirolimus to other people even if they have the same symptoms that you have. It may harm them.</p>\n<p>This Medication Guide summarizes the most important information about sirolimus. If you would like more information talk to your doctor. You can ask your pharmacist or doctor for information about sirolimus that is written for health professionals.</p>\n<p>For more information about sirolimus call 1-877-446-3679.</p>\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 sirolimus?</span>\n</p>\n<p>Active ingredients: sirolimus</p>\n<p>Inactive ingredients: sirolimus tablets: sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, <span class=\"Italics\">dl</span>-alpha tocopherol, and other ingredients. The 0.5 mg and 2 mg dosage strengths also contain yellow iron (ferric) oxide and brown iron (ferric) oxide.</p>\n<a name=\"id4251\"></a><img alt=\"Logo\" src=\"/dailymed/image.cfm?name=sirolimus-04.jpg&amp;setid=5908cd1a-fc5a-462f-99ed-1d8983e253c9\"/><p>For sirolimus oral tablets:</p>\n<p>LAB-0621-8.0</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

ALWAYS DISPENSE WITH MEDICATION GUIDE

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NDC 59762-1001-1100 Tablets

{ "type": "p", "children": [], "text": "\nNDC 59762-1001-1100 Tablets " }

GREENSTONE® BRAND

{ "type": "p", "children": [], "text": "\nGREENSTONE® BRAND\n" }

sirolimus tablets

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0.5 mg For oral use only Rx only

{ "type": "p", "children": [], "text": "\n0.5 mg\nFor oral use only\nRx only" }

ALWAYS DISPENSE WITH MEDICATION GUIDE

{ "type": "p", "children": [], "text": "\nALWAYS DISPENSE WITH\n\nMEDICATION GUIDE\n" }

NDC 59762-1002-1100 Tablets

{ "type": "p", "children": [], "text": "\nNDC 59762-1002-1100 Tablets" }

GREENSTONE® BRAND

{ "type": "p", "children": [], "text": "\nGREENSTONE® BRAND\n" }

sirolimus tablets

{ "type": "p", "children": [], "text": "\nsirolimus\n\ntablets\n" }

1 mg For oral use only Rx only

{ "type": "p", "children": [], "text": "\n1 mg\nFor oral use only\nRx only" }

ALWAYS DISPENSE WITH MEDICATION GUIDE

{ "type": "p", "children": [], "text": "\nALWAYS DISPENSE WITH\n\nMEDICATION GUIDE\n" }

NDC 59762-1003-1100 Tablets

{ "type": "p", "children": [], "text": "\nNDC 59762-1003-1100 Tablets" }

GREENSTONE® BRAND

{ "type": "p", "children": [], "text": "\nGREENSTONE® BRAND\n" }

sirolimus tablets

{ "type": "p", "children": [], "text": "\nsirolimus\n\ntablets\n" }

2 mg For oral use only Rx only

{ "type": "p", "children": [], "text": "\n2 mg\nFor oral use only\nRx only" }

HYFTOR is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients 6 years of age and older.

{ "type": "p", "children": [], "text": "HYFTOR is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients 6 years of age and older." }

{ "type": "ul", "children": [ "Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to HYFTOR initiation \n \n \n [see \n \n \n Warning and Precautions (5.6)]\n \n \n .\n \n \n ", "Apply HYFTOR to the skin of the face affected with angiofibroma twice daily in the morning and at bedtime.", "The maximum recommended daily dosage is:\n \n \n \n600 mg (2 cm) for pediatric patients 6 to 11 years of age\n800 mg (2.5 cm) for adults and pediatric patients 12 years of age and older\n\n", "If symptoms do not improve within 12 weeks of treatment, reevaluate the need for continuing HYFTOR.", "Do not use HYFTOR with occlusive dressings.", "For topical use only. Not for oral, ophthalmic, or intravaginal use." ], "text": "" }

Topical gel , 0.2%: Each gram contains 2 mg of sirolimus in a colorless and transparent gel in 10-gram tubes.

{ "type": "p", "children": [], "text": "Topical gel\n \n \n , 0.2%: Each gram contains 2 mg of sirolimus in a colorless and transparent gel in 10-gram tubes. \n \n\n " }

HYFTOR is contraindicated in patients with a history of hypersensitivity to sirolimus or any other component of HYFTOR. Reactions to sirolimus have included anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis [see Warning and Precautions (5.1)] .

{ "type": "p", "children": [], "text": "HYFTOR is contraindicated in patients with a history of hypersensitivity to sirolimus or any other component of HYFTOR. Reactions to sirolimus have included anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis \n \n \n [see \n \n \n Warning and Precautions (5.1)]\n \n \n .\n \n\n " }

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis have been associated with the oral administration of sirolimus. The concomitant use of HYFTOR with other drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema. Elevated sirolimus levels (with or without concomitant ACE inhibitors) may also potentiate angioedema. Discontinue HYFTOR immediately if symptoms of hypersensitivity occur.

Serious infections, including opportunistic infections, have been reported after oral administration of sirolimus. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients treated with oral sirolimus. Discontinue HYFTOR immediately if symptoms of infection occur.

Lymphoma and other malignancies, particularly of the skin, have been observed after oral administration of sirolimus. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using HYFTOR. If patients need to be outdoors while using HYFTOR, they should wear protective clothing and discuss other sun protection measures with their physician.

Increased serum cholesterol and triglycerides requiring treatment have been observed with oral administration of sirolimus. Monitor for hyperlipidemia during treatment with HYFTOR.

Cases of interstitial lung disease [ILD] (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving oral sirolimus. In some cases, the ILD has resolved upon discontinuation or dosage reduction of oral sirolimus. Discontinue HYFTOR immediately if symptoms of ILD occur.

During treatment with HYFTOR, vaccinations may be less effective. Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with HYFTOR. The use of live vaccines should be avoided during treatment with HYFTOR.

Based on animal studies and the mechanism of action, oral sirolimus can cause fetal harm when administered to a pregnant woman. In animal studies, oral sirolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. HYFTOR is systemically absorbed after topical administration and may result in fetal exposure. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant. They should use effective contraception prior to, throughout treatment and for 12 weeks after the final dose of HYFTOR [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1, 12.3)].

Azoospermia or oligospermia has been observed after oral administration of sirolimus [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. Sirolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells. Advise males that HYFTOR may impair fertility.

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 a randomized, double-blind, vehicle-controlled trial, subjects aged 6 years and older with facial angiofibroma associated with tuberous sclerosis applied HYFTOR twice daily for 12 weeks. A total of 30 subjects were treated with HYFTOR and 32 with the vehicle. The majority of the subjects were female (54.8%). A total of 40.3% were less than 18 years of age.

The most common adverse reactions reported by ≥1% of subjects treated with HYFTOR and more frequently than in subjects treated with vehicle are presented in Table 1. Adverse reactions occurred with similar frequency in pediatric subjects 6 years of age and older.

<div class="scrollingtable"><table width="60%"> <caption> <span>Table 1: Adverse Reactions in ≥1% of Subjects Aged 6 Years and Older with Facial Angiofibroma Associated with Tuberous Sclerosis Through Week 12</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Preferred Term</th><th align="center" class="Rrule">HYFTOR <br/>N = 30 </th><th align="center" class="Rrule">Vehicle <br/>N = 32 </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Dry skin includes dry skin and asteatosis</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Dry skin <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Rrule">12 (40%)</td><td align="center" class="Rrule">4 (13%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Application site irritation</td><td align="center" class="Rrule">11 (37%)</td><td align="center" class="Rrule">9 (28%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Pruritus</td><td align="center" class="Rrule">5 (17%)</td><td align="center" class="Rrule">4 (13%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Acne</td><td align="center" class="Rrule">2 (7%)</td><td align="center" class="Rrule">0 (0%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Acneiform dermatitis</td><td align="center" class="Rrule">1 (3%)</td><td align="center" class="Rrule">0 (0%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Ocular hyperemia</td><td align="center" class="Rrule">1 (3%)</td><td align="center" class="Rrule">0 (0%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Skin hemorrhage</td><td align="center" class="Rrule">1 (3%)</td><td align="center" class="Rrule">0 (0%)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Skin irritation</td><td align="center" class="Rrule">1 (3%)</td><td align="center" class="Rrule">0 (0%)</td> </tr> </tbody> </table></div>

In a 104-week, open-label safety trial, the most common adverse reactions associated with HYFTOR application were application site irritation (31%), dry skin (28%), acne (20%), pruritus (9%), eye irritation (9%), erythema (7%), acneiform dermatitis (6%), contact dermatitis (5%), solar dermatitis (1%), and photosensitivity reaction (1%). Adverse reactions occurred with similar frequency in adult and pediatric subjects 6 years of age and older.

Table 2 presents clinically significant drug interactions involving drugs that affect HYFTOR.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 2: Effects of CYP3A4 Inhibitors on HYFTOR</span> </caption> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="80%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Concomitant use of HYFTOR with inhibitors of CYP3A4 has the potential to increase the systemic exposure of sirolimus and increase the risk of HYFTOR adverse reactions.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Monitor for adverse reactions of HYFTOR.</td> </tr> </tbody> </table></div>

Systemic exposure of drugs that are both substrates and inhibitors of CYP3A could be increased with coadministration with HYFTOR. Monitor for adverse reactions of such co-administered drugs.

Risk Summary

Based on animal studies and mechanism of action, oral sirolimus can cause fetal harm when administered to a pregnant woman. HYFTOR is systemically absorbed after topical administration and may result in fetal exposure. The available data from case reports on HYFTOR use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with HYFTOR. In an animal reproduction study, oral administration of 0.5 mg/kg/day sirolimus caused embryo-fetal lethality in pregnant rats when administered during the period of organogenesis (see Data). The available data do not allow the calculation of relevant comparisons between the systemic exposure of sirolimus observed in animal studies to the systemic exposure that would be expected in humans after topical use of HYFTOR.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Data

Animal Data

In embryo-fetal development studies in rats, oral administration of sirolimus to pregnant rats during the period of organogenesis (gestation days 6 -15) induced embryo-fetal lethality at 0.5 mg/kg/day, reduced fetal body weight at 1.0 mg/kg/day and caused maternal toxicity at 2.0 mg/kg/day. No treatment related embryo-fetal developmental effects were observed at 0.1 mg/kg/day.

In embryo-fetal development studies in rabbits, oral administration of sirolimus to pregnant rabbits during the period of organogenesis (gestation days 6 -18) induced maternal toxicity (decreased body weight) at 0.05 mg/kg/day, which was associated with embryo-fetal loss or early resorption. No treatment related developmental effects were observed at 0.025 mg/kg/day.

In a pre- and postnatal development toxicity study, oral administration of sirolimus to pregnant rats during gestation and lactation (gestation day 6 through lactation day 20) increased the incidence of dead pups, resulting in reduced live litter size at 0.5 mg/kg/day. No treatment related developmental effects were observed at 0.1 mg/kg/day.

Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg/day, the highest dose tested.

Risk Summary

There are no available data on the presence of sirolimus in human milk, the effects on the breastfed infant, or the effects on milk production. After oral administration, sirolimus was present in the milk of lactating rats. Because of the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during treatment with HYFTOR.

Contraception

Based on animal studies with oral sirolimus, HYFTOR may cause fetal harm when administered to pregnant women. Females of reproductive potential are recommended to avoid becoming pregnant and to use an effective contraceptive method. Effective contraception should be initiated before HYFTOR therapy and used throughout treatment and for 12 weeks after the final dose of HYFTOR [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)] .

Infertility

Based on clinical findings and findings in animal studies, male and female fertility may be compromised by the treatment with sirolimus [see Warnings and Precautions (5.8), Nonclinical Toxicology (13.1)]. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of oral sirolimus. Azoospermia has been reported in males with the use of oral sirolimus and have been reversible upon discontinuation of sirolimus in most cases.

The safety and effectiveness of HYFTOR have been established in pediatric patients aged 6 years and older for the topical treatment of facial angiofibroma associated with tuberous sclerosis. Use of HYFTOR in this age group is supported by data from a randomized, vehicle-controlled, double-blind 12-week trial along with additional efficacy and long-term safety data from a 104-week open label safety trial. A total of 13 pediatric subjects aged 6 years to 17 years received HYFTOR in the Phase 3 clinical trial along with 48 pediatric subjects aged 3 years to 17 years in the 104-week open label safety trial. Adverse reactions occurred with similar frequency in adult and pediatric subjects [see Adverse Reaction (6.1), Clinical Studies (14)].

The safety and effectiveness of HYFTOR for this indication have not been established in pediatric patients less than 6 years of age.

Clinical studies of HYFTOR did not include sufficient numbers of subjects aged 65 years 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.

HYFTOR™ (sirolimus topical gel) 0.2% is an mTOR inhibitor immunosuppressant for topical use. Each gram contains 2 mg of sirolimus, which is solubilized in a gel consisting of alcohol 51%, Carbomer 940, purified water, and trolamine.

{ "type": "p", "children": [], "text": "HYFTOR™ (sirolimus topical gel) 0.2% is an mTOR inhibitor immunosuppressant for topical use. Each gram contains 2 mg of sirolimus, which is solubilized in a gel consisting of alcohol 51%, Carbomer 940, purified water, and trolamine." }

Chemically, sirolimus is designated as (3 S,6 R,7 E,9 R,10 R,12 R,14 S,15 E,17 E,19 E,21 S,23 S,26 R,27 R,34a S)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1 R)-2-[(1 S,3 R,4 R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3 H-pyrido[2,1- c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4 H,6 H,31 H)-pentone. It has the following structural formula:

{ "type": "p", "children": [], "text": "Chemically, sirolimus is designated as (3\n \n \n S,6\n \n \n R,7\n \n \n E,9\n \n \n R,10\n \n \n R,12\n \n \n R,14\n \n \n S,15\n \n \n E,17\n \n \n E,19\n \n \n E,21\n \n \n S,23\n \n \n S,26\n \n \n R,27\n \n \n R,34a\n \n \n S)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1\n \n \n R)-2-[(1\n \n \n S,3\n \n \n R,4\n \n \n R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3\n \n \n H-pyrido[2,1-\n \n \n c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4\n \n \n H,6\n \n \n H,31\n \n \n H)-pentone. It has the following structural formula:\n \n\n " }

Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in chloroform, acetone and acetonitrile. Sirolimus has a molecular formula of C 51H 79NO 13 and a molecular weight of 914.19.

{ "type": "p", "children": [], "text": "Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in chloroform, acetone and acetonitrile. Sirolimus has a molecular formula of C\n \n \n 51H\n \n \n 79NO\n \n \n 13 and a molecular weight of 914.19.\n \n\n " }

The mechanism of action of sirolimus in the treatment of angiofibroma associated with tuberous sclerosis is unknown. Tuberous sclerosis is associated with genetic defects in TSC1 and TSC2 which leads to the constitutive activation of mammalian target of rapamycin (mTOR). Sirolimus inhibits mTOR activation.

Absorption

Following 12 weeks of treatment with HYFTOR in adult and pediatric subjects aged 6 years and older, sirolimus blood concentrations ranged from undetectable to 0.50 ng/mL after multiple doses of HYFTOR in the Phase 3 trial. Periodic blood samples were obtained in the 52-week trial and the maximum sirolimus concentration measured at any time in adult subjects was 3.27 ng/mL and the maximum sirolimus concentration measured at any time in pediatric subjects was 1.80 ng/mL.

Distribution

There was no evidence based on blood concentrations that sirolimus accumulates systemically upon topical application in patients with tuberous sclerosis for periods of up to 1 year.

Elimination

Metabolism

Studies evaluating the metabolism of HYFTOR have not been conducted.

Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized after oral administration in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations. Sirolimus is extensively metabolized by O-demethylation and/or hydroxylation. Seven (7) major metabolites, including hydroxy, demethyl, and hydroxydemethyl, are identifiable in whole blood. Some of these metabolites are also detectable in plasma, fecal, and urine samples. Sirolimus is the major component in human whole blood and contributes to more than 90% of the immunosuppressive activity.

Excretion

Studies evaluating the excretion of HYFTOR have not been conducted.

After a single dose of [ 14C] sirolimus oral solution in healthy volunteers, the majority (91%) of radioactivity was recovered from the feces, and only a minor amount (2.2%) was excreted in urine. The mean ± SD terminal elimination half-life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours.

Drug Interaction Studies

Drug interaction studies with HYFTOR have not been conducted. Sirolimus is known to be a substrate for both cytochrome P-450 3A4 (CYP3A4) and p-glycoprotein (P-gp). [see Drug Interactions (7.1, 7.2)] .

Oral carcinogenicity studies were conducted in mice and rats. In an oral carcinogenicity study conducted in female mice, sirolimus administered once daily for 86 weeks was associated with a statistically significant increase in malignant lymphoma at all dose levels compared with control animals. In a second oral mouse carcinogenicity study, sirolimus-related hepatocellular adenoma and carcinoma were induced in male mice. In an oral carcinogenicity study conducted in rats with sirolimus there were no significant findings.

Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.

Fertility was decreased in both male and female rats following oral administration of sirolimus 2.0 and 0.5 mg/kg, respectively. In male rats, atrophy of testes, epididymides, prostate, seminiferous tubules and/or reduced sperm counts were observed. In female rats, decreased ovarian and uterine weights and decreased implantation were observed. Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at 0.1 mg/kg.

A single, randomized, double-blind, vehicle-controlled, multi-center, Phase 3 trial was conducted in Japan to evaluate HYFTOR for the treatment of adults and pediatric patients 6 years of age and older with facial angiofibroma associated with tuberous sclerosis (NCT02635789). A total of 62 Japanese subjects with 3 or more angiofibromas (≥2 mm in diameter with redness in each) on the face were enrolled in this trial. Overall, 28 subjects (45%) were male and 34 (55%) were female. A total of 25 subjects (40%) were between 6 and <18 years of age. In this trial, subjects applied either HYFTOR or vehicle twice daily to the skin of their face affected with angiofibroma for 12 weeks.

{ "type": "p", "children": [], "text": "A single, randomized, double-blind, vehicle-controlled, multi-center, Phase 3 trial was conducted in Japan to evaluate HYFTOR for the treatment of adults and pediatric patients 6 years of age and older with facial angiofibroma associated with tuberous sclerosis (NCT02635789). A total of 62 Japanese subjects with 3 or more angiofibromas (≥2 mm in diameter with redness in each) on the face were enrolled in this trial. Overall, 28 subjects (45%) were male and 34 (55%) were female. A total of 25 subjects (40%) were between 6 and <18 years of age. In this trial, subjects applied either HYFTOR or vehicle twice daily to the skin of their face affected with angiofibroma for 12 weeks." }

The efficacy was assessed by the investigator (live assessment) based on the composite improvement from baseline in size and redness of facial angiofibroma, using subjects' baseline photographs as reference. The proportion of subjects assessed as 'Improved' or 'Markedly Improved' at Week 12 is presented in Table 3. An assessment of 'Improved' was defined as at least a 50% reduction in the size and a 2-level reduction in redness and an assessment of 'Markedly Improved' was defined as at least a 75% reduction in the size and a 3-level reduction in redness.

{ "type": "p", "children": [], "text": "The efficacy was assessed by the investigator (live assessment) based on the composite improvement from baseline in size and redness of facial angiofibroma, using subjects' baseline photographs as reference. The proportion of subjects assessed as 'Improved' or 'Markedly Improved' at Week 12 is presented in Table 3. An assessment of 'Improved' was defined as at least a 50% reduction in the size and a 2-level reduction in redness and an assessment of 'Markedly Improved' was defined as at least a 75% reduction in the size and a 3-level reduction in redness." }

<div class="scrollingtable"><table width="60%"> <caption> <span>Table 3: Improvement in Facial Angiofibroma Associated with Tuberous Sclerosis in Patients Aged 6 Years and Older at Week 12</span> </caption> <col align="left" valign="top" width="50%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Proportion of Subjects Assessed by the Investigator as:</th><th align="center" class="Rrule" valign="top">HYFTOR <br/>N=30 </th><th align="center" class="Rrule" valign="top">Vehicle <br/>N=32 </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">'Improved' or 'Markedly Improved'</td><td align="center" class="Rrule">23%</td><td align="center" class="Rrule">6%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">'Improved'</td><td align="center" class="Rrule">13%</td><td align="center" class="Rrule">3%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">'Markedly Improved'</td><td align="center" class="Rrule">10%</td><td align="center" class="Rrule">3%</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"60%\">\n<caption>\n<span>Table 3: Improvement in Facial Angiofibroma Associated with Tuberous Sclerosis in Patients Aged 6 Years and Older at Week 12</span>\n</caption>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"center\" valign=\"middle\" width=\"25%\"/>\n<col align=\"center\" valign=\"middle\" width=\"25%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Lrule Rrule\">Proportion of Subjects Assessed by the Investigator as:</th><th align=\"center\" class=\"Rrule\" valign=\"top\">HYFTOR\n \n \n <br/>N=30\n \n \n </th><th align=\"center\" class=\"Rrule\" valign=\"top\">Vehicle \n \n \n <br/>N=32\n \n \n </th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\">'Improved' or 'Markedly Improved'</td><td align=\"center\" class=\"Rrule\">23%</td><td align=\"center\" class=\"Rrule\">6%</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">'Improved'</td><td align=\"center\" class=\"Rrule\">13%</td><td align=\"center\" class=\"Rrule\">3%</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\">'Markedly Improved'</td><td align=\"center\" class=\"Rrule\">10%</td><td align=\"center\" class=\"Rrule\">3%</td>\n</tr>\n</tbody>\n</table></div>" }

How Supplied

HYFTOR™ (sirolimus topical gel) 0.2% is a colorless and transparent gel supplied as 10 g in aluminum tubes (NDC 73683-101-10). Each gram contains 2 mg of sirolimus.

Storage and Handling

Store refrigerated at 2° to 8°C (36° to 46°F). Protect from light.

Hypersensitivity

Inform patients that oral sirolimus has been associated with hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis. Advise patients to discontinue HYFTOR immediately and seek medical attention if symptoms occur [see Warnings and Precautions (5.1)] .

Serious Infections

Inform patients that oral sirolimus has been associated with increased susceptibility to infections, including opportunistic infections and latent viral infections, such as progressive multifocal leukoencephalopathy (PML). Advise patients to discontinue HYFTOR immediately and seek medical attention if symptoms occur [see Warnings and Precautions (5.2)] .

Malignancy

Inform patients that oral sirolimus has been associated with malignancy, including lymphoma and skin cancer. Advise patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment), and to use protective measures if exposure cannot be avoided, while using HYFTOR [see Warnings and Precautions (5.3)] .

Hyperlipidemia

Inform patients that oral sirolimus has been associated with increased serum cholesterol and triglycerides requiring treatment and that periodic laboratory monitoring may be needed [see Warnings and Precautions (5.4)] .

Interstitial Lung Disease

Inform patients that oral sirolimus has been associated with interstitial lung disease [ILD] sometimes fatal, with no identified infectious etiology. Advise patients to discontinue HYFTOR immediately and seek medical attention if symptoms (e.g. shortness of breath) occur [see Warnings and Precautions (5.5)] .

Immunization

Inform patients that during treatment with HYFTOR, vaccinations may be less effective. Instruct patients that vaccination with live vaccines should be avoided during treatment with HYFTOR and to inform the healthcare practitioner that they are using HYFTOR prior to a potential vaccination [see Warnings and Precautions (5.6)] .

Pregnancy

HYFTOR may cause fetal harm if used during pregnancy. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception prior to, throughout treatment, and for 12 weeks after the final dose of HYFTOR. Advise pregnant women of the potential risk to a fetus [see Warnings and Precautions (5.7), Use in Specific Populations (8.1, 8.3)].

Lactation

Advise lactating women that breastfeeding is not recommended during treatment with HYFTOR [see Use in Specific Populations (8.2)].

Infertility

Inform male and female patients that HYFTOR may impair fertility [see Warnings and Precautions (5.8), Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Administration Information

Inform patients that the skin being treated with HYFTOR should not be covered with bandages, dressings or wraps [see Dosage and Administration (2)].

Distributed by: Nobelpharma America, LLC 4520 East-West Highway, Suite 400 Bethesda, MD 20814

{ "type": "p", "children": [], "text": "Distributed by:\n \n \n Nobelpharma America, LLC\n \n \n 4520 East-West Highway, Suite 400 \n \n \n Bethesda, MD 20814\n \n\n " }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="3%"/> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="3%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="18%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="4">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="left" colspan="1">Issued: 2/2022 </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="5"><span class="Bold">PATIENT INFORMATION <br/>HYFTOR™ (hyfe tore) <br/>(sirolimus topical gel) </span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Important: HYFTOR is for use on the skin only (topical use).</span> Do not use HYFTOR in your mouth, eyes, or vagina. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What is HYFTOR?</span> <br/>HYFTOR is a prescription medicine that is used on the skin (topical) to treat adults and children 6 years of age and older with a type of noncancerous tumor called angiofibroma on your face caused by the genetic condition tuberous sclerosis. <br/>It is not known if HYFTOR is safe and effective in children under 6 years of age. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Do not use HYFTOR if</span> you are allergic to sirolimus or any of the other ingredients in HYFTOR. See the end of this leaflet for a complete list of ingredients in HYFTOR. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Before using HYFTOR, tell your healthcare provider about all of your medical conditions, including if you:</span> <ul class="Disc"> <li>have a skin infection at the treatment site</li> <li>have high cholesterol or high triglycerides (fat or lipids) in your blood</li> <li>are scheduled to receive an immunization (vaccine). You should avoid receiving live vaccines during treatment with HYFTOR. Vaccines may be less effective during treatment with HYFTOR.</li> <li>are pregnant or plan to become pregnant. HYFTOR may harm your unborn baby. You should not become pregnant during treatment with HYFTOR. <ul class="Circle"> <li>Females who are able to become pregnant should use effective birth control (contraception) before starting treatment with HYFTOR, during treatment, and for 12 weeks after your final dose of HYFTOR. Talk to your healthcare provider about types of birth control that you can use during this time.</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. It is not known if HYFTOR passes into your breast milk. You should not breastfeed during treatment with HYFTOR.</li> </ul> <span class="Bold">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using HYFTOR with certain medicines may affect each other causing side effects. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">How should I use HYFTOR?</span> <ul class="Disc"> <li>Use HYFTOR exactly as your healthcare provider tells you to use it.</li> <li>Before you use HYFTOR, your healthcare provider or pharmacist should show you how to correctly measure your dose.</li> <li>Wash your hands before and after applying HYFTOR.</li> <li>Apply HYFTOR to the skin of the face affected with angiofibroma 2 times a day, in the morning and at bedtime.</li> <li> <span class="Bold">Do not</span> cover, wrap, apply dressings, or bandage the skin area treated with HYFTOR. </li> <li>Tell your healthcare provider if the treated skin area does not improve within 12 weeks of treatment.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What should I avoid while using HYFTOR?</span> <br/>Limit your exposure to sunlight and ultraviolet light, such as tanning beds and ultraviolet light therapy, during treatment with HYFTOR. Wear clothing that covers your skin if you need to go outside. Talk with your healthcare provider about other ways you can protect your skin from the sun. </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are the possible side effects of HYFTOR? <br/>HYFTOR may cause serious side effects, including: </span> <ul class="Disc"> <li> <span class="Bold">Allergic reactions.</span> Serious allergic reactions have happened in people who have taken sirolimus by mouth. Stop using HYFTOR and get medical help right away if you get any of these symptoms of a serious allergic reaction: </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul class="Circle"> <li>swelling of your face, eyes, or mouth</li> <li>trouble breathing or wheezing</li> <li>throat tightness</li> </ul> </td><td align="left"></td><td align="left" class="Rrule" colspan="2"> <ul class="Circle"> <li>chest pain or tightness</li> <li>feeling dizzy or faint</li> <li>rash or peeling of your skin</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">Infections.</span> Serious infections, including infections that can happen when your immune system is weak, have happened in people who have taken sirolimus by mouth. Some people have developed a rare, serious brain infection called progressive multifocal leukoencephalopathy (PML) which can sometimes cause death. Stop using HYFTOR and call your healthcare provider right away if you get symptoms of an infection including fever or chills. </li> <li> <span class="Bold">Risk of cancer.</span> Lymphoma and other cancers, especially skin cancer, have happened in people who have taken sirolimus by mouth. Talk with your healthcare provider about your risk for cancer if you use HYFTOR. </li> <li> <span class="Bold">Increased levels of cholesterol and triglycerides (fat or lipids) in the blood</span> have happened in people who have taken sirolimus by mouth <span class="Bold">.</span> Your healthcare provider may do blood tests to check you for high lipid levels during treatment with HYFTOR and treat you, if needed. </li> <li> <span class="Bold">Lung or breathing problems.</span> Lung or breathing problems, including problems that have sometimes caused death, have happened in people who have taken sirolimus by mouth. Stop using HYFTOR and get medical help right away if you get symptoms such as shortness of breath, new or worsening cough, or chest pain. </li> </ul> <span class="Bold">The most common side effects of HYFTOR include</span> dry skin, application site irritation, itching, acne, acne-like rash, eye redness, skin bleeding, and skin irritation. <br/>HYFTOR may cause fertility problems in males and females, which may affect your ability to have children. Talk to your healthcare provider if this is a concern for you. <br/>These are not all the possible side effects of HYFTOR. <br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">How should I store HYFTOR ?</span> <ul class="Disc"> <li>Store HYFTOR in the refrigerator between at 36°F to 46°F (2°C to 8°C).</li> <li>Keep HYFTOR out of light.</li> </ul> <span class="Bold">Keep HYFTOR and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">General information about the safe and effective use of HYFTOR. </span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use HYFTOR for a condition for which it was not prescribed. Do not give HYFTOR to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about HYFTOR that is written for health professionals. </td> </tr> <tr> <td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are the ingredients in HYFTOR? <br/>Active ingredient: </span> sirolimus <br/> <span class="Bold">Inactive ingredients:</span> alcohol 51%, Carbomer 940, purified water, and trolamine. <br/>Distributed by: Nobelpharma America, LLC <br/>4520 East-West Highway, Suite 400, Bethesda, MD 20814 <br/>For more information, go to www.Hyftor.com or call 887-375-0825. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"3%\"/>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"left\" valign=\"top\" width=\"3%\"/>\n<col align=\"left\" valign=\"top\" width=\"30%\"/>\n<col align=\"left\" valign=\"top\" width=\"18%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"4\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"left\" colspan=\"1\">Issued: 2/2022\t</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">PATIENT INFORMATION\n \n \n <br/>HYFTOR™ (hyfe tore) \n \n \n <br/>(sirolimus topical gel)\n \n \n </span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Important: HYFTOR is for use on the skin only (topical use).</span> Do not use HYFTOR in your mouth, eyes, or vagina. \n \n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What is HYFTOR?</span>\n<br/>HYFTOR is a prescription medicine that is used on the skin (topical) to treat adults and children 6 years of age and older with a type of noncancerous tumor called angiofibroma on your face caused by the genetic condition tuberous sclerosis.\n \n \n <br/>It is not known if HYFTOR is safe and effective in children under 6 years of age.\n \n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Do not use HYFTOR if</span> you are allergic to sirolimus or any of the other ingredients in HYFTOR. See the end of this leaflet for a complete list of ingredients in HYFTOR. \n \n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Before using HYFTOR, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<ul class=\"Disc\">\n<li>have a skin infection at the treatment site</li>\n<li>have high cholesterol or high triglycerides (fat or lipids) in your blood</li>\n<li>are scheduled to receive an immunization (vaccine). You should avoid receiving live vaccines during treatment with HYFTOR. Vaccines may be less effective during treatment with HYFTOR.</li>\n<li>are pregnant or plan to become pregnant. HYFTOR may harm your unborn baby. You should not become pregnant during treatment with HYFTOR.\n \n \n <ul class=\"Circle\">\n<li>Females who are able to become pregnant should use effective birth control (contraception) before starting treatment with HYFTOR, during treatment, and for 12 weeks after your final dose of HYFTOR. Talk to your healthcare provider about types of birth control that you can use during this time.</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if HYFTOR passes into your breast milk. You should not breastfeed during treatment with HYFTOR.</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using HYFTOR with certain medicines may affect each other causing side effects.\n \n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">How should I use HYFTOR?</span>\n<ul class=\"Disc\">\n<li>Use HYFTOR exactly as your healthcare provider tells you to use it.</li>\n<li>Before you use HYFTOR, your healthcare provider or pharmacist should show you how to correctly measure your dose.</li>\n<li>Wash your hands before and after applying HYFTOR.</li>\n<li>Apply HYFTOR to the skin of the face affected with angiofibroma 2 times a day, in the morning and at bedtime.</li>\n<li>\n<span class=\"Bold\">Do not</span> cover, wrap, apply dressings, or bandage the skin area treated with HYFTOR.\n \n \n </li>\n<li>Tell your healthcare provider if the treated skin area does not improve within 12 weeks of treatment.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What should I avoid while using HYFTOR?</span>\n<br/>Limit your exposure to sunlight and ultraviolet light, such as tanning beds and ultraviolet light therapy, during treatment with HYFTOR. Wear clothing that covers your skin if you need to go outside. Talk with your healthcare provider about other ways you can protect your skin from the sun.\n \n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are the possible side effects of HYFTOR?\n \n \n <br/>HYFTOR may cause serious side effects, including:\n \n \n </span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Allergic reactions.</span> Serious allergic reactions have happened in people who have taken sirolimus by mouth. Stop using HYFTOR and get medical help right away if you get any of these symptoms of a serious allergic reaction:\n \n \n </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>swelling of your face, eyes, or mouth</li>\n<li>trouble breathing or wheezing</li>\n<li>throat tightness</li>\n</ul>\n</td><td align=\"left\"></td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Circle\">\n<li>chest pain or tightness</li>\n<li>feeling dizzy or faint</li>\n<li>rash or peeling of your skin</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Infections.</span> Serious infections, including infections that can happen when your immune system is weak, have happened in people who have taken sirolimus by mouth. Some people have developed a rare, serious brain infection called progressive multifocal leukoencephalopathy (PML) which can sometimes cause death. Stop using HYFTOR and call your healthcare provider right away if you get symptoms of an infection including fever or chills.\n \n \n </li>\n<li>\n<span class=\"Bold\">Risk of cancer.</span> Lymphoma and other cancers, especially skin cancer, have happened in people who have taken sirolimus by mouth. Talk with your healthcare provider about your risk for cancer if you use HYFTOR. \n \n \n </li>\n<li>\n<span class=\"Bold\">Increased levels of cholesterol and triglycerides (fat or lipids) in the blood</span> have happened in people who have taken sirolimus by mouth\n \n \n <span class=\"Bold\">.</span> Your healthcare provider may do blood tests to check you for high lipid levels during treatment with HYFTOR and treat you, if needed.\n \n \n </li>\n<li>\n<span class=\"Bold\">Lung or breathing problems.</span> Lung or breathing problems, including problems that have sometimes caused death, have happened in people who have taken sirolimus by mouth. Stop using HYFTOR and get medical help right away if you get symptoms such as shortness of breath, new or worsening cough, or chest pain.\n \n \n </li>\n</ul>\n<span class=\"Bold\">The most common side effects of HYFTOR include</span> dry skin, application site irritation, itching, acne, acne-like rash, eye redness, skin bleeding, and skin irritation.\n \n \n <br/>HYFTOR may cause fertility problems in males and females, which may affect your ability to have children. Talk to your healthcare provider if this is a concern for you. \n \n \n <br/>These are not all the possible side effects of HYFTOR. \n \n \n <br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n \n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">How should I store HYFTOR ?</span>\n<ul class=\"Disc\">\n<li>Store HYFTOR in the refrigerator between at 36°F to 46°F (2°C to 8°C).</li>\n<li>Keep HYFTOR out of light.</li>\n</ul>\n<span class=\"Bold\">Keep HYFTOR and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">General information about the safe and effective use of HYFTOR. </span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use HYFTOR for a condition for which it was not prescribed. Do not give HYFTOR to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about HYFTOR that is written for health professionals.\n \n \n </td>\n</tr>\n<tr>\n<td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are the ingredients in HYFTOR?\n \n \n <br/>Active ingredient:\n \n \n </span> sirolimus\n \n \n <br/>\n<span class=\"Bold\">Inactive ingredients:</span> alcohol 51%, Carbomer 940, purified water, and trolamine.\n \n \n <br/>Distributed by: Nobelpharma America, LLC \n \n \n <br/>4520 East-West Highway, Suite 400, Bethesda, MD 20814\n \n \n <br/>For more information, go to www.Hyftor.com or call 887-375-0825.\n \n \n </td>\n</tr>\n</tbody>\n</table></div>" }

NDC 73683-101-10

{ "type": "p", "children": [], "text": "NDC 73683-101-10" }

HYFTOR™ (sirolimus topical gel) 0.2%

{ "type": "p", "children": [], "text": "HYFTOR™\n \n \n (sirolimus topical gel) 0.2%\n \n\n " }

Nobel pharma

{ "type": "p", "children": [], "text": "Nobel pharma" }

For topical use only | Keep refrigerated | 10 g tube | Rx Only

{ "type": "p", "children": [], "text": "For topical use only | Keep refrigerated | 10 g tube | Rx Only" }

Dispense enclosed Patient Information to patient

{ "type": "p", "children": [], "text": "Dispense enclosed Patient Information to patient" }

Sirolimus is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants.

In patients at low- to moderate-immunologic risk, it is recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [see Dosage and Administration (2.2)].

In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level >80%]), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation [see Dosage and Administration (2.3), Clinical Studies (14.3)].

Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine >4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies [see Clinical Studies (14.2)].

In patients at high-immunologic risk, the safety and efficacy of sirolimus used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient [see Clinical Studies (14.3)].

In pediatric patients, the safety and efficacy of sirolimus have not been established in patients <13 years old, or in pediatric (<18 years) renal transplant patients considered at high-immunologic risk [see Adverse Reactions (6.5), Clinical Studies (14.6)].

The safety and efficacy of de novo use of sirolimus without cyclosporine have not been established in renal transplant patients [see Warnings and Precautions (5.12)].

The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established [see Clinical Studies (14.4)].

Sirolimus is indicated for the treatment of patients with lymphangioleiomyomatosis (LAM).

The initial dose of sirolimus should be administered as soon as possible after transplantation. It is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [see Drug Interactions (7.2)].

Frequent sirolimus dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dose adjustments can be based on simple proportion: new sirolimus dose = current dose × (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: sirolimus loading dose = 3 × (new maintenance dose - current maintenance dose). The maximum sirolimus dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

Two milligrams (2 mg) of sirolimus oral solution have been demonstrated to be clinically equivalent to 2 mg sirolimus tablets; hence, at this dose these two formulations are interchangeable. However, it is not known if higher doses of sirolimus oral solution are clinically equivalent to higher doses of sirolimus tablets on a mg-to-mg basis [see Clinical Pharmacology (12.3)].

Sirolimus and Cyclosporine Combination Therapy

For de novo renal transplant patients, it is recommended that sirolimus oral solution and tablets be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of sirolimus equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range [see Dosage and Administration (2.5)].

Sirolimus Following Cyclosporine Withdrawal

At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the sirolimus dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range [see Dosage and Administration (2.5)]. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased [see Clinical Pharmacology (12.3)].

In patients with high-immunologic risk, it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation [see Clinical Studies (14.3)]. The safety and efficacy of this combination in high-immunologic risk patients has not been studied beyond the first 12 months. Therefore, after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient.

For patients receiving sirolimus with cyclosporine, sirolimus therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of sirolimus should thereafter be adjusted [see Dosage and Administration (2.5)].

The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations [see Dosage and Administration (2.5)]. Prednisone should be administered at a minimum of 5 mg/day.

Antibody induction therapy may be used.

For patients with lymphangioleiomyomatosis, the initial Sirolimus dose should be 2 mg/day. Sirolimus whole blood trough concentrations should be measured in 10–20 days, with dosage adjustment to maintain concentrations between 5–15 ng/mL [see Dosage and Administration (2.5)].

In most patients, dose adjustments can be based on simple proportion: new Sirolimus dose = current dose × (target concentration/current concentration). Frequent Sirolimus dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or under dosing because sirolimus has a long half-life. Once Sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. Once a stable dose is achieved, therapeutic drug monitoring should be performed at least every three months.

Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients ≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment, when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [see Warnings and Precautions (5.20, 5.21),Drug Interactions (7)].

Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters.

When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range [see Clinical Studies (14), Clinical Pharmacology (12.3)]. Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL.

The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable [see Warnings and Precautions (5.17), Clinical Pharmacology (12.3)]. Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Therefore, communication should be maintained with the laboratory performing the assay. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see References (15)].

The initial dosage in patients ≥13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m2/day. The loading dose should be 3 mg/m2.

It is recommended that the maintenance dose of sirolimus be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. It is not necessary to modify the sirolimus loading dose [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Dosage adjustment is not needed in patients with impaired renal function [see Use in Specific Populations (8.7)].

The amber oral dose syringe should be used to withdraw the prescribed amount of sirolimus oral solution from the bottle. Empty the correct amount of sirolimus from the syringe into only a glass or plastic container holding at least two (2) ounces (1/4 cup, 60 mL) of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution [see Drug Interactions (7.3), Clinical Pharmacology (12.3)]. Stir vigorously and drink at once. Refill the container with an additional volume [minimum of four (4) ounces (1/2 cup, 120 mL)] of water or orange juice, stir vigorously, and drink at once.

Sirolimus oral solution contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of sirolimus oral solution. It is important that these recommendations be followed closely.

Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus [see Warnings and Precautions (5.4)]." }

Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. The rates of lymphoma/lymphoproliferative disease observed in Studies 1 and 2 were 0.7–3.2% (for sirolimus-treated patients) versus 0.6–0.8% (azathioprine and placebo control) [see Adverse Reactions (6.1) and (6.2)]. Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended. The use of sirolimus has been associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss and hepatic artery thrombosis (HAT).

In a study in de novo liver transplant patients, the use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss (22% in combination versus 9% on tacrolimus alone). Many of these patients had evidence of infection at or near the time of death.

In this and another study in de novo liver transplant patients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT (7% in combination versus 2% in the control arm); most cases of HAT occurred within 30 days post-transplantation, and most led to graft loss or death.

In a clinical study in stable liver transplant patients 6–144 months post-liver transplantation and receiving a CNI-based regimen, an increased number of deaths was observed in the group converted to a sirolimus-based regimen compared to the group who was continued on a CNI-based regimen, although the difference was not statistically significant (3.8% versus 1.4%) [see Clinical Studies (14.5)].

Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen.

The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended.

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the administration of sirolimus [see Adverse Reactions (6.7)].

Sirolimus has been associated with the development of angioedema. The concomitant use of sirolimus with other drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema. Elevated sirolimus levels (with/without concomitant ACE inhibitors) may also potentiate angioedema [see Drug Interactions (7.2)]. In some cases, the angioedema has resolved upon discontinuation or dose reduction of sirolimus.

There have been reports of impaired or delayed wound healing in patients receiving sirolimus, including lymphocele and wound dehiscence [see Adverse Reactions (6.1)]. Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in patients treated with sirolimus [see Adverse Reactions (6.1)]. Appropriate measures should be considered to minimize such complications. Patients with a body mass index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature.

There have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion, ascites, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving sirolimus.

Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with sirolimus compared with azathioprine or placebo controls in Studies 1 and 2 [see Adverse Reactions (6.1)]. There were increased incidences of hypercholesterolemia (43–46%) and/or hypertriglyceridemia (45–57%) in patients receiving sirolimus compared with placebo controls (each 23%). The risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including sirolimus.

Any patient who is administered sirolimus should be monitored for hyperlipidemia. If detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines.

In clinical trials of patients receiving sirolimus plus cyclosporine or sirolimus after cyclosporine withdrawal, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels. The concomitant administration of sirolimus and HMG-CoA reductase inhibitors resulted in adverse reactions such as CPK elevations (3%), myalgia (6.7%) and rhabdomyolysis (<1%). In these trials, the number of patients was too small and duration of follow-up too short to evaluate the long-term impact of sirolimus on cardiovascular mortality.

During sirolimus therapy with or without cyclosporine, patients should be monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents.

Renal function should be closely monitored during the co-administration of sirolimus with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function. Patients treated with cyclosporine and sirolimus were noted to have higher serum creatinine levels and lower glomerular filtration rates compared with patients treated with cyclosporine and placebo or azathioprine controls (Studies 1 and 2). The rate of decline in renal function in these studies was greater in patients receiving sirolimus and cyclosporine compared with control therapies.

Appropriate adjustment of the immunosuppressive regimen, including discontinuation of sirolimus and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels. In patients at low- to moderate-immunologic risk, continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when the benefits outweigh the risks of this combination for the individual patients. Caution should be exercised when using agents (e.g., aminoglycosides and amphotericin B) that are known to have a deleterious effect on renal function.

In patients with delayed graft function, sirolimus may delay recovery of renal function.

Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors (CNI) to sirolimus in maintenance renal transplant patients 6–120 months post-transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to sirolimus compared with CNI continuation [see Clinical Studies (14.4), Adverse Reactions (6.4)]. Patients with the greatest amount of urinary protein excretion prior to sirolimus conversion were those whose protein excretion increased the most after conversion. New onset nephrosis (nephrotic syndrome) was also reported as a treatment-emergent adverse reaction in 2.2% of the sirolimus conversion group patients in comparison to 0.4% in the CNI continuation group of patients. Nephrotic range proteinuria (defined as urinary protein to creatinine ratio >3.5) was also reported in 9.2% in the sirolimus conversion group of patients in comparison to 3.7% in the CNI continuation group of patients. In some patients, reduction in the degree of urinary protein excretion was observed for individual patients following discontinuation of sirolimus. The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established.

Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus-associated nephropathy, which has been observed in renal transplant patients receiving immunosuppressants, including sirolimus. This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss [see Adverse Reactions (6.7)]. Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy.

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients treated with immunosuppressants, including sirolimus. PML commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Consideration should be given to reducing the amount of immunosuppression in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.

Cases of interstitial lung disease [ILD] (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including sirolimus. In some cases, the ILD was reported with pulmonary hypertension (including pulmonary arterial hypertension [PAH]) as a secondary event. In some cases, the ILD has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the trough sirolimus concentration increases [see Adverse Reactions (6.7)].

The safety and efficacy of de novo use of sirolimus without cyclosporine is not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with sirolimus, mycophenolate mofetil (MMF), steroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of sirolimus without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial.

The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) [see Adverse Reactions (6.7)].

Cases of Pneumocystis carinii pneumonia have been reported in transplant patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for 1 year following transplantation.

Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], sirolimus can cause fetal harm when administered to a pregnant woman. In animal studies, sirolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using sirolimus and for 12 weeks after ending treatment [see Use in Specific Populations (8.1)].

Azoospermia or oligospermia may be observed [see Adverse Reactions (6.7), Nonclinical Toxicology (13.1)]. Sirolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells.

Currently in clinical practice, sirolimus whole blood concentrations are being measured by various chromatographic and immunoassay methodologies. Patient sample concentration values from different assays may not be interchangeable [see Dosage and Administration (2.5)].

Patients on immunosuppressive therapy are at increased risk for skin cancer. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Adverse Reactions (6.1, 6.2, 6.7)].

The use of live vaccines should be avoided during treatment with sirolimus; live vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid. Immunosuppressants may affect response to vaccination. Therefore, during treatment with sirolimus, vaccination may be less effective.

Avoid concomitant use of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) [see Drug Interactions (7.2)].

When cannabidiol and sirolimus are co-administered, closely monitor for an increase in sirolimus blood levels and for adverse reactions suggestive of sirolimus toxicity. A dose reduction of sirolimus should be considered as needed when sirolimus is co-administered with cannabidiol [see Dosage and Administration (2.5),Drug Interactions (7.5)].

The safety and efficacy of sirolimus oral solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials [see Clinical Studies (14.1)]. The safety profiles in the two studies were similar.

The incidence of adverse reactions in the randomized, double-blind, multicenter, placebo-controlled trial (Study 2) in which 219 renal transplant patients received sirolimus oral solution 2 mg/day, 208 received sirolimus oral solution 5 mg/day, and 124 received placebo is presented in Table 1 below. The study population had a mean age of 46 years (range 15 to 71 years), the distribution was 67% male, and the composition by race was: White (78%), Black (11%), Asian (3%), Hispanic (2%), and Other (5%). All patients were treated with cyclosporine and corticosteroids. Data (≥ 12 months post-transplant) presented in the following table show the adverse reactions that occurred in at least one of the sirolimus treatment groups with an incidence of ≥20%.

The safety profile of the tablet did not differ from that of the oral solution formulation [see Clinical Studies (14.1)].

In general, adverse reactions related to the administration of sirolimus were dependent on dose/concentration. Although a daily maintenance dose of 5 mg, with a loading dose of 15 mg, was shown to be safe and effective, no efficacy advantage over the 2 mg dose could be established for renal transplant patients. Patients receiving 2 mg of sirolimus oral solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of sirolimus oral solution per day.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 1: ADVERSE REACTIONS OCCURRING AT A FREQUENCY OF ≥20% IN AT LEAST ONE OF THE SIROLIMUS TREATMENT GROUPS IN A STUDY OF PROPHYLAXIS OF ORGAN REJECTION FOLLOWING RENAL TRANSPLANTATION (%) AT ≥12 MONTHS POST-TRANSPLANTATION (STUDY 2)<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span> </caption> <col width="40%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <thead> <tr class="First"> <th align="left" class="Toprule" valign="top"></th><th align="center" class="Toprule" colspan="2" valign="top"><span class="Bold">–––Sirolimus Oral Solution–––</span></th><th align="left" class="Toprule" valign="top"></th> </tr> <tr class="Last"> <th align="left" class="Botrule" valign="bottom"><span class="Bold">Adverse Reaction</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">2 mg/day</span> <br/> <span class="Bold">(n = 218)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">5 mg/day</span> <br/> <span class="Bold">(n = 208)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">Placebo</span> <br/> <span class="Bold">(n = 124)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Peripheral edema</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">54</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">58</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">48</p> </td> </tr> <tr> <td valign="top"> <p class="First">Hypertriglyceridemia</p> </td><td align="center" valign="top"> <p class="First">45</p> </td><td align="center" valign="top"> <p class="First">57</p> </td><td align="center" valign="top"> <p class="First">23</p> </td> </tr> <tr> <td valign="top"> <p class="First">Hypertension</p> </td><td align="center" valign="top"> <p class="First">45</p> </td><td align="center" valign="top"> <p class="First">49</p> </td><td align="center" valign="top"> <p class="First">48</p> </td> </tr> <tr> <td valign="top"> <p class="First">Hypercholesterolemia</p> </td><td align="center" valign="top"> <p class="First">43</p> </td><td align="center" valign="top"> <p class="First">46</p> </td><td align="center" valign="top"> <p class="First">23</p> </td> </tr> <tr> <td valign="top"> <p class="First">Creatinine increased</p> </td><td align="center" valign="top"> <p class="First">39</p> </td><td align="center" valign="top"> <p class="First">40</p> </td><td align="center" valign="top"> <p class="First">38</p> </td> </tr> <tr> <td valign="top"> <p class="First">Constipation</p> </td><td align="center" valign="top"> <p class="First">36</p> </td><td align="center" valign="top"> <p class="First">38</p> </td><td align="center" valign="top"> <p class="First">31</p> </td> </tr> <tr> <td valign="top"> <p class="First">Abdominal pain</p> </td><td align="center" valign="top"> <p class="First">29</p> </td><td align="center" valign="top"> <p class="First">36</p> </td><td align="center" valign="top"> <p class="First">30</p> </td> </tr> <tr> <td valign="top"> <p class="First">Diarrhea</p> </td><td align="center" valign="top"> <p class="First">25</p> </td><td align="center" valign="top"> <p class="First">35</p> </td><td align="center" valign="top"> <p class="First">27</p> </td> </tr> <tr> <td valign="top"> <p class="First">Headache</p> </td><td align="center" valign="top"> <p class="First">34</p> </td><td align="center" valign="top"> <p class="First">34</p> </td><td align="center" valign="top"> <p class="First">31</p> </td> </tr> <tr> <td valign="top"> <p class="First">Fever</p> </td><td align="center" valign="top"> <p class="First">23</p> </td><td align="center" valign="top"> <p class="First">34</p> </td><td align="center" valign="top"> <p class="First">35</p> </td> </tr> <tr> <td valign="top"> <p class="First">Urinary tract infection</p> </td><td align="center" valign="top"> <p class="First">26</p> </td><td align="center" valign="top"> <p class="First">33</p> </td><td align="center" valign="top"> <p class="First">26</p> </td> </tr> <tr> <td valign="top"> <p class="First">Anemia</p> </td><td align="center" valign="top"> <p class="First">23</p> </td><td align="center" valign="top"> <p class="First">33</p> </td><td align="center" valign="top"> <p class="First">21</p> </td> </tr> <tr> <td valign="top"> <p class="First">Nausea</p> </td><td align="center" valign="top"> <p class="First">25</p> </td><td align="center" valign="top"> <p class="First">31</p> </td><td align="center" valign="top"> <p class="First">29</p> </td> </tr> <tr> <td valign="top"> <p class="First">Arthralgia</p> </td><td align="center" valign="top"> <p class="First">25</p> </td><td align="center" valign="top"> <p class="First">31</p> </td><td align="center" valign="top"> <p class="First">18</p> </td> </tr> <tr> <td valign="top"> <p class="First">Thrombocytopenia</p> </td><td align="center" valign="top"> <p class="First">14</p> </td><td align="center" valign="top"> <p class="First">30</p> </td><td align="center" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td valign="top"> <p class="First">Pain</p> </td><td align="center" valign="top"> <p class="First">33</p> </td><td align="center" valign="top"> <p class="First">29</p> </td><td align="center" valign="top"> <p class="First">25</p> </td> </tr> <tr> <td valign="top"> <p class="First">Acne</p> </td><td align="center" valign="top"> <p class="First">22</p> </td><td align="center" valign="top"> <p class="First">22</p> </td><td align="center" valign="top"> <p class="First">19</p> </td> </tr> <tr> <td valign="top"> <p class="First">Rash</p> </td><td align="center" valign="top"> <p class="First">10</p> </td><td align="center" valign="top"> <p class="First">20</p> </td><td align="center" valign="top"> <p class="First">6</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Edema</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">18</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">15</p> </td> </tr> </tbody> </table></div>

The following adverse reactions were reported less frequently (≥3%, but <20%)

Less frequently (<3%) occurring adverse reactions included: lymphoma/post-transplant lymphoproliferative disorder, mycobacterial infections (including M. tuberculosis), pancreatitis, cytomegalovirus (CMV), and Epstein-Barr virus.

Increased Serum Cholesterol and Triglycerides

The use of sirolimus in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment.

In Studies 1 and 2, in de novo renal transplant patients who began the study with fasting, total serum cholesterol <200 mg/dL or fasting, total serum triglycerides <200 mg/dL, there was an increased incidence of hypercholesterolemia (fasting serum cholesterol >240 mg/dL) or hypertriglyceridemia (fasting serum triglycerides >500 mg/dL), respectively, in patients receiving both sirolimus 2 mg and sirolimus 5 mg compared with azathioprine and placebo controls.

Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42–52% of patients enrolled in the sirolimus arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm. In other sirolimus renal transplant studies, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels [see Warnings and Precautions (5.7)].

Abnormal Healing

Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia, and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary).

Malignancies

Table 2 below summarizes the incidence of malignancies in the two controlled trials (Studies 1 and 2) for the prevention of acute rejection [see Clinical Studies (14.1)].

At 24 months (Study 1) and 36 months (Study 2) post-transplant, there were no significant differences among treatment groups.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 2: INCIDENCE (%) OF MALIGNANCIES IN STUDY 1 (24 MONTHS) AND STUDY 2 (36 MONTHS) POST-TRANSPLANT<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-3" name="footnote-reference-3">†</a></span> </caption> <col width="30%"/> <col width="14%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="13%"/> <col width="12%"/> <thead> <tr class="First"> <th align="left" class="Toprule" rowspan="2" valign="bottom"><span class="Bold">Malignancy</span></th><th align="center" class="Toprule" colspan="2" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">2 mg/day</span></th><th align="center" class="Toprule" colspan="2" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">5 mg/day</span></th><th align="center" class="Toprule" valign="top"><span class="Bold">Azathioprine</span> <br/> <span class="Bold">2–3 mg/kg/day</span></th><th align="center" class="Toprule" valign="bottom"><span class="Bold">Placebo</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule" valign="top"><span class="Bold">Study 1</span> <br/> <span class="Bold">(n = 284)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">Study 2</span> <br/> <span class="Bold">(n = 227)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">Study 1</span> <br/> <span class="Bold">(n = 274)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">Study 2</span> <br/> <span class="Bold">(n = 219)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">Study 1</span> <br/> <span class="Bold">(n = 161)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">Study 2</span> <br/> <span class="Bold">(n = 130)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">‡</a> </dt> <dd>Patients may be counted in more than one category.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Lymphoma/lymphoproliferative disease</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">0.7</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">1.8</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">1.1</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">3.2</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">0.6</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">0.8</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Skin Carcinoma</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Any Squamous Cell<a class="Sup" href="#footnote-4" name="footnote-reference-4">‡</a> </p> </td><td align="center" valign="top"> <p class="First">0.4</p> </td><td align="center" valign="top"> <p class="First">2.7</p> </td><td align="center" valign="top"> <p class="First">2.2</p> </td><td align="center" valign="top"> <p class="First">0.9</p> </td><td align="center" valign="top"> <p class="First">3.8</p> </td><td align="center" valign="top"> <p class="First">3.0</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Any Basal Cell<a class="Sup" href="#footnote-4">‡</a> </p> </td><td align="center" valign="top"> <p class="First">0.7</p> </td><td align="center" valign="top"> <p class="First">2.2</p> </td><td align="center" valign="top"> <p class="First">1.5</p> </td><td align="center" valign="top"> <p class="First">1.8</p> </td><td align="center" valign="top"> <p class="First">2.5</p> </td><td align="center" valign="top"> <p class="First">5.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Melanoma</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.4</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">1.4</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Miscellaneous/Not Specified</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.8</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Total</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">1.1</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">4.4</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">3.3</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">4.1</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">4.3</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">7.7</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Other Malignancy</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">1.1</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">2.2</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">1.5</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">1.4</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">0.6</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">2.3</span> </p> </td> </tr> </tbody> </table></div>

The incidence of adverse reactions was determined through 36 months in a randomized, multicenter, controlled trial (Study 3) in which 215 renal transplant patients received sirolimus as a maintenance regimen following cyclosporine withdrawal, and 215 patients received sirolimus with cyclosporine therapy [see Clinical Studies (14.2)]. All patients were treated with corticosteroids. The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2 mg sirolimus groups in Studies 1 and 2.

Following randomization (at 3 months), patients who had cyclosporine eliminated from their therapy experienced higher incidences of the following adverse reactions: abnormal liver function tests (including increased AST/SGOT and increased ALT/SGPT), hypokalemia, thrombocytopenia, and abnormal healing. Conversely, the incidence of the following adverse events was higher in patients who remained on cyclosporine than those who had cyclosporine withdrawn from therapy: hypertension, cyclosporine toxicity, increased creatinine, abnormal kidney function, toxic nephropathy, edema, hyperkalemia, hyperuricemia, and gum hyperplasia. Mean systolic and diastolic blood pressure improved significantly following cyclosporine withdrawal.

Malignancies

The incidence of malignancies in Study 3 [see Clinical Studies (14.2)] is presented in Table 3.

In Study 3, the incidence of lymphoma/lymphoproliferative disease was similar in all treatment groups. The overall incidence of malignancy was higher in patients receiving sirolimus plus cyclosporine compared with patients who had cyclosporine withdrawn. Conclusions regarding these differences in the incidence of malignancy could not be made because Study 3 was not designed to consider malignancy risk factors or systematically screen subjects for malignancy. In addition, more patients in the sirolimus with cyclosporine group had a pre-transplantation history of skin carcinoma.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 3: INCIDENCE (%) OF MALIGNANCIES IN STUDY 3 (CYCLOSPORINE WITHDRAWAL STUDY) AT 36 MONTHS POST-TRANSPLANT<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a></span> </caption> <col width="32%"/> <col width="23%"/> <col width="23%"/> <col width="23%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">Malignancy</span></th><th align="center" class="Botrule Toprule" valign="bottom"><span class="Bold">Nonrandomized</span> <br/> <span class="Bold">(n = 95)</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus with Cyclosporine Therapy</span> <br/> <span class="Bold">(n = 215)</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Following Cyclosporine Withdrawal</span> <br/> <span class="Bold">(n = 215)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">‡</a> </dt> <dd>Patients may be counted in more than one category.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Lymphoma/lymphoproliferative disease</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">1.1</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">1.4</span> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First"> <span class="Bold">0.5</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Skin Carcinoma</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Any Squamous Cell<a class="Sup" href="#footnote-7" name="footnote-reference-7">‡</a> </p> </td><td align="center" valign="top"> <p class="First">3.2</p> </td><td align="center" valign="top"> <p class="First">3.3</p> </td><td align="center" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Any Basal Cell<a class="Sup" href="#footnote-7">‡</a> </p> </td><td align="center" valign="top"> <p class="First">3.2</p> </td><td align="center" valign="top"> <p class="First">6.5</p> </td><td align="center" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Melanoma</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td><td align="center" valign="top"> <p class="First">0.5</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Miscellaneous/Not Specified</p> </td><td align="center" valign="top"> <p class="First">1.1</p> </td><td align="center" valign="top"> <p class="First">0.9</p> </td><td align="center" valign="top"> <p class="First">0.0</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Total</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">4.2</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">7.9</span> </p> </td><td align="center" valign="top"> <p class="First"> <span class="Bold">3.7</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Other Malignancy</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">3.2</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">3.3</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">1.9</span> </p> </td> </tr> </tbody> </table></div>

Safety was assessed in 224 patients who received at least one dose of sirolimus with cyclosporine [see Clinical Studies (14.3)]. Overall, the incidence and nature of adverse reactions was similar to those seen in previous combination studies with sirolimus. The incidence of malignancy was 1.3% at 12 months.

The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant population have not been established [see Clinical Studies (14.4)]. In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (initial target sirolimus concentrations of 12–20 ng/mL, and then 8–20 ng/mL, by chromatographic assay) in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n = 87) with a baseline glomerular filtration rate of less than 40 mL/min. There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this stratum of the sirolimus treatment arm.

The subset of patients with a baseline glomerular filtration rate of less than 40 mL/min had 2 years of follow-up after randomization. In this population, the rate of pneumonia was 25.9% (15/58) versus 13.8% (4/29), graft loss (excluding death with functioning graft loss) was 22.4% (13/58) versus 31.0% (9/29), and death was 15.5% (9/58) versus 3.4% (1/29) in the sirolimus conversion group and CNI continuation group, respectively.

In the subset of patients with a baseline glomerular filtration rate of greater than 40 mL/min, there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the sirolimus conversion arm.

Overall in this study, a 5-fold increase in the reports of tuberculosis among sirolimus 2.0% (11/551) and comparator 0.4% (1/273) treatment groups was observed with 2:1 randomization scheme.

In a second study evaluating the safety and efficacy of conversion from tacrolimus to sirolimus 3 to 5 months post-kidney transplant, a higher rate of adverse events, discontinuations due to adverse events, acute rejection, and new onset diabetes mellitus was observed following conversion to sirolimus. There was also no benefit with respect to renal function and a greater incidence of proteinuria was observed after conversion to sirolimus [see Clinical Studies (14.4)].

Safety was assessed in a controlled clinical trial in pediatric (<18 years of age) renal transplant patients considered at high-immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy [see Clinical Studies (14.6)]. The use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with a higher incidence of deterioration of renal function (creatinine increased) compared to calcineurin inhibitor-based therapy, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections.

Safety was assessed in a controlled trial involving 89 patients with lymphangioleiomyomatosis, 46 of whom were treated with sirolimus [see Clinical Studies (14.7)]. The adverse drug reactions observed in this trial were consistent with the known safety profile for renal transplant patients receiving sirolimus, with the addition of weight decreased which was reported at a greater incidence with sirolimus when compared to placebo. Adverse reactions occurring at a frequency of ≥20% in the sirolimus treatment group and greater than placebo include stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.

The following adverse reactions have been identified during post-approval use of sirolimus in transplant patients. 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.

Cyclosporine, a substrate and inhibitor of CYP3A4 and P-gp, was demonstrated to increase sirolimus concentrations when co-administered with sirolimus. In order to diminish the effect of this interaction with cyclosporine, it is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). If cyclosporine is withdrawn from combination therapy with sirolimus, higher doses of sirolimus are needed to maintain the recommended sirolimus trough concentration ranges [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp. Alternative agents with lesser interaction potential with sirolimus should be considered [see Warnings and Precautions (5.20), Clinical Pharmacology (12.3)].

Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with or be used for dilution of sirolimus [see Dosage and Administration (2.9), Drug Interactions (7.3), Clinical Pharmacology (12.3)].

Exercise caution when using sirolimus with drugs or agents that are modulators of CYP3A4 and P-gp. The dosage of sirolimus and/or the co-administered drug may need to be adjusted [see Clinical Pharmacology (12.3)].

Risk Summary

Based on animal studies and the mechanism of action, sirolimus can cause fetal harm when administered to a pregnant woman [see Data, Clinical Pharmacology (12.1)]. There are limited data on the use of sirolimus during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal studies, sirolimus was embryo/fetotoxic in rats at sub-therapeutic doses [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for 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 2–4% and 15–20%, respectively.

Data

Animal Data

Sirolimus crossed the placenta and was toxic to the conceptus.

In rat embryo-fetal development studies, pregnant rats were administered sirolimus orally during the period of organogenesis (Gestational Day 6–15). Sirolimus produced embryo-fetal lethality at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) and reduced fetal weight at 1 mg/kg (5-fold the clinical dose of 2 mg). The no observed adverse effect level (NOAEL) for fetal toxicity in rats was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg). Maternal toxicity (weight loss) was observed at 2 mg/kg (10-fold the clinical dose of 2 mg). The NOAEL for maternal toxicity was 1 mg/kg. In combination with cyclosporine, rats had increased embryo-fetal mortality compared with sirolimus alone.

In rabbit embryo-fetal development studies, pregnant rabbits were administered sirolimus orally during the period of organogenesis (Gestational Day 6–18). There were no effects on embryo-fetal development at doses up to 0.05 mg/kg (0.5-fold the clinical dose of 2 mg, on a body surface area basis); however, at doses of 0.05 mg/kg and above, the ability to sustain a successful pregnancy was impaired (i.e., embryo-fetal abortion or early resorption). Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg (0.25-fold the clinical dose of 2 mg).

In a pre- and post-natal development study in rats, pregnant females were dosed during gestation and lactation (Gestational Day 6 through Lactation Day 20). An increased incidence of dead pups, resulting in reduced live litter size, occurred at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg/kg on a body surface area basis). At 0.1 mg/kg (0.5-fold the clinical dose of 2 mg), there were no adverse effects on offspring. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest dose tested.

Risk Summary

It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action [see Clinical Pharmacology (12.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sirolimus and any potential adverse effects on the breastfed child from sirolimus.

Contraception

Females should not be pregnant or become pregnant while receiving sirolimus. Advise females of reproductive potential that animal studies have been shown sirolimus to be harmful to the developing fetus. Females of reproductive potential are recommended to use highly effective contraceptive method. Effective contraception must be initiated before sirolimus therapy, during sirolimus therapy, and for 12 weeks after sirolimus therapy has been stopped [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)].

Infertility

Based on clinical findings and findings in animals, male and female fertility may be compromised by the treatment with sirolimus [see Adverse Reactions (6.7), Nonclinical Toxicology (13.1)]. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of sirolimus. Azoospermia has been reported in males with the use of sirolimus and has been reversible upon discontinuation of sirolimus in most cases.

Renal Transplant

The safety and efficacy of sirolimus in pediatric patients <13 years have not been established.

The safety and efficacy of sirolimus oral solution and sirolimus tablets have been established for prophylaxis of organ rejection in renal transplantation in children ≥13 years judged to be at low- to moderate-immunologic risk. Use of sirolimus oral solution and sirolimus tablets in this subpopulation of children ≥13 years is supported by evidence from adequate and well-controlled trials of sirolimus oral solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients [see Clinical Pharmacology (12.3)].

Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (<18 years of age) renal transplant patients judged to be at high-immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of sirolimus oral solution or tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival [see Clinical Studies (14.6)].

Lymphangioleiomyomatosis

The safety and efficacy of Sirolimus in pediatric patients <18 years have not been established.

Clinical studies of sirolimus oral solution or tablets did not include sufficient numbers of patients ≥65 years to determine whether they respond differently from younger patients. Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary. Differences in responses between the elderly and younger patients have not been identified. 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, or cardiac function, and of concomitant disease or other drug therapy.

The maintenance dose of sirolimus should be reduced in patients with hepatic impairment [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)].

Dosage adjustment is not required in patients with renal impairment [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)].

Reports of overdose with sirolimus have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section [see Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "Reports of overdose with sirolimus have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section [see Adverse Reactions (6)]." }

General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD50 was greater than 800 mg/kg.

{ "type": "p", "children": [], "text": "General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD50 was greater than 800 mg/kg." }

Sirolimus is an mTOR inhibitor immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone. Its molecular formula is C51H79NO13 and its molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows.

{ "type": "p", "children": [], "text": "Sirolimus is an mTOR inhibitor immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone. Its molecular formula is C51H79NO13 and its molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows. " }

Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.

{ "type": "p", "children": [], "text": "Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile. " }

Sirolimus is available for administration as an oral solution containing 1 mg/mL sirolimus.

{ "type": "p", "children": [], "text": "Sirolimus is available for administration as an oral solution containing 1 mg/mL sirolimus. " }

The inactive ingredients in sirolimus oral solution are Phosal 50 PG® (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Sirolimus oral solution contains 1.5% – 2.5% ethanol.

{ "type": "p", "children": [], "text": "The inactive ingredients in sirolimus oral solution are Phosal 50 PG® (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Sirolimus oral solution contains 1.5% – 2.5% ethanol." }

Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.

Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability.

Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats. In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific.

In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.

Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.

Orally-administered sirolimus, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at 6 months following transplantation compared with either azathioprine or placebo [see Clinical Studies (14.1)]. There was no demonstrable efficacy advantage of a daily maintenance dose of 5 mg with a loading dose of 15 mg over a daily maintenance dose of 2 mg with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range [see Dosage and Administration (2.5)].

Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients.

The pharmacokinetic parameters of sirolimus in low- to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in Table 4.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 4: MEAN ± SD STEADY STATE SIROLIMUS PHARMACOKINETIC PARAMETERS IN LOW- TO MODERATE-IMMUNOLOGIC RISK ADULT RENAL TRANSPLANT PATIENTS FOLLOWING SIROLIMUS 2 MG DAILY<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-9" name="footnote-reference-9">†</a></span> </caption> <col width="46%"/> <col width="27%"/> <col width="27%"/> <thead> <tr class="First"> <th align="left" class="Toprule" valign="top"></th><th align="center" class="Toprule" colspan="2" valign="top"><span class="Bold">Multiple Dose (daily dose)</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule" valign="top"></th><th align="center" class="Botrule" valign="top"><span class="Bold">Solution</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">Tablets</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>In presence of cyclosporine administered 4 hours before sirolimus dosing.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">†</a> </dt> <dd>Based on data collected at months 1 and 3 post-transplantation.</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">‡</a> </dt> <dd>Average C<span class="Sub">min</span> over 6 months.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">C<span class="Sub">max</span> (ng/mL)</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">14.4 ± 5.3</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">15.0 ± 4.9</p> </td> </tr> <tr> <td valign="top"> <p class="First">t<span class="Sub">max</span> (hr)</p> </td><td align="center" valign="top"> <p class="First">2.1 ± 0.8</p> </td><td align="center" valign="top"> <p class="First">3.5 ± 2.4</p> </td> </tr> <tr> <td valign="top"> <p class="First">AUC (ng∙h/mL)</p> </td><td align="center" valign="top"> <p class="First">194 ± 78</p> </td><td align="center" valign="top"> <p class="First">230 ± 67</p> </td> </tr> <tr> <td valign="top"> <p class="First">C<span class="Sub">min</span> (ng/mL)<a class="Sup" href="#footnote-10" name="footnote-reference-10">‡</a> </p> </td><td align="center" valign="top"> <p class="First">7.1 ± 3.5</p> </td><td align="center" valign="top"> <p class="First">7.6 ± 3.1</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">CL/F (mL/h/kg)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">173 ± 50</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">139 ± 63</p> </td> </tr> </tbody> </table></div>

Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUCτ,ss. Upon repeated, twice-daily administration without an initial loading dose in a multiple-dose study, the average trough concentration of sirolimus increases approximately 2- to 3-fold over the initial 6 days of therapy, at which time steady-state is reached. A loading dose of 3 times the maintenance dose will provide near steady-state concentrations within 1 day in most patients [see Dosage and Administration (2.3, 2.5), Warning and Precautions (5.17)].

Absorption

Following administration of sirolimus oral solution, the mean times to peak concentration (tmax) of sirolimus are approximately 1 hour and 2 hours in healthy subjects and renal transplant patients, respectively. The systemic availability of sirolimus is low, and was estimated to be approximately 14% after the administration of sirolimus oral solution. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of sirolimus oral solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m2.

Food Effects

To minimize variability in sirolimus concentrations, both sirolimus oral solution and tablets should be taken consistently with or without food [see Dosage and Administration (2)]. In healthy subjects, a high-fat meal (861.8 kcal, 54.9% kcal from fat) increased the mean total exposure (AUC) of sirolimus by 23 to 35%, compared with fasting. The effect of food on the mean sirolimus Cmax was inconsistent depending on the sirolimus dosage form evaluated.

Distribution

The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (Vss/F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins, mainly serum albumin (97%), α1-acid glycoprotein, and lipoproteins.

Metabolism

Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations [see Warnings and Precautions (5.20) and Drug Interactions (7)]. Sirolimus is extensively metabolized by O-demethylation and/or hydroxylation. Seven (7) major metabolites, including hydroxy, demethyl, and hydroxydemethyl, are identifiable in whole blood. Some of these metabolites are also detectable in plasma, fecal, and urine samples. Sirolimus is the major component in human whole blood and contributes to more than 90% of the immunosuppressive activity.

Excretion

After a single dose of [14C] sirolimus oral solution in healthy volunteers, the majority (91%) of radioactivity was recovered from the feces, and only a minor amount (2.2%) was excreted in urine. The mean ± SD terminal elimination half-life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours.

Sirolimus Concentrations (Chromatographic Equivalent) Observed in Phase 3 Clinical Studies

The following sirolimus concentrations (chromatographic equivalent) were observed in phase 3 clinical studies for prophylaxis of organ rejection in de novo renal transplant patients [see Clinical Studies (14)].

<div class="scrollingtable"><table width="95%"> <caption> <span>TABLE 5: SIROLIMUS WHOLE BLOOD TROUGH CONCENTRATIONS OBSERVED IN RENAL TRANSPLANT PATIENTS ENROLLED IN PHASE 3 STUDIES</span> </caption> <col width="19%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <thead> <tr class="First"> <th align="left" class="Toprule" rowspan="2" valign="bottom"><span class="Bold">Patient Population(Study number)</span></th><th align="center" class="Toprule" rowspan="2" valign="middle"><span class="Bold">Treatment</span></th><th align="center" class="Toprule" colspan="2" valign="top"><span class="Bold">Year 1</span></th><th align="center" class="Toprule" colspan="2" valign="top"><span class="Bold">Year 3</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule" valign="top"><span class="Bold">Mean</span> <br/> <span class="Bold">(ng/mL)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">10<span class="Sup">th</span> – 90<span class="Sup">th</span> percentiles</span> <br/> <span class="Bold">(ng/mL)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">Mean</span> <br/> <span class="Bold">(ng/mL)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">10<span class="Sup">th</span> – 90<span class="Sup">th</span> percentiles</span> <br/> <span class="Bold">(ng/mL)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-11" name="footnote-11">*</a> </dt> <dd>Months 4 through 12</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">†</a> </dt> <dd>Up to Week 2; observed CsA C<span class="Sub">min</span> was 217 (56 – 432) ng/mL</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">‡</a> </dt> <dd>Week 2 to Week 26; observed CsA C<span class="Sub">min</span> range was 174 (71 – 288) ng/mL</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">§</a> </dt> <dd>Week 26 to Week 52; observed CsA C<span class="Sub">min</span> was 136 (54.5 – 218) ng/mL</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Toprule" rowspan="2" valign="top"> <p class="First">Low-to-moderate risk<br/>(Studies 1 &amp; 2)</p> </td><td class="Botrule Toprule" valign="top"> <p class="First">Sirolimus<br/>(2 mg/day) + CsA</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">7.2</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">3.6 – 11</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">–</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">–</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Sirolimus<br/>(5 mg/day) + CsA</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8 – 22</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">–</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">–</p> </td> </tr> <tr> <td class="Botrule" rowspan="2" valign="top"> <p class="First">Low-to-moderate risk<br/>(Study 3)</p> </td><td class="Botrule" valign="top"> <p class="First">Sirolimus + CsA</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8.6</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">5 – 13<a class="Sup" href="#footnote-11" name="footnote-reference-11">*</a> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">9.1</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">5.4 – 14</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Sirolimus alone</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14 – 22<a class="Sup" href="#footnote-11">*</a> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">11 – 22</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">High risk<br/>(Study 4)</p> </td><td class="Botrule" valign="top"> <p class="First">Sirolimus + CsA</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">15.7<br/>11.8<br/>11.5</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">5.4 – 27.3<a class="Sup" href="#footnote-12" name="footnote-reference-12">†</a> <br/>6.2 – 16.9<a class="Sup" href="#footnote-13" name="footnote-reference-13">‡</a> <br/>6.3 – 17.3<a class="Sup" href="#footnote-14" name="footnote-reference-14">§</a> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">–</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">–</p> </td> </tr> </tbody> </table></div>

The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state required approximately 6 weeks. Following cyclosporine withdrawal, larger sirolimus doses were required due to the absence of the inhibition of sirolimus metabolism and transport by cyclosporine and to achieve higher target sirolimus trough concentrations during concentration-controlled administration [see Dosage and Administration (2.1), Drug Interactions (7.1)].

Lymphangioleiomyomatosis

In a clinical trial of patients with lymphangioleiomyomatosis, the median whole blood sirolimus trough concentration after 3 weeks of receiving sirolimus tablets at a dose of 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to 9.0 ng/mL; n = 37).

Pharmacokinetics in Specific Populations

Hepatic Impairment

Sirolimus was administered as a single, oral dose to subjects with normal hepatic function and to patients with Child-Pugh classification A (mild), B (moderate), or C (severe) hepatic impairment. Compared with the values in the normal hepatic function group, the patients with mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, with no statistically significant differences in mean Cmax. As the severity of hepatic impairment increased, there were steady increases in mean sirolimus t1/2, and decreases in the mean sirolimus clearance normalized for body weight (CL/F/kg).

The maintenance dose of sirolimus should be reduced by approximately one third in patients with mild to moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment [see Dosage and Administration (2.5)]. It is not necessary to modify the sirolimus loading dose in patients with mild, moderate, and severe hepatic impairment. Therapeutic drug monitoring is necessary in all patients with hepatic impairment [see Dosage and Administration (2.7)].

Renal Impairment

The effect of renal impairment on the pharmacokinetics of sirolimus is not known. However, there is minimal (2.2%) renal excretion of the drug or its metabolites in healthy volunteers. The loading and the maintenance doses of sirolimus need not be adjusted in patients with renal impairment [see Dosage and Administration (2.6)].

Pediatric Renal Transplant Patients

Sirolimus pharmacokinetic data were collected in concentration-controlled trials of pediatric renal transplant patients who were also receiving cyclosporine and corticosteroids. The target ranges for trough concentrations were either 10–20 ng/mL for the 21 children receiving tablets, or 5–15 ng/mL for the one child receiving oral solution. The children aged 6–11 years (n = 8) received mean ± SD doses of 1.75 ± 0.71 mg/day (0.064 ± 0.018 mg/kg, 1.65 ± 0.43 mg/m2). The children aged 12–18 years (n = 14) received mean ± SD doses of 2.79 ± 1.25 mg/day (0.053 ± 0.0150 mg/kg, 1.86 ± 0.61 mg/m2). At the time of sirolimus blood sampling for pharmacokinetic evaluation, the majority (80%) of these pediatric patients received the sirolimus dose at 16 hours after the once-daily cyclosporine dose. See Table 6 below.

<div class="scrollingtable"><table width="95%"> <caption> <span>TABLE 6: SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC RENAL TRANSPLANT PATIENTS (MULTIPLE-DOSE CONCENTRATION CONTROL)<a class="Sup" href="#footnote-15" name="footnote-reference-15">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-16" name="footnote-reference-16">†</a></span> </caption> <col width="8%"/> <col width="5%"/> <col width="12%"/> <col width="13%"/> <col width="10%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <thead> <tr class="First Last"> <th align="center" class="Botrule Toprule" valign="bottom"><span class="Bold">Age</span> <br/> <span class="Bold">(y)</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">n</span></th><th align="center" class="Botrule Toprule" valign="bottom"><span class="Bold">Body weight</span> <br/> <span class="Bold">(kg)</span></th><th align="center" class="Botrule Toprule" valign="bottom"><span class="Bold">C<span class="Sub">max,ss</span></span> <br/> <span class="Bold">(ng/mL)</span></th><th align="center" class="Botrule Toprule" valign="bottom"><span class="Bold">t<span class="Sub">max,ss</span></span> <br/> <span class="Bold">(h)</span></th><th align="center" class="Botrule Toprule" valign="bottom"><span class="Bold">C<span class="Sub">min,ss</span></span> <br/> <span class="Bold">(ng/mL)</span></th><th align="center" class="Botrule Toprule" valign="bottom"><span class="Bold">AUC<span class="Sub">т,ss</span></span> <br/> <span class="Bold">(ng∙h/mL)</span></th><th align="center" class="Botrule Toprule" valign="bottom"><span class="Bold">CL/F</span><a class="Sup" href="#footnote-17" name="footnote-reference-17">‡</a> <br/> <span class="Bold">(mL/h/kg)</span></th><th align="center" class="Botrule Toprule" valign="bottom"><span class="Bold">CL/F</span><a class="Sup" href="#footnote-17">‡</a> <br/> <span class="Bold">(L/h/m<span class="Sup">2</span>)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="9"> <dl class="Footnote"> <dt> <a href="#footnote-reference-15" name="footnote-15">*</a> </dt> <dd>Sirolimus co-administered with cyclosporine oral solution [MODIFIED] (e.g., Neoral<span class="Sup">®</span> Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral<span class="Sup">®</span> Soft Gelatin Capsules).</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">†</a> </dt> <dd>As measured by Liquid Chromatographic/Tandem Mass Spectrometric Method (LC/MS/MS)</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">‡</a> </dt> <dd>Oral-dose clearance adjusted by either body weight (kg) or body surface area (m<span class="Sup">2</span>).</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="center" class="Toprule" valign="top"> <p class="First">6–11</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">27 ± 10</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">22.1 ± 8.9</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">5.88 ± 4.05</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">10.6 ± 4.3</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">356 ± 127</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">214 ± 129</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">5.4 ± 2.8</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule" valign="top"> <p class="First">12–18</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">52 ± 15</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">34.5 ± 12.2</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">2.7 ± 1.5</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14.7 ± 8.6</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">466 ± 236</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">136 ± 57</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">4.7 ± 1.9</p> </td> </tr> </tbody> </table></div>

Table 7 below summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically impaired renal function.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 7: SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC PATIENTS WITH END-STAGE KIDNEY DISEASE MAINTAINED ON HEMODIALYSIS OR PERITONEAL DIALYSIS (1, 3, 9, 15 mg/m<span class="Sup">2</span> SINGLE DOSE)<a class="Sup" href="#footnote-18" name="footnote-reference-18">*</a></span> </caption> <col width="24%"/> <col width="6%"/> <col width="20%"/> <col width="15%"/> <col width="35%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="top"><span class="Bold">Age Group (y)</span></th><th align="left" class="Botrule Toprule" valign="top"><span class="Bold">n</span></th><th align="left" class="Botrule Toprule" valign="top"><span class="Bold">t<span class="Sub">max</span> (h)</span></th><th align="left" class="Botrule Toprule" valign="top"><span class="Bold">t<span class="Sub">1/2</span> (h)</span></th><th align="left" class="Botrule Toprule" valign="top"><span class="Bold">CL/F/WT (mL/h/kg)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-18" name="footnote-18">*</a> </dt> <dd>All subjects received sirolimus oral solution.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">5–11</p> </td><td class="Toprule" valign="top"> <p class="First">9</p> </td><td class="Toprule" valign="top"> <p class="First">1.1 ± 0.5</p> </td><td class="Toprule" valign="top"> <p class="First">71 ± 40</p> </td><td class="Toprule" valign="top"> <p class="First">580 ± 450</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">12–18</p> </td><td class="Botrule" valign="top"> <p class="First">11</p> </td><td class="Botrule" valign="top"> <p class="First">0.79 ± 0.17</p> </td><td class="Botrule" valign="top"> <p class="First">55 ± 18</p> </td><td class="Botrule" valign="top"> <p class="First">450 ± 232</p> </td> </tr> </tbody> </table></div>

Geriatric

Clinical studies of sirolimus did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. After the administration of sirolimus oral solution or tablets, sirolimus trough concentration data in renal transplant patients >65 years of age were similar to those in the adult population 18 to 65 years of age.

Gender

Sirolimus clearance in males was 12% lower than that in females; male subjects had a significantly longer t1/2 than did female subjects (72.3 hours versus 61.3 hours). Dose adjustments based on gender are not recommended.

Race

In the phase 3 trials for the prophylaxis of organ rejection following renal transplantation using sirolimus solution or tablets and cyclosporine oral solution [MODIFIED] (e.g., Neoral® Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral® Soft Gelatin Capsules) [see Clinical Studies (14)], there were no significant differences in mean trough sirolimus concentrations over time between Black (n = 190) and non-Black (n = 852) patients during the first 6 months after transplantation.

Drug-Drug Interactions

Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below.

Cyclosporine: Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). Sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased [see Dosage and Administration (2.2), Drug Interactions (7.1)].

In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus tablets either simultaneously or 4 hours after a 300-mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, mean Cmax and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimus Cmax and AUC were both increased by only 33% compared with administration of sirolimus alone.

In a single dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus oral solution either simultaneously or 4 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean Cmax and AUC of sirolimus, following simultaneous administration were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus Cmax and AUC were increased by only 37% and 80%, respectively, compared with administration of sirolimus alone.

In a single-dose cross-over drug-drug interaction study, 33 healthy volunteers received 5 mg sirolimus oral solution alone, 2 hours before, and 2 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). When given 2 hours before Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus Cmax and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean Cmax and AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone.

Mean cyclosporine Cmax and AUC were not significantly affected when sirolimus oral solution was given simultaneously or when administered 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after Neoral® in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were needed to maintain target cyclosporine concentration.

In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5, 1.5, and 3 mg/m2/day was administered simultaneously with Sandimmune® Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (% CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune® Oral Solution (cyclosporine oral solution) administration. However, the % CV was higher (range 85.9% – 165%) than those from previous studies.

Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary [see Drug Interactions (7.4)]. The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem.

Erythromycin: Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and erythromycin is not recommended [see Warnings and Precautions (5.20), Drug Interactions (7.2)]. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 800 mg q 8h of erythromycin as erythromycin ethylsuccinate tablets at steady state to 24 healthy volunteers significantly affected the bioavailability of sirolimus and erythromycin. Sirolimus Cmax and AUC were increased 4.4- and 4.2-fold respectively and tmax was increased by 0.4 hr. Erythromycin Cmax and AUC were increased 1.6- and 1.7-fold, respectively, and tmax was increased by 0.3 hr.

Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and ketoconazole is not recommended [see Warnings and Precautions (5.20), Drug Interactions (7.2)]. Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of sirolimus oral solution, as reflected by increases in sirolimus Cmax, tmax, and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal t½ of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations.

Rifampin: Rifampin is a strong inducer of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and rifampin is not recommended. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered [see Warnings and Precautions (5.20), Drug Interactions (7.2)]. Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20 mg dose of sirolimus oral solution, greatly decreased sirolimus AUC and Cmax by about 82% and 71%, respectively.

Verapamil: Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary; [see Drug Interactions (7.4)]. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady state to 25 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus Cmax and AUC were increased 2.3- and 2.2-fold, respectively, without substantial change in tmax. The Cmax and AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and tmax was decreased by 1.2 hr.

Drugs Which May Be Co-administered Without Dose Adjustment

Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. Sirolimus and these drugs may be co-administered without dose adjustments.

Other Drug-Drug Interactions

Co-administration of sirolimus with other known strong inhibitors of CYP3A4 and/or P-gp (such as voriconazole, itraconazole, telithromycin, or clarithromycin) or other known strong inducers of CYP3A4 and/or P-gp (such as rifabutin) is not recommended [see Warnings and Precautions (5.20), Drug Interactions (7.2)]. In patients in whom strong inhibitors or inducers of CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 should be considered.

Care should be exercised when drugs or other substances that are substrates and/or inhibitors or inducers of CYP3A4 are administered concomitantly with sirolimus. Other drugs that have the potential to increase sirolimus blood concentrations include (but are not limited to):

Other drugs that have the potential to decrease sirolimus concentrations include (but are not limited to):

Other Drug-Food Interactions

Grapefruit juice reduces CYP3A4-mediated drug metabolism. Grapefruit juice must not be taken with or used for dilution of sirolimus [see Dosage and Administration (2.9), Drug Interactions (7.3)].

Drug-Herb Interactions

St. John's Wort (Hypericum perforatum) induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. John's Wort in patients receiving sirolimus could result in reduced sirolimus concentrations [see Drug Interactions (7.4)].

Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings.

Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.

When female rats were treated by oral gavage with sirolimus and mated to untreated males, female fertility was decreased at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) due to decreased implantation. In addition, reduced ovary and uterus weight were observed. The NOAEL for female rat fertility was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg).

When male rats were treated by oral gavage with sirolimus and mated to untreated females, male fertility was decreased at 2 mg/kg (9.7-fold the clinical dose of 2 mg, on a body surface area basis). Atrophy of testes, epididymides, prostate, seminiferous tubules, and reduced sperm counts were observed. The NOAEL for male rat fertility was 0.5 mg/kg (2.5-fold the clinical dose of 2 mg).

Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at 0.1 mg/kg (1-fold the clinical dose of 2 mg, on a body surface area basis).

Sirolimus Oral Solution

The safety and efficacy of sirolimus oral solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials. These studies compared two dose levels of sirolimus oral solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids. Study 1 was conducted in the United States at 38 sites. Seven hundred nineteen (719) patients were enrolled in this trial and randomized following transplantation; 284 were randomized to receive sirolimus oral solution 2 mg/day; 274 were randomized to receive sirolimus oral solution 5 mg/day, and 161 to receive azathioprine 2–3 mg/kg/day. Study 2 was conducted in Australia, Canada, Europe, and the United States, at a total of 34 sites. Five hundred seventy-six (576) patients were enrolled in this trial and randomized before transplantation; 227 were randomized to receive sirolimus oral solution 2 mg/day; 219 were randomized to receive sirolimus oral solution 5 mg/day, and 130 to receive placebo. In both studies, the use of antilymphocyte antibody induction therapy was prohibited. In both studies, the primary efficacy endpoint was the rate of efficacy failure in the first 6 months after transplantation. Efficacy failure was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft loss, or death.

The tables below summarize the results of the primary efficacy analyses from these trials. sirolimus oral solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of efficacy failure (statistically significant at the <0.025 level; nominal significance level adjusted for multiple [2] dose comparisons) at 6 months following transplantation compared with both azathioprine and placebo.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 8: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 24 MONTHS FOR STUDY 1<a class="Sup" href="#footnote-19" name="footnote-reference-19">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-20" name="footnote-reference-20">†</a></span> </caption> <col width="37%"/> <col width="21%"/> <col width="21%"/> <col width="21%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">Parameter </span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">2 mg/day</span> <br/> <span class="Bold">(n = 284)</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">5 mg/day</span> <br/> <span class="Bold">(n = 274) </span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Azathioprine</span> <br/> <span class="Bold">2–3 mg/kg/day</span> <br/> <span class="Bold">(n = 161)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-19" name="footnote-19">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-20" name="footnote-20">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-21" name="footnote-21">‡</a> </dt> <dd>Primary endpoint.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Efficacy failure at 6 months</span><a class="Sup" href="#footnote-21" name="footnote-reference-21">‡</a> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First">18.7</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">16.8</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">32.3</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Italics">Components of efficacy failure</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Biopsy-proven acute rejection</p> </td><td align="center" valign="top"> <p class="First">16.5</p> </td><td align="center" valign="top"> <p class="First">11.3</p> </td><td align="center" valign="top"> <p class="First">29.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Graft loss</p> </td><td align="center" valign="top"> <p class="First">1.1</p> </td><td align="center" valign="top"> <p class="First">2.9</p> </td><td align="center" valign="top"> <p class="First">2.5</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Death</p> </td><td align="center" valign="top"> <p class="First">0.7</p> </td><td align="center" valign="top"> <p class="First">1.8</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Lost to follow-up</p> </td><td align="center" valign="top"> <p class="First">0.4</p> </td><td align="center" valign="top"> <p class="First">0.7</p> </td><td align="center" valign="top"> <p class="First">0.6</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Efficacy failure at 24 months</span> </p> </td><td align="center" valign="top"> <p class="First">32.8</p> </td><td align="center" valign="top"> <p class="First">25.9</p> </td><td align="center" valign="top"> <p class="First">36.0</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Italics">Components of efficacy failure</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Biopsy-proven acute rejection</p> </td><td align="center" valign="top"> <p class="First">23.6</p> </td><td align="center" valign="top"> <p class="First">17.5</p> </td><td align="center" valign="top"> <p class="First">32.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Graft loss</p> </td><td align="center" valign="top"> <p class="First">3.9</p> </td><td align="center" valign="top"> <p class="First">4.7</p> </td><td align="center" valign="top"> <p class="First">3.1</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Death</p> </td><td align="center" valign="top"> <p class="First">4.2</p> </td><td align="center" valign="top"> <p class="First">3.3</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Lost to follow-up</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1.1</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.4</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.6</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 9: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 36 MONTHS FOR STUDY 2<a class="Sup" href="#footnote-22" name="footnote-reference-22">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-23" name="footnote-reference-23">†</a></span> </caption> <col width="37%"/> <col width="21%"/> <col width="21%"/> <col width="21%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">Parameter </span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">2 mg/day</span> <br/> <span class="Bold">(n = 227)</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">5 mg/day</span> <br/> <span class="Bold">(n = 219) </span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Placebo</span> <br/> <span class="Bold">(n = 130)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-22" name="footnote-22">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-23" name="footnote-23">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-24" name="footnote-24">‡</a> </dt> <dd>Primary endpoint.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Efficacy failure at 6 months</span><a class="Sup" href="#footnote-24" name="footnote-reference-24">‡</a> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First">30.0</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">25.6</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">47.7</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Italics">Components of efficacy failure</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Biopsy-proven acute rejection</p> </td><td align="center" valign="top"> <p class="First">24.7</p> </td><td align="center" valign="top"> <p class="First">19.2</p> </td><td align="center" valign="top"> <p class="First">41.5</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Graft loss</p> </td><td align="center" valign="top"> <p class="First">3.1</p> </td><td align="center" valign="top"> <p class="First">3.7</p> </td><td align="center" valign="top"> <p class="First">3.9</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Death</p> </td><td align="center" valign="top"> <p class="First">2.2</p> </td><td align="center" valign="top"> <p class="First">2.7</p> </td><td align="center" valign="top"> <p class="First">2.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Lost to follow-up</p> </td><td align="center" valign="top"> <p class="First">0</p> </td><td align="center" valign="top"> <p class="First">0</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Efficacy failure at 36 months</span> </p> </td><td align="center" valign="top"> <p class="First">44.1</p> </td><td align="center" valign="top"> <p class="First">41.6</p> </td><td align="center" valign="top"> <p class="First">54.6</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Italics">Components of efficacy failure</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Biopsy-proven acute rejection</p> </td><td align="center" valign="top"> <p class="First">32.2</p> </td><td align="center" valign="top"> <p class="First">27.4</p> </td><td align="center" valign="top"> <p class="First">43.9</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Graft loss</p> </td><td align="center" valign="top"> <p class="First">6.2</p> </td><td align="center" valign="top"> <p class="First">7.3</p> </td><td align="center" valign="top"> <p class="First">4.6</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Death</p> </td><td align="center" valign="top"> <p class="First">5.7</p> </td><td align="center" valign="top"> <p class="First">5.9</p> </td><td align="center" valign="top"> <p class="First">5.4</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Lost to follow-up</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.9</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.8</p> </td> </tr> </tbody> </table></div>

Patient and graft survival at 1 year were co-primary endpoints. The following table shows graft and patient survival at 1 and 2 years in Study 1, and 1 and 3 years in Study 2. The graft and patient survival rates were similar in patients treated with sirolimus and comparator-treated patients.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 10: GRAFT AND PATIENT SURVIVAL (%) FOR STUDY 1 (12 AND 24 MONTHS) AND STUDY 2 (12 AND 36 MONTHS)<a class="Sup" href="#footnote-25" name="footnote-reference-25">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-26" name="footnote-reference-26">†</a></span> </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">  Parameter </span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">2 mg/day</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">5 mg/day </span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Azathioprine</span> <br/> <span class="Bold">2–3 mg/kg/day</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Placebo</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-25" name="footnote-25">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-26" name="footnote-26">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Toprule" valign="top"> <p class="First">Study 1</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">(n = 284)</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">(n = 274)</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First">(n = 161)</p> </td><td class="Botrule Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Graft survival</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">94.7</p> </td><td align="center" valign="top"> <p class="First">92.7</p> </td><td align="center" valign="top"> <p class="First">93.8</p> </td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 24</p> </td><td align="center" valign="top"> <p class="First">85.2</p> </td><td align="center" valign="top"> <p class="First">89.1</p> </td><td align="center" valign="top"> <p class="First">90.1</p> </td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Patient survival</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">97.2</p> </td><td align="center" valign="top"> <p class="First">96.0</p> </td><td align="center" valign="top"> <p class="First">98.1</p> </td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 24</p> </td><td align="center" valign="top"> <p class="First">92.6</p> </td><td align="center" valign="top"> <p class="First">94.9</p> </td><td align="center" valign="top"> <p class="First">96.3</p> </td><td valign="top"></td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Study 2</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(n = 227)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(n = 219)</p> </td><td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">(n = 130)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Graft survival</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">89.9</p> </td><td align="center" valign="top"> <p class="First">90.9</p> </td><td valign="top"></td><td align="center" valign="top"> <p class="First">87.7</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Month 36</p> </td><td align="center" valign="top"> <p class="First">81.1</p> </td><td align="center" valign="top"> <p class="First">79.9</p> </td><td valign="top"></td><td align="center" valign="top"> <p class="First">80.8</p> </td> </tr> <tr> <td valign="top"> <p class="First">Patient survival</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">96.5</p> </td><td align="center" valign="top"> <p class="First">95.0</p> </td><td valign="top"></td><td align="center" valign="top"> <p class="First">94.6</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Month 36</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">90.3</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">89.5</p> </td><td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">90.8</p> </td> </tr> </tbody> </table></div>

The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with sirolimus compared with the control groups included a reduction in all grades of rejection.

In Study 1, which was prospectively stratified by race within center, efficacy failure was similar for sirolimus oral solution 2 mg/day and lower for sirolimus oral solution 5 mg/day compared with azathioprine in Black patients. In Study 2, which was not prospectively stratified by race, efficacy failure was similar for both sirolimus oral solution doses compared with placebo in Black patients. The decision to use the higher dose of sirolimus oral solution in Black patients must be weighed against the increased risk of dose-dependent adverse events that were observed with the sirolimus oral solution 5-mg dose [see Adverse Reactions (6.1)].

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 11: PERCENTAGE OF EFFICACY FAILURE BY RACE AT 6 MONTHS<a class="Sup" href="#footnote-27" name="footnote-reference-27">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-28" name="footnote-reference-28">†</a></span> </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">  Parameter</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">2 mg/day</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">5 mg/day</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Azathioprine</span> <br/> <span class="Bold">2–3 mg/kg/day</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Placebo</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-27" name="footnote-27">*</a> </dt> <dd>Patients received cyclosporine and corticosteroids.</dd> <dt> <a href="#footnote-reference-28" name="footnote-28">†</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Study 1</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Black (n = 166)</p> </td><td align="center" valign="top"> <p class="First">34.9 (n = 63)</p> </td><td align="center" valign="top"> <p class="First">18.0 (n = 61)</p> </td><td align="center" valign="top"> <p class="First">33.3 (n = 42)</p> </td><td valign="top"></td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">  Non-Black (n = 553)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14.0 (n = 221)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">16.4 (n = 213)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">31.9 (n = 119)</p> </td><td class="Botrule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Study 2</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Black (n = 66)</p> </td><td align="center" valign="top"> <p class="First">30.8 (n = 26)</p> </td><td align="center" valign="top"> <p class="First">33.7 (n = 27)</p> </td><td valign="top"></td><td align="center" valign="top"> <p class="First">38.5 (n = 13)</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Non-Black (n = 510)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">29.9 (n = 201)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">24.5 (n = 192)</p> </td><td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">48.7 (n = 117)</p> </td> </tr> </tbody> </table></div>

Mean glomerular filtration rates (GFR) post-transplant were calculated by using the Nankivell equation at 12 and 24 months for Study 1, and 12 and 36 months for Study 2. Mean GFR was lower in patients treated with cyclosporine and sirolimus oral solution compared with those treated with cyclosporine and the respective azathioprine or placebo control.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 12: OVERALL CALCULATED GLOMERULAR FILTRATION RATES (Mean ± SEM, cc/min) BY NANKIVELL EQUATION POST-TRANSPLANT<a class="Sup" href="#footnote-29" name="footnote-reference-29">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-30" name="footnote-reference-30">†</a></span> </caption> <col width="18%"/> <col width="18%"/> <col width="22%"/> <col width="22%"/> <col width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">Parameter</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">2 mg/day</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Oral Solution</span> <br/> <span class="Bold">5 mg/day</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Azathioprine</span> <br/> <span class="Bold">2–3 mg/kg/day</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Placebo</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-29" name="footnote-29">*</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-30" name="footnote-30">†</a> </dt> <dd>Patients who had a graft loss were included in the analysis with GFR set to 0.0.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Study 1</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">57.4 ± 1.3<br/>(n = 269)</p> </td><td align="center" valign="top"> <p class="First">54.6 ± 1.3<br/>(n = 248)</p> </td><td align="center" valign="top"> <p class="First">64.1 ± 1.6)<br/>(n = 149)</p> </td><td valign="top"></td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">  Month 24</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">58.4 ± 1.5<br/>(n = 221)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">52.6 ± 1.5<br/>(n = 222)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">62.4 ± 1.9<br/>(n = 132)</p> </td><td class="Botrule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Study 2</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Month 12</p> </td><td align="center" valign="top"> <p class="First">52.4 ± 1.5<br/>(n = 211)</p> </td><td align="center" valign="top"> <p class="First">51.5 ± 1.5<br/>(n = 199)</p> </td><td valign="top"></td><td align="center" valign="top"> <p class="First">58.0 ± 2.1<br/>(n = 117)</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Month 36</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">48.1 ± 1.8<br/>(n = 183)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">46.1 ± 2.0<br/>(n = 177)</p> </td><td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">53.4 ± 2.7<br/>(n = 102)</p> </td> </tr> </tbody> </table></div>

Within each treatment group in Studies 1 and 2, mean GFR at one-year post-transplant was lower in patients who experienced at least one episode of biopsy-proven acute rejection, compared with those who did not.

Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels [see Warnings and Precautions (5.8)].

Sirolimus Tablets

The safety and efficacy of sirolimus oral solution and sirolimus tablets for the prevention of organ rejection following renal transplantation were demonstrated to be clinically equivalent in a randomized, multicenter, controlled trial [see Clinical Pharmacology (12.3)].

The safety and efficacy of sirolimus as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months after renal transplantation. Study 3 was a randomized, multicenter, controlled trial conducted at 57 centers in Australia, Canada, and Europe. Five hundred twenty-five (525) patients were enrolled. All patients in this study received the tablet formulation. This study compared patients who were administered sirolimus, cyclosporine, and corticosteroids continuously with patients who received this same standardized therapy for the first 3 months after transplantation (pre-randomization period) followed by the withdrawal of cyclosporine. During cyclosporine withdrawal, the sirolimus dosages were adjusted to achieve targeted sirolimus whole blood trough concentration ranges (16 to 24 ng/mL until month 12, then 12 to 20 ng/mL thereafter, expressed as chromatographic assay values). At 3 months, 430 patients were equally randomized to either continue sirolimus with cyclosporine therapy or to receive sirolimus as a maintenance regimen following cyclosporine withdrawal.

Eligibility for randomization included no Banff Grade 3 acute rejection or vascular rejection episode in the 4 weeks before random assignment, serum creatinine ≤4.5 mg/dL, and adequate renal function to support cyclosporine withdrawal (in the opinion of the investigator). The primary efficacy endpoint was graft survival at 12 months after transplantation. Secondary efficacy endpoints were the rate of biopsy-confirmed acute rejection, patient survival, incidence of efficacy failure (defined as the first occurrence of either biopsy-proven acute rejection, graft loss, or death), and treatment failure (defined as the first occurrence of either discontinuation, acute rejection, graft loss, or death).

The following table summarizes the resulting graft and patient survival at 12, 24, and 36 months for this trial. At 12, 24, and 36 months, graft and patient survival were similar for both groups.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 13: GRAFT AND PATIENT SURVIVAL (%): STUDY 3<a class="Sup" href="#footnote-31" name="footnote-reference-31">*</a></span> </caption> <col width="24%"/> <col width="36%"/> <col width="40%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">Parameter </span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus with Cyclosporine Therapy</span> <br/> <span class="Bold">(n = 215)</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Following Cyclosporine Withdrawal</span> <br/> <span class="Bold">(n = 215) </span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-31" name="footnote-31">*</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-32" name="footnote-32">†</a> </dt> <dd>Primary efficacy endpoint.</dd> <dt> <a href="#footnote-reference-33" name="footnote-33">‡</a> </dt> <dd>Survival including loss to follow-up as an event.</dd> <dt> <a href="#footnote-reference-34" name="footnote-34">§</a> </dt> <dd>Initial planned duration of the study.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Graft Survival</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Month 12<a class="Sup" href="#footnote-32" name="footnote-reference-32">†</a> </p> </td><td align="center" valign="top"> <p class="First">95.3<a class="Sup" href="#footnote-33" name="footnote-reference-33">‡</a> </p> </td><td align="center" valign="top"> <p class="First">97.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">Month 24</p> </td><td align="center" valign="top"> <p class="First">91.6</p> </td><td align="center" valign="top"> <p class="First">94.0</p> </td> </tr> <tr> <td valign="top"> <p class="First">Month 36<a class="Sup" href="#footnote-34" name="footnote-reference-34">§</a> </p> </td><td align="center" valign="top"> <p class="First">87.0</p> </td><td align="center" valign="top"> <p class="First">91.6</p> </td> </tr> <tr> <td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Patient Survival</p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Month 12</p> </td><td align="center" valign="top"> <p class="First">97.2</p> </td><td align="center" valign="top"> <p class="First">98.1</p> </td> </tr> <tr> <td valign="top"> <p class="First">Month 24</p> </td><td align="center" valign="top"> <p class="First">94.4</p> </td><td align="center" valign="top"> <p class="First">95.8</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Month 36<a class="Sup" href="#footnote-34">§</a> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">91.6</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">94.0</p> </td> </tr> </tbody> </table></div>

The following table summarizes the results of first biopsy-proven acute rejection at 12 and 36 months. There was a significant difference in first biopsy-proven rejection rates between the two groups after randomization and through 12 months. Most of the post-randomization acute rejections occurred in the first 3 months following randomization.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 14: INCIDENCE OF FIRST BIOPSY-PROVEN ACUTE REJECTION (%) BY TREATMENT GROUP AT 36 MONTHS: STUDY 3<a class="Sup" href="#footnote-35" name="footnote-reference-35">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-36" name="footnote-reference-36">†</a></span> </caption> <col width="40%"/> <col width="30%"/> <col width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">Period</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus with Cyclosporine Therapy</span> <br/> <span class="Bold">(n = 215)</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Following Cyclosporine Withdrawal</span> <br/> <span class="Bold">(n = 215)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-35" name="footnote-35">*</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-36" name="footnote-36">†</a> </dt> <dd>All patients received corticosteroids.</dd> <dt> <a href="#footnote-reference-37" name="footnote-37">‡</a> </dt> <dd>Randomization occurred at 3 months ± 2 weeks.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Pre-randomization<a class="Sup" href="#footnote-37" name="footnote-reference-37">‡</a> </p> </td><td align="center" class="Toprule" valign="top"> <p class="First">9.3</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">10.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">Post-randomization through 12 months<a class="Sup" href="#footnote-37">‡</a> </p> </td><td align="center" valign="top"> <p class="First">4.2</p> </td><td align="center" valign="top"> <p class="First">9.8</p> </td> </tr> <tr> <td valign="top"> <p class="First">Post-randomization from 12 to 36 months</p> </td><td align="center" valign="top"> <p class="First">1.4</p> </td><td align="center" valign="top"> <p class="First">0.5</p> </td> </tr> <tr> <td valign="top"> <p class="First">Post-randomization through 36 months</p> </td><td align="center" valign="top"> <p class="First">5.6</p> </td><td align="center" valign="top"> <p class="First">10.2</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Total at 36 months</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">14.9</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">20.5</p> </td> </tr> </tbody> </table></div>

Patients receiving renal allografts with ≥4 HLA mismatches experienced significantly higher rates of acute rejection following randomization to the cyclosporine withdrawal group, compared with patients who continued cyclosporine (15.3% versus 3.0%). Patients receiving renal allografts with ≤3 HLA mismatches demonstrated similar rates of acute rejection between treatment groups (6.8% versus 7.7%) following randomization.

The following table summarizes the mean calculated GFR in Study 3 (cyclosporine withdrawal study).

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 15: CALCULATED GLOMERULAR FILTRATION RATES (mL/min) BY NANKIVELL EQUATION AT 12, 24, AND 36 MONTHS POST-TRANSPLANT: STUDY 3<a class="Sup" href="#footnote-38" name="footnote-reference-38">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-39" name="footnote-reference-39">†</a><span class="Sup">,</span><a class="Sup" href="#footnote-40" name="footnote-reference-40">‡</a></span> </caption> <col width="24%"/> <col width="36%"/> <col width="40%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">Parameter</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus with Cyclosporine Therapy</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus Following Cyclosporine Withdrawal</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-38" name="footnote-38">*</a> </dt> <dd>Includes patients who prematurely discontinued treatment.</dd> <dt> <a href="#footnote-reference-39" name="footnote-39">†</a> </dt> <dd>Patients who had a graft loss were included in the analysis and had their GFR set to 0.0.</dd> <dt> <a href="#footnote-reference-40" name="footnote-40">‡</a> </dt> <dd>All patients received corticosteroids.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Month 12</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Mean ± SEM</p> </td><td align="center" valign="top"> <p class="First">53.2 ± 1.5<br/>(n = 208)</p> </td><td align="center" valign="top"> <p class="First">59.3 ± 1.5<br/>(n = 203)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Month 24</p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Mean ± SEM</p> </td><td align="center" valign="top"> <p class="First">48.4 ± 1.7<br/>(n = 203)</p> </td><td align="center" valign="top"> <p class="First">58.4 ± 1.6<br/>(n = 201)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Month 36</p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Mean ± SEM</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">47.0 ± 1.8<br/>(n = 196)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">58.5 ± 1.9<br/>(n = 199)</p> </td> </tr> </tbody> </table></div>

The mean GFR at 12, 24, and 36 months, calculated by the Nankivell equation, was significantly higher for patients receiving sirolimus as a maintenance regimen following cyclosporine withdrawal than for those in the sirolimus with cyclosporine therapy group. Patients who had an acute rejection prior to randomization had a significantly higher GFR following cyclosporine withdrawal compared to those in the sirolimus with cyclosporine group. There was no significant difference in GFR between groups for patients who experienced acute rejection post-randomization.

Although the initial protocol was designed for 36 months, there was a subsequent amendment to extend this study. The results for the cyclosporine withdrawal group at months 48 and 60 were consistent with the results at month 36. Fifty-two percent (112/215) of the patients in the sirolimus with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR.

Sirolimus was studied in a one-year, clinical trial in high risk patients (Study 4) who were defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reasons and/or patients with high panel-reactive antibodies (PRA; peak PRA level >80%). Patients received concentration-controlled sirolimus and cyclosporine (MODIFIED), and corticosteroids per local practice. The sirolimus dose was adjusted to achieve target whole blood trough sirolimus concentrations of 10–15 ng/mL (chromatographic method) throughout the 12-month study period. The cyclosporine dose was adjusted to achieve target whole blood trough concentrations of 200–300 ng/mL through week 2, 150–200 ng/mL from week 2 to week 26, and 100–150 ng/mL from week 26 to week 52 [see Clinical Pharmacology (12.3)] for the observed trough concentrations ranges. Antibody induction was allowed per protocol as prospectively defined at each transplant center, and was used in 88.4% of patients. The study was conducted at 35 centers in the United States. A total of 224 patients received a transplant and at least one dose of sirolimus and cyclosporine and was comprised of 77.2% Black patients, 24.1% repeat renal transplant recipients, and 13.5% patients with high PRA. Efficacy was assessed with the following endpoints, measured at 12 months: efficacy failure (defined as the first occurrence of biopsy-confirmed acute rejection, graft loss, or death), first occurrence of graft loss or death, and renal function as measured by the calculated GFR using the Nankivell formula. The table below summarizes the result of these endpoints.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 16: EFFICACY FAILURE, GRAFT LOSS OR DEATH AND CALCULATED GLOMERULAR FUNCTION RATES (mL/min) BY NANKIVELL EQUATION AT 12 MONTHS POST-TRANSPLANT: STUDY 4</span> </caption> <col width="50%"/> <col width="50%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">  Parameter</span></th><th align="center" class="Botrule Toprule" valign="top"><span class="Bold">Sirolimus with Cyclosporine, Corticosteroids</span> <br/> <span class="Bold">(n = 224)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-41" name="footnote-41">*</a> </dt> <dd>Calculated glomerular filtration rate by Nankivell equation.</dd> <dt> <a href="#footnote-reference-42" name="footnote-42">†</a> </dt> <dd>Patients who had graft loss were included in this analysis with GFR set to 0.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Efficacy Failure (%)</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">23.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">Graft Loss or Death (%)</p> </td><td align="center" valign="top"> <p class="First">9.8</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Renal Function (mean ± SEM)<a class="Sup" href="#footnote-41" name="footnote-reference-41">*</a><span class="Sup">,</span><a class="Sup" href="#footnote-42" name="footnote-reference-42">†</a> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">52.6 ± 1.6<br/>(n = 222)</p> </td> </tr> </tbody> </table></div>

Patient survival at 12 months was 94.6%. The incidence of biopsy-confirmed acute rejection was 17.4% and the majority of the episodes of acute rejection were mild in severity.

Conversion from calcineurin inhibitors (CNI) to sirolimus was assessed in maintenance renal transplant patients 6 months to 10 years post-transplant (Study 5). This study was a randomized, multicenter, controlled trial conducted at 111 centers globally, including US and Europe, and was intended to show that renal function was improved by conversion from CNI to sirolimus. Eight hundred thirty (830) patients were enrolled and stratified by baseline calculated glomerular filtration rate (GFR, 20–40 mL/min versus greater than 40 mL/min). In this trial there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the sirolimus conversion arm. In addition, enrollment of patients with baseline calculated GFR less than 40 mL/min was discontinued due to a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death [see Adverse Reactions (6.4)].

This study compared renal transplant patients (6–120 months after transplantation) who were converted from calcineurin inhibitors to sirolimus, with patients who continued to receive calcineurin inhibitors. Concomitant immunosuppressive medications included mycophenolate mofetil (MMF), azathioprine (AZA), and corticosteroids. Sirolimus was initiated with a single loading dose of 12–20 mg, after which dosing was adjusted to achieve a target sirolimus whole blood trough concentration of 8–20 ng/mL (chromatographic method). The efficacy endpoint was calculated GFR at 12 months post-randomization. Additional endpoints included biopsy-confirmed acute rejection, graft loss, and death. Findings in the patient stratum with baseline calculated GFR greater than 40 mL/min (sirolimus conversion, n = 497; CNI continuation, n = 246) are summarized below. There was no clinically or statistically significant improvement in Nankivell GFR compared to baseline.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 17: RENAL FUNCTION IN STABLE RENAL TRANSPLANT PATIENTS IN PATIENTS WITH BASELINE GFR &gt;40 mL/min THE SIROLIMUS CONVERSION STUDY (STUDY 5)</span> </caption> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Parameter</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Sirolimus Conversion</span> <br/> <span class="Bold">N=496</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">CNI Continuation</span> <br/> <span class="Bold">N=245</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Difference (95% CI)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">GFR mL/min (Nankivell) at 1 year</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">59.0</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">57.7</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">1.3 (-1.1, 3.7)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">GFR mL/min (Nankivell) at 2 year</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">53.7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">52.1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.6 (-1.4, 4.6)</p> </td> </tr> </tbody> </table></div>

The rates of acute rejection, graft loss, and death were similar at 1 and 2 years. Treatment-emergent adverse events occurred more frequently during the first 6 months after sirolimus conversion. The rates of pneumonia were significantly higher for the sirolimus conversion group.

While the mean and median values for urinary protein to creatinine ratio were similar between treatment groups at baseline, significantly higher mean and median levels of urinary protein excretion were seen in the sirolimus conversion arm at 1 year and at 2 years, as shown in the table below [see Warnings and Precautions (5.9)]. In addition, when compared to patients who continued to receive calcineurin inhibitors, a higher percentage of patients had urinary protein to creatinine ratios >1 at 1 and 2 years after sirolimus conversion. This difference was seen in both patients who had a urinary protein to creatinine ratio ≤1 and those who had a protein to creatinine ratio >1 at baseline. More patients in the sirolimus conversion group developed nephrotic range proteinuria, as defined by a urinary protein to creatinine ratio >3.5 (46/482 [9.5%] versus 9/239 [3.8%]), even when the patients with baseline nephrotic range proteinuria were excluded. The rate of nephrotic range proteinuria was significantly higher in the sirolimus conversion group compared to the calcineurin inhibitor continuation group with baseline urinary protein to creatinine ratio >1 (13/29 versus 1/14), excluding patients with baseline nephrotic range proteinuria.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 18: MEAN AND MEDIAN VALUES FOR URINARY PROTEIN TO CREATININE RATIO (mg/mg) BETWEEN TREATMENT GROUPS AT BASELINE, 1 AND 2 YEARS IN THE STRATUM WITH BASELINE CALCULATED GFR &gt;40 mL/min</span> </caption> <col width="12%"/> <col width="12%"/> <col width="13%"/> <col width="13%"/> <col width="12%"/> <col width="13%"/> <col width="13%"/> <col width="12%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Study period</span></th><th align="center" class="Botrule Rrule Toprule" colspan="3" valign="bottom"><span class="Bold">Sirolimus Conversion</span></th><th align="center" class="Botrule Rrule Toprule" colspan="4" valign="bottom"><span class="Bold">CNI Continuation</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" valign="bottom"></th><th align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">N</span></th><th align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Mean ± SD</span></th><th align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Median</span></th><th align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">N</span></th><th align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Mean ± SD</span></th><th align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Median</span></th><th align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">p-value</span></th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Baseline</p> </td><td align="center" class="Botrule Rrule Toprule" valign="bottom"> <p class="First">410</p> </td><td align="center" class="Botrule Rrule Toprule" valign="bottom"> <p class="First">0.35 ± 0.76</p> </td><td align="center" class="Botrule Rrule Toprule" valign="bottom"> <p class="First">0.13</p> </td><td align="center" class="Botrule Rrule Toprule" valign="bottom"> <p class="First">207</p> </td><td align="center" class="Botrule Rrule Toprule" valign="bottom"> <p class="First">0.28 ± 0.61</p> </td><td align="center" class="Botrule Rrule Toprule" valign="bottom"> <p class="First">0.11</p> </td><td align="center" class="Botrule Rrule Toprule" valign="bottom"> <p class="First">0.381</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">1 year</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">423</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">0.88 ± 1.61</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">0.31</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">203</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">0.37 ± 0.88</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">0.14</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">&lt;0.001</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">2 years</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">373</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">0.86 ± 1.48</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">0.32</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">190</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">0.47 ± 0.98</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">0.13</p> </td><td align="center" class="Botrule Rrule" valign="bottom"> <p class="First">&lt;0.001</p> </td> </tr> </tbody> </table></div>

The above information should be taken into account when considering conversion from calcineurin inhibitors to sirolimus in stable renal transplant patients due to the lack of evidence showing that renal function improves following conversion, and the finding of a greater increment in urinary protein excretion, and an increased incidence of treatment-emergent nephrotic range proteinuria following conversion to sirolimus. This was particularly true among patients with existing abnormal urinary protein excretion prior to conversion.

In an open-label, randomized, comparative, multicenter study where kidney transplant patients were either converted from tacrolimus to sirolimus 3 to 5 months post-transplant (sirolimus group) or remained on tacrolimus, there was no significant difference in renal function at 2 years post-transplant. Overall, 44/131 (33.6%) discontinued treatment in the sirolimus group versus 12/123 (9.8%) in the tacrolimus group. More patients reported adverse events 130/131 (99.2%) versus 112/123 (91.1%) and more patients reported discontinuations from the treatment due to adverse events 28/131 (21.4%) versus 4/123 (3.3%) in the sirolimus group compared to the tacrolimus group.

The incidence of biopsy-confirmed acute rejection was higher for patients in the sirolimus group 11/131 (8.4%) compared to the tacrolimus group 2/123 (1.6%) through 2 years post-transplant. The rate of new-onset diabetes mellitus post-randomization, defined as 30 days or longer of continuous or at least 25 days non-stop (without gap) use of any diabetic treatment after randomization, a fasting glucose ≥126 mg/dL or a non-fasting glucose ≥200 mg/dL, was higher in the sirolimus group 15/82 (18.3%) compared to the tacrolimus group 4/72 (5.6%). A greater incidence of proteinuria, was seen in the sirolimus group 19/131 (14.5%) versus 2/123 (1.6%) in the tacrolimus group.

Conversion from a CNI-based regimen to a sirolimus-based regimen was assessed in stable liver transplant patients 6–144 months post-transplant. The clinical study was a 2:1 randomized, multi-center, controlled trial conducted at 82 centers globally, including the US and Europe, and was intended to show that renal function was improved by conversion from a CNI to sirolimus without adversely impacting efficacy or safety. A total of 607 patients were enrolled.

The study failed to demonstrate superiority of conversion to a sirolimus-based regimen compared to continuation of a CNI-based regimen in baseline-adjusted GFR, as estimated by Cockcroft-Gault, at 12 months (62 mL/min in the sirolimus conversion group and 63 mL/min in the CNI continuation group). The study also failed to demonstrate non-inferiority, with respect to the composite endpoint consisting of graft loss and death (including patients with missing survival data) in the sirolimus conversion group compared to the CNI continuation group (6.6% versus 5.6%). The number of deaths in the sirolimus conversion group (15/393, 3.8%) was higher than in the CNI continuation group (3/214, 1.4%), although the difference was not statistically significant. The rates of premature study discontinuation (primarily due to adverse events or lack of efficacy), adverse events overall (infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the sirolimus conversion group compared to the CNI continuation group.

Sirolimus was evaluated in a 36-month, open-label, randomized, controlled clinical trial at 14 North American centers in pediatric (aged 3 to <18 years) renal transplant patients considered to be at high-immunologic risk for developing chronic allograft nephropathy, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. Seventy-eight (78) subjects were randomized in a 2:1 ratio to sirolimus (sirolimus target concentrations of 5 to 15 ng/mL, by chromatographic assay, n = 53) in combination with a calcineurin inhibitor and corticosteroids or to continue calcineurin-inhibitor-based immunosuppressive therapy (n = 25). The primary endpoint of the study was efficacy failure as defined by the first occurrence of biopsy-confirmed acute rejection, graft loss, or death, and the trial was designed to show superiority of sirolimus added to a calcineurin-inhibitor-based immunosuppressive regimen compared to a calcineurin-inhibitor-based regimen. The cumulative incidence of efficacy failure up to 36 months was 45.3% in the sirolimus group compared to 44.0% in the control group, and did not demonstrate superiority. There was one death in each group. The use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections [see Warnings and Precautions (5.8)]. This study does not support the addition of sirolimus to calcineurin-inhibitor-based immunosuppressive therapy in this subpopulation of pediatric renal transplant patients.

The safety and efficacy of sirolimus for treatment of lymphangioleiomyomatosis (LAM) were assessed in a randomized, double-blind, multicenter, controlled trial. This study compared sirolimus (dose-adjusted to maintain blood trough concentrations between 5–15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observation period. Eighty-nine (89) patients were enrolled; 43 patients were randomized to receive placebo and 46 patients to receive sirolimus. The primary endpoint was the difference between the groups in the rate of change (slope) per month in forced expiratory volume in 1 second (FEV1). During the treatment period, the FEV1 slope was -12±2 mL per month in the placebo group and 1±2 mL per month in the sirolimus group (treatment difference = 13 mL (95% CI: 7, 18). The absolute between-group difference in the mean change in FEV1 during the 12-month treatment period was 153 mL, or approximately 11% of the mean FEV1 at enrollment. Similar improvements were seen for forced vital capacity (FVC). After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group (see Figure 1).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="100%"/> <tbody class="Headless"> <tr> <td align="center" valign="top"> <p class="First"> <span class="Bold">FIGURE 1: CHANGE IN FORCED EXPIRATORY VOLUME IN 1 SECOND (FEV1) DURING THE TREATMENT AND OBSERVATION PHASES OF THE STUDY IN LAM PATIENTS</span> </p> </td> </tr> <tr> <td valign="top"><a name="id3345"></a><img alt="Figure 1" src="/dailymed/image.cfm?name=sirolimus-02.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84"/></td> </tr> </tbody> </table></div>

The rate of change over 12 months of vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor which has been shown to be elevated in patients with LAM, was significantly different in the sirolimus-treated group (-88.0 ± 16.6 pg/mL/month) compared to placebo (-2.42 ± 17.2 pg/mL/month) with a treatment difference of -86 pg/mL/month (95% CI: -133, -39). The absolute between-group difference in the mean change in VEGF-D during the 12-month treatment period was -1017.2, or approximately 50% of the mean VEGF-D at enrollment.

Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see Dosage and Administration (2.5)].

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Each sirolimus oral solution carton, NDC 59762-1205-6, contains one 2 oz (60 mL fill) amber glass bottle of sirolimus (concentration of 1 mg/mL), one oral syringe adapter for fitting into the neck of the bottle, sufficient disposable oral syringes (amber color) and caps for daily dosing, and a carrying case.

Sirolimus oral solution bottles should be stored protected from light and refrigerated at 2°C to 8°C (36°F to 46°F). Once the bottle is opened, the contents should be used within one month. If necessary, the patient may store the bottles at room temperatures up to 25°C (77°F) for a short period of time (e.g., not more than 15 days for the bottles).

A syringe (amber color) and cap are provided for dosing, and the product may be kept in the syringe for a maximum of 24 hours at room temperatures up to 25°C (77°F) or refrigerated at 2°C to 8°C (36°F to 46°F). The syringe should be discarded after one use. After dilution, the preparation should be used immediately.

Sirolimus oral solution provided in bottles may develop a slight haze when refrigerated. If such a haze occurs, allow the product to stand at room temperature and shake gently until the haze disappears. The presence of this haze does not affect the quality of the product.

Patients should be given complete dosage instructions [see FDA-Approved Medication Guide].

Advise patients that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor because of the increased risk for skin cancer [see Warnings and Precautions (5.18)].

Advise female patients of reproductive potential to avoid becoming pregnant throughout treatment and for 12 weeks after sirolimus therapy has stopped. Sirolimus can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to her fetus. Before making a decision to breastfeed, inform the patient that the effects of breastfeeding in infants while taking this drug are unknown, but there is potential for serious adverse effects [see Warnings and Precautions (5.15), Use in Specific Populations (8.1, 8.2, 8.3)].

Inform male and female patients that sirolimus may impair fertility [see Warnings and Precautions (5.16), Adverse Reactions (6.7), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

LAB-0686-13.0

{ "type": "p", "children": [], "text": "LAB-0686-13.0" }

<div class="scrollingtable"><table width="100.1%"> <col width="3%"/> <col width="42%"/> <col width="27%"/> <col width="29%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First"> <span class="Bold">MEDICATION GUIDE</span> <br/>Sirolimus Oral Solution</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <a name="Ref_MG2"></a><span class="Bold">What is the most important information I should know about sirolimus?</span> <br/>Sirolimus can cause serious side effects, including: </p> <dl> <dt>•</dt> <dd> <span class="Bold">Increased risk of getting infections.</span> Serious infections can happen including infections caused by viruses, bacteria, and fungi (yeast). Your doctor may put you on medicine to help prevent some of these infections.<br/>Call your doctor right away if you have symptoms of infection including fever or chills while taking sirolimus.</dd> <dt>•</dt> <dd> <span class="Bold">Increased risk of getting certain cancers.</span> People who take sirolimus have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Talk with your doctor about your risk for cancer.</dd> </dl> <p> <span class="Bold">Sirolimus has not been shown to be safe and effective in people who have had liver or lung transplants. Serious complications and death may happen in people who take sirolimus after a liver or lung transplant.</span> You should not take sirolimus if you have had a liver or lung transplant without talking with your doctor.<br/> <span class="Bold">See the section "<a href="#Ref_MG1">What are the possible side effects of sirolimus</a>?" for information about other side effects of sirolimus.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What is sirolimus?</span> <br/>Sirolimus is a prescription medicine used to prevent rejection (anti-rejection medicine) in people 13 years of age and older who have received a kidney transplant. Rejection is when your body's immune system recognizes the new organ as a "foreign" threat and attacks it. <br/>Sirolimus is used with other medicines called cyclosporine (Gengraf, Neoral, Sandimmune), and corticosteroids. Your doctor will decide: </p> <dl> <dt>•</dt> <dd>if sirolimus is right for you, and</dd> <dt>•</dt> <dd>how to best use it with cyclosporine and corticosteroids after your transplant.</dd> </dl> <p>It is not known if sirolimus is safe and effective in children under 13 years of age.<br/>Sirolimus is a prescription medicine also used to treat lymphangioleiomyomatosis (LAM). LAM is a rare progressive lung disease that affects predominantly women of childbearing age.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Who should not take sirolimus?</span> <br/>Do not take sirolimus if you are allergic to sirolimus or any of the other ingredients in sirolimus. See the end of this leaflet for a complete list of ingredients in sirolimus.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <a name="Ref_MG3"></a><span class="Bold">What should I tell my doctor before taking sirolimus?</span> </p> <dl> <dt>•</dt> <dd>have liver problems</dd> <dt>•</dt> <dd>have skin cancer or it runs in your family</dd> <dt>•</dt> <dd>have high cholesterol or triglycerides (fat in your blood) </dd> <dt>•</dt> <dd>are pregnant or are a female who can become pregnant. Sirolimus can harm your unborn baby. You should not become pregnant during treatment with sirolimus and for 12 weeks after ending treatment with sirolimus. In order to avoid pregnancy, a female who can get pregnant should use effective birth control during treatment and for 12 weeks after your final dose of sirolimus. Talk with your doctor about what birth control method is right for you during this time. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with sirolimus or within 12 weeks after your final dose of sirolimus.</dd> <dt>•</dt> <dd>It is not known whether sirolimus passes into breast milk; however, there is a risk of serious side effects in breastfed infants. You and your doctor should decide about the best way to feed your baby if you take sirolimus.</dd> </dl> <p> <span class="Bold">Tell your doctor about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins and herbal supplements. Using sirolimus with certain medicines may affect each other causing serious side effects. <br/>Sirolimus may affect the way other medicines work, and other medicines may affect how sirolimus works. <br/>Especially tell your doctor if you take: </p> <dl> <dt>•</dt> <dd>a medicine to lower your cholesterol or triglycerides</dd> <dt>•</dt> <dd>cyclosporine (including Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf) or other medicines that suppress the immune system</dd> <dt>•</dt> <dd>an antibiotic</dd> <dt>•</dt> <dd>an antifungal medicine</dd> <dt>•</dt> <dd>a medicine for high blood pressure or heart problems</dd> <dt>•</dt> <dd>an anti-seizure medicine</dd> <dt>•</dt> <dd>medicines used to treat stomach acid, ulcers, or other gastrointestinal problems</dd> <dt>•</dt> <dd>bromocriptine mesylate (Parlodel, Cycloset)</dd> <dt>•</dt> <dd>danazol</dd> <dt>•</dt> <dd>letermovir (Prevymis)</dd> <dt>•</dt> <dd>medicines to treat HIV or hepatitis C</dd> <dt>•</dt> <dd>St.John’s Wort</dd> <dt>•</dt> <dd>Cannabidiol (Epidiolex)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">How should I take sirolimus?</span> </p> <dl> <dt>•</dt> <dd>Read the Instructions for Use that comes with your sirolimus for information about the right way to take sirolimus oral solution.</dd> <dt>•</dt> <dd>Take sirolimus exactly as your doctor tells you to take it.</dd> <dt>•</dt> <dd>Your doctor will tell you how much sirolimus to take and when to take it. Do not change your dose of sirolimus unless your doctor tells you to.</dd> <dt>•</dt> <dd>If you also take cyclosporine (Gengraf, Neoral, Sandimmune), you should take your sirolimus and cyclosporine about 4 hours apart.</dd> <dt>•</dt> <dd>Do not stop taking sirolimus or your other anti-rejection medicines unless your doctor tells you to.</dd> <dt>•</dt> <dd>Your doctor will check the levels of sirolimus in your blood. Your doctor may change your dose of sirolimus depending on your blood test results.</dd> <dt>•</dt> <dd>Sirolimus is taken by mouth 1 time each day.</dd> <dt>•</dt> <dd>Take each dose of sirolimus the same way, either with or without food. Food can affect the amount of medicine that gets into your bloodstream. Taking each dose of sirolimus the same way helps keep your blood levels of sirolimus more stable. Do not take sirolimus with grapefruit juice.</dd> <dt>•</dt> <dd>Sirolimus oral solution can develop a slight haze when it is refrigerated. If this happens, bring the sirolimus oral solution to room temperature and then gently shake the bottle until the haze goes away.</dd> <dt>•</dt> <dd>If you get sirolimus oral solution on your skin, wash the area with soap and water.</dd> <dt>•</dt> <dd>If you get sirolimus oral solution in your eyes, rinse your eyes with water.</dd> <dt>•</dt> <dd>If you have taken more medicine than you were told, contact a doctor or go to the nearest hospital emergency department right away.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What should I avoid while taking sirolimus?</span> </p> <dl> <dt>•</dt> <dd>Avoid receiving live vaccines while taking sirolimus. Some vaccines may not work as well while you are taking sirolimus.</dd> <dt>•</dt> <dd>Limit your time in sunlight and UV light. Cover your skin with clothing and use a broad spectrum sunscreen with a high protection factor because of the increased risk for skin cancer with sirolimus.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <a name="Ref_MG1"></a><span class="Bold">What are the possible side effects of sirolimus?</span> <br/> <span class="Bold">Sirolimus may cause serious side effects, including:</span> </p> <dl> <dt>•</dt> <dd>See <span class="Bold">"<a href="#Ref_MG2">What is the most important information I should know about sirolimus?</a>"</span> </dd> <dt>•</dt> <dd> <span class="Bold">Serious allergic reactions. Tell your doctor or get medical help right away</span> if you get any of following symptoms of an allergic reaction:</dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>•</dt> <dd>swelling of your face, eyes, or mouth</dd> <dt>•</dt> <dd>trouble breathing or wheezing</dd> <dt>•</dt> <dd>throat tightness</dd> </dl> </td><td class="Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>chest pain or tightness</dd> <dt>•</dt> <dd>feeling dizzy or faint</dd> <dt>•</dt> <dd>rash or peeling of your skin</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Swelling (edema).</span> Fluid may collect in your hands and feet and in various tissues of your body, including in the sac around your heart or lungs. Call your doctor if you have trouble breathing.</dd> <dt>•</dt> <dd> <span class="Bold">Poor wound healing.</span> Sirolimus may cause your wounds to heal slowly or not heal well. Tell your doctor if you have any redness or drainage, your wound does not heal, or the wound opens up. </dd> <dt>•</dt> <dd> <span class="Bold">Increased levels of cholesterol and triglycerides (lipids or fat) in your blood.</span> Your doctor should do blood tests to check your lipids during treatment with sirolimus. Your doctor may prescribe treatment with diet, exercise, or medicine if your lipid levels are too high. During treatment with sirolimus, your blood levels of cholesterol and triglycerides may remain high even if you follow your prescribed treatment plan.</dd> <dt>•</dt> <dd> <span class="Bold">Effects on kidney function.</span> When sirolimus is taken with cyclosporine (Gengraf, Neoral, Sandimmune), the function of your transplanted kidney may be affected. Your doctor should regularly do tests to check your kidney function while you are taking sirolimus with cyclosporine (Gengraf, Neoral, Sandimmune).</dd> <dt>•</dt> <dd> <span class="Bold">Increased protein in your urine.</span> Your doctor may regularly test your urine protein. </dd> <dt>•</dt> <dd> <span class="Bold">Increased risk for viral infections.</span> <dl> <dt>o</dt> <dd>Certain viruses can live in your body and cause active infections when your immune system is weak. BK virus can affect how your kidney works and cause your transplanted kidney to fail.</dd> <dt>o</dt> <dd>A certain virus can cause a rare serious brain infection called Progressive Multifocal Leukoencephalopathy (PML). PML usually causes death or severe disability. Call your doctor right away if you notice any new or worsening medical problems such as:<dl> <dt>▪</dt> <dd>confusion</dd> <dt>▪</dt> <dd>sudden change in thinking, walking, strength on one side of your body</dd> <dt>▪</dt> <dd>other problems that have lasted over several days </dd> </dl> </dd> </dl> </dd> <dt>•</dt> <dd> <span class="Bold">Lung or breathing problems.</span> This can sometimes lead to death. Tell your doctor if you have a new or worsening cough, shortness of breath, difficulty breathing or any new breathing problems. Your doctor may need to stop sirolimus or lower your dose.</dd> <dt>•</dt> <dd> <span class="Bold">Blood clotting problems.</span> When sirolimus is taken with cyclosporine or tacrolimus, you may develop a blood clotting problem. Tell your doctor if you get any unexplained bleeding or bruising.</dd> <dt>•</dt> <dd> <span class="Bold">Possible harm to your unborn baby.</span> Sirolimus can harm your unborn baby. You should not become pregnant during treatment with sirolimus and for 12 weeks after ending treatment with sirolimus. See <span class="Bold">"<a href="#Ref_MG3">What should I tell my doctor before taking sirolimus?</a>".</span> </dd> </dl> <p class="First"> <span class="Bold">The most common side effects of sirolimus in people with renal transplant include:</span> </p> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>•</dt> <dd>high blood pressure</dd> <dt>•</dt> <dd>pain (including stomach and joint pain)</dd> <dt>•</dt> <dd>diarrhea</dd> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>fever</dd> </dl> </td><td class="Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>urinary tract infection</dd> <dt>•</dt> <dd>low red blood cell count (anemia)</dd> <dt>•</dt> <dd>nausea</dd> <dt>•</dt> <dd>low platelet count (cells that help blood to clot)</dd> <dt>•</dt> <dd>high blood sugar (diabetes)</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">The most common side effects of sirolimus in people with LAM include:</span> </p> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>•</dt> <dd>mouth sores</dd> <dt>•</dt> <dd>diarrhea</dd> <dt>•</dt> <dd>stomach pain</dd> <dt>•</dt> <dd>nausea</dd> <dt>•</dt> <dd>sore throat</dd> <dt>•</dt> <dd>acne</dd> </dl> </td><td class="Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>chest pain</dd> <dt>•</dt> <dd>upper respiratory tract infection</dd> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>dizziness</dd> <dt>•</dt> <dd>sore muscles</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Other side effects that may occur with sirolimus: </span> </p> <dl> <dt>•</dt> <dd>Sirolimus may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.</dd> <dt>•</dt> <dd>Sirolimus may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.</dd> </dl> <p>Tell your doctor if you have any side effect that bothers you or that does not go away. <br/>These are not all of the possible side effects of sirolimus. For more information ask your doctor or pharmacist.<br/> <span class="Bold">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <a name="Ref_MG4"></a><span class="Bold">How should I store sirolimus?</span> <br/> <span class="Bold">Sirolimus oral solution:</span> </p> <dl> <dt>•</dt> <dd>Store bottles of sirolimus oral solution in the refrigerator between 36°F to 46°F (2°C to 8°C). Protect from light.</dd> <dt>•</dt> <dd>If necessary, bottles of sirolimus oral solution can be stored at room temperature up to 77°F (25°C) for up to 15 days.</dd> <dt>•</dt> <dd>When a bottle of sirolimus oral solution is opened, it should be used within 1 month.</dd> <dt>•</dt> <dd>Use any diluted sirolimus oral solution right away.</dd> </dl> <p>Do not use sirolimus after the expiration date. The expiration date refers to the last day of that month.<br/>Safely throw away medicine that is out of date or no longer needed.<br/> <span class="Bold">Keep sirolimus and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of sirolimus.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use sirolimus for a condition for which it was not prescribed. Do not give sirolimus to other people even if they have the same symptoms that you have. It may harm them.<br/>This Medication Guide summarizes the most important information about sirolimus. If you would like more information talk to your doctor. You can ask your pharmacist or doctor for information about sirolimus that is written for health professionals. <br/>For more information about sirolimus call 1-877-446-3679.</p> </td> </tr> <tr> <td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in sirolimus?</span> <br/>Active ingredients: sirolimus<br/>Inactive ingredients: Inactive ingredients: sirolimus oral solution: Phosal 50 PG<span class="Sup">®</span> (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Sirolimus oral solution contains 1.5%–2.5% ethanol. <br/> </p> <a name="id3698"></a><img alt="Logo" src="/dailymed/image.cfm?name=sirolimus-03a.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84"/><p>For sirolimus oral solution: <br/>LAB-0688-8.0</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100.1%\">\n<col width=\"3%\"/>\n<col width=\"42%\"/>\n<col width=\"27%\"/>\n<col width=\"29%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">MEDICATION GUIDE</span>\n<br/>Sirolimus Oral Solution</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<a name=\"Ref_MG2\"></a><span class=\"Bold\">What is the most important information I should know about sirolimus?</span>\n<br/>Sirolimus can cause serious side effects, including: </p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased risk of getting infections.</span> Serious infections can happen including infections caused by viruses, bacteria, and fungi (yeast). Your doctor may put you on medicine to help prevent some of these infections.<br/>Call your doctor right away if you have symptoms of infection including fever or chills while taking sirolimus.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased risk of getting certain cancers.</span> People who take sirolimus have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Talk with your doctor about your risk for cancer.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Sirolimus has not been shown to be safe and effective in people who have had liver or lung transplants. Serious complications and death may happen in people who take sirolimus after a liver or lung transplant.</span> You should not take sirolimus if you have had a liver or lung transplant without talking with your doctor.<br/>\n<span class=\"Bold\">See the section \"<a href=\"#Ref_MG1\">What are the possible side effects of sirolimus</a>?\" for information about other side effects of sirolimus.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is sirolimus?</span>\n<br/>Sirolimus is a prescription medicine used to prevent rejection (anti-rejection medicine) in people 13 years of age and older who have received a kidney transplant. Rejection is when your body's immune system recognizes the new organ as a \"foreign\" threat and attacks it. <br/>Sirolimus is used with other medicines called cyclosporine (Gengraf, Neoral, Sandimmune), and corticosteroids. Your doctor will decide: </p>\n<dl>\n<dt>•</dt>\n<dd>if sirolimus is right for you, and</dd>\n<dt>•</dt>\n<dd>how to best use it with cyclosporine and corticosteroids after your transplant.</dd>\n</dl>\n<p>It is not known if sirolimus is safe and effective in children under 13 years of age.<br/>Sirolimus is a prescription medicine also used to treat lymphangioleiomyomatosis (LAM). LAM is a rare progressive lung disease that affects predominantly women of childbearing age.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take sirolimus?</span>\n<br/>Do not take sirolimus if you are allergic to sirolimus or any of the other ingredients in sirolimus. See the end of this leaflet for a complete list of ingredients in sirolimus.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<a name=\"Ref_MG3\"></a><span class=\"Bold\">What should I tell my doctor before taking sirolimus?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have liver problems</dd>\n<dt>•</dt>\n<dd>have skin cancer or it runs in your family</dd>\n<dt>•</dt>\n<dd>have high cholesterol or triglycerides (fat in your blood) </dd>\n<dt>•</dt>\n<dd>are pregnant or are a female who can become pregnant. Sirolimus can harm your unborn baby. You should not become pregnant during treatment with sirolimus and for 12 weeks after ending treatment with sirolimus. In order to avoid pregnancy, a female who can get pregnant should use effective birth control during treatment and for 12 weeks after your final dose of sirolimus. Talk with your doctor about what birth control method is right for you during this time. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with sirolimus or within 12 weeks after your final dose of sirolimus.</dd>\n<dt>•</dt>\n<dd>It is not known whether sirolimus passes into breast milk; however, there is a risk of serious side effects in breastfed infants. You and your doctor should decide about the best way to feed your baby if you take sirolimus.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your doctor about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins and herbal supplements. Using sirolimus with certain medicines may affect each other causing serious side effects. <br/>Sirolimus may affect the way other medicines work, and other medicines may affect how sirolimus works. <br/>Especially tell your doctor if you take: </p>\n<dl>\n<dt>•</dt>\n<dd>a medicine to lower your cholesterol or triglycerides</dd>\n<dt>•</dt>\n<dd>cyclosporine (including Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf) or other medicines that suppress the immune system</dd>\n<dt>•</dt>\n<dd>an antibiotic</dd>\n<dt>•</dt>\n<dd>an antifungal medicine</dd>\n<dt>•</dt>\n<dd>a medicine for high blood pressure or heart problems</dd>\n<dt>•</dt>\n<dd>an anti-seizure medicine</dd>\n<dt>•</dt>\n<dd>medicines used to treat stomach acid, ulcers, or other gastrointestinal problems</dd>\n<dt>•</dt>\n<dd>bromocriptine mesylate (Parlodel, Cycloset)</dd>\n<dt>•</dt>\n<dd>danazol</dd>\n<dt>•</dt>\n<dd>letermovir (Prevymis)</dd>\n<dt>•</dt>\n<dd>medicines to treat HIV or hepatitis C</dd>\n<dt>•</dt>\n<dd>St.John’s Wort</dd>\n<dt>•</dt>\n<dd>Cannabidiol (Epidiolex)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take sirolimus?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Read the Instructions for Use that comes with your sirolimus for information about the right way to take sirolimus oral solution.</dd>\n<dt>•</dt>\n<dd>Take sirolimus exactly as your doctor tells you to take it.</dd>\n<dt>•</dt>\n<dd>Your doctor will tell you how much sirolimus to take and when to take it. Do not change your dose of sirolimus unless your doctor tells you to.</dd>\n<dt>•</dt>\n<dd>If you also take cyclosporine (Gengraf, Neoral, Sandimmune), you should take your sirolimus and cyclosporine about 4 hours apart.</dd>\n<dt>•</dt>\n<dd>Do not stop taking sirolimus or your other anti-rejection medicines unless your doctor tells you to.</dd>\n<dt>•</dt>\n<dd>Your doctor will check the levels of sirolimus in your blood. Your doctor may change your dose of sirolimus depending on your blood test results.</dd>\n<dt>•</dt>\n<dd>Sirolimus is taken by mouth 1 time each day.</dd>\n<dt>•</dt>\n<dd>Take each dose of sirolimus the same way, either with or without food. Food can affect the amount of medicine that gets into your bloodstream. Taking each dose of sirolimus the same way helps keep your blood levels of sirolimus more stable. Do not take sirolimus with grapefruit juice.</dd>\n<dt>•</dt>\n<dd>Sirolimus oral solution can develop a slight haze when it is refrigerated. If this happens, bring the sirolimus oral solution to room temperature and then gently shake the bottle until the haze goes away.</dd>\n<dt>•</dt>\n<dd>If you get sirolimus oral solution on your skin, wash the area with soap and water.</dd>\n<dt>•</dt>\n<dd>If you get sirolimus oral solution in your eyes, rinse your eyes with water.</dd>\n<dt>•</dt>\n<dd>If you have taken more medicine than you were told, contact a doctor or go to the nearest hospital emergency department right away.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking sirolimus?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Avoid receiving live vaccines while taking sirolimus. Some vaccines may not work as well while you are taking sirolimus.</dd>\n<dt>•</dt>\n<dd>Limit your time in sunlight and UV light. Cover your skin with clothing and use a broad spectrum sunscreen with a high protection factor because of the increased risk for skin cancer with sirolimus.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<a name=\"Ref_MG1\"></a><span class=\"Bold\">What are the possible side effects of sirolimus?</span>\n<br/>\n<span class=\"Bold\">Sirolimus may cause serious side effects, including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>See <span class=\"Bold\">\"<a href=\"#Ref_MG2\">What is the most important information I should know about sirolimus?</a>\"</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Serious allergic reactions. Tell your doctor or get medical help right away</span> if you get any of following symptoms of an allergic reaction:</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\"></td><td valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>swelling of your face, eyes, or mouth</dd>\n<dt>•</dt>\n<dd>trouble breathing or wheezing</dd>\n<dt>•</dt>\n<dd>throat tightness</dd>\n</dl>\n</td><td class=\"Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>chest pain or tightness</dd>\n<dt>•</dt>\n<dd>feeling dizzy or faint</dd>\n<dt>•</dt>\n<dd>rash or peeling of your skin</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Swelling (edema).</span> Fluid may collect in your hands and feet and in various tissues of your body, including in the sac around your heart or lungs. Call your doctor if you have trouble breathing.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Poor wound healing.</span> Sirolimus may cause your wounds to heal slowly or not heal well. Tell your doctor if you have any redness or drainage, your wound does not heal, or the wound opens up. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased levels of cholesterol and triglycerides (lipids or fat) in your blood.</span> Your doctor should do blood tests to check your lipids during treatment with sirolimus. Your doctor may prescribe treatment with diet, exercise, or medicine if your lipid levels are too high. During treatment with sirolimus, your blood levels of cholesterol and triglycerides may remain high even if you follow your prescribed treatment plan.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Effects on kidney function.</span> When sirolimus is taken with cyclosporine (Gengraf, Neoral, Sandimmune), the function of your transplanted kidney may be affected. Your doctor should regularly do tests to check your kidney function while you are taking sirolimus with cyclosporine (Gengraf, Neoral, Sandimmune).</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased protein in your urine.</span> Your doctor may regularly test your urine protein. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Increased risk for viral infections.</span>\n<dl>\n<dt>o</dt>\n<dd>Certain viruses can live in your body and cause active infections when your immune system is weak. BK virus can affect how your kidney works and cause your transplanted kidney to fail.</dd>\n<dt>o</dt>\n<dd>A certain virus can cause a rare serious brain infection called Progressive Multifocal Leukoencephalopathy (PML). PML usually causes death or severe disability. Call your doctor right away if you notice any new or worsening medical problems such as:<dl>\n<dt>▪</dt>\n<dd>confusion</dd>\n<dt>▪</dt>\n<dd>sudden change in thinking, walking, strength on one side of your body</dd>\n<dt>▪</dt>\n<dd>other problems that have lasted over several days </dd>\n</dl>\n</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Lung or breathing problems.</span> This can sometimes lead to death. Tell your doctor if you have a new or worsening cough, shortness of breath, difficulty breathing or any new breathing problems. Your doctor may need to stop sirolimus or lower your dose.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Blood clotting problems.</span> When sirolimus is taken with cyclosporine or tacrolimus, you may develop a blood clotting problem. Tell your doctor if you get any unexplained bleeding or bruising.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Possible harm to your unborn baby.</span> Sirolimus can harm your unborn baby. You should not become pregnant during treatment with sirolimus and for 12 weeks after ending treatment with sirolimus. See <span class=\"Bold\">\"<a href=\"#Ref_MG3\">What should I tell my doctor before taking sirolimus?</a>\".</span>\n</dd>\n</dl>\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of sirolimus in people with renal transplant include:</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>high blood pressure</dd>\n<dt>•</dt>\n<dd>pain (including stomach and joint pain)</dd>\n<dt>•</dt>\n<dd>diarrhea</dd>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>fever</dd>\n</dl>\n</td><td class=\"Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>urinary tract infection</dd>\n<dt>•</dt>\n<dd>low red blood cell count (anemia)</dd>\n<dt>•</dt>\n<dd>nausea</dd>\n<dt>•</dt>\n<dd>low platelet count (cells that help blood to clot)</dd>\n<dt>•</dt>\n<dd>high blood sugar (diabetes)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of sirolimus in people with LAM include:</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>mouth sores</dd>\n<dt>•</dt>\n<dd>diarrhea</dd>\n<dt>•</dt>\n<dd>stomach pain</dd>\n<dt>•</dt>\n<dd>nausea</dd>\n<dt>•</dt>\n<dd>sore throat</dd>\n<dt>•</dt>\n<dd>acne</dd>\n</dl>\n</td><td class=\"Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>chest pain</dd>\n<dt>•</dt>\n<dd>upper respiratory tract infection</dd>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>dizziness</dd>\n<dt>•</dt>\n<dd>sore muscles</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Other side effects that may occur with sirolimus: </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Sirolimus may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.</dd>\n<dt>•</dt>\n<dd>Sirolimus may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.</dd>\n</dl>\n<p>Tell your doctor if you have any side effect that bothers you or that does not go away. <br/>These are not all of the possible side effects of sirolimus. For more information ask your doctor or pharmacist.<br/>\n<span class=\"Bold\">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<a name=\"Ref_MG4\"></a><span class=\"Bold\">How should I store sirolimus?</span>\n<br/>\n<span class=\"Bold\">Sirolimus oral solution:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store bottles of sirolimus oral solution in the refrigerator between 36°F to 46°F (2°C to 8°C). Protect from light.</dd>\n<dt>•</dt>\n<dd>If necessary, bottles of sirolimus oral solution can be stored at room temperature up to 77°F (25°C) for up to 15 days.</dd>\n<dt>•</dt>\n<dd>When a bottle of sirolimus oral solution is opened, it should be used within 1 month.</dd>\n<dt>•</dt>\n<dd>Use any diluted sirolimus oral solution right away.</dd>\n</dl>\n<p>Do not use sirolimus after the expiration date. The expiration date refers to the last day of that month.<br/>Safely throw away medicine that is out of date or no longer needed.<br/>\n<span class=\"Bold\">Keep sirolimus 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=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of sirolimus.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use sirolimus for a condition for which it was not prescribed. Do not give sirolimus to other people even if they have the same symptoms that you have. It may harm them.<br/>This Medication Guide summarizes the most important information about sirolimus. If you would like more information talk to your doctor. You can ask your pharmacist or doctor for information about sirolimus that is written for health professionals. <br/>For more information about sirolimus call 1-877-446-3679.</p>\n</td>\n</tr>\n<tr>\n<td valign=\"top\"></td><td valign=\"top\"></td><td valign=\"top\"></td><td valign=\"top\"></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in sirolimus?</span>\n<br/>Active ingredients: sirolimus<br/>Inactive ingredients: Inactive ingredients: sirolimus oral solution: Phosal 50 PG<span class=\"Sup\">®</span> (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Sirolimus oral solution contains 1.5%–2.5% ethanol. <br/>\n</p>\n<a name=\"id3698\"></a><img alt=\"Logo\" src=\"/dailymed/image.cfm?name=sirolimus-03a.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84\"/><p>For sirolimus oral solution: <br/>LAB-0688-8.0</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide has been approved by the U.S. Food and Drug Administration.     Revised: Nov 2024

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration.     Revised: Nov 2024" }

Sirolimus Oral Solution

{ "type": "p", "children": [], "text": "\nSirolimus\n\nOral Solution\n" }

Be sure that you read and understand the following instructions for the correct way to dilute and take sirolimus oral solution. Ask your pharmacist or doctor if you are not sure.

{ "type": "p", "children": [], "text": "Be sure that you read and understand the following instructions for the correct way to dilute and take sirolimus oral solution. Ask your pharmacist or doctor if you are not sure." }

Important:

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

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

Each sirolimus oral solution carton contains:

{ "type": "p", "children": [], "text": "Each sirolimus oral solution carton contains:" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="30%"/> <col width="70%"/> <tbody class="Headless"> <tr> <td valign="top"><a name="id3734"></a><img alt="Figure" src="/dailymed/image.cfm?name=sirolimus-04.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84"/></td><td valign="top"> <dl> <dt>•</dt> <dd>a 2 oz. (60 mL fill) amber glass bottle of sirolimus (concentration of 1 mg/mL)</dd> <dt>•</dt> <dd>1 oral syringe adapter for fitting into the neck of the bottle</dd> <dt>•</dt> <dd>enough disposable oral syringes (amber color) and caps for daily dosing</dd> <dt>•</dt> <dd>1 carrying case</dd> </dl> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col width=\"30%\"/>\n<col width=\"70%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td valign=\"top\"><a name=\"id3734\"></a><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=sirolimus-04.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84\"/></td><td valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>a 2 oz. (60 mL fill) amber glass bottle of sirolimus (concentration of 1 mg/mL)</dd>\n<dt>•</dt>\n<dd>1 oral syringe adapter for fitting into the neck of the bottle</dd>\n<dt>•</dt>\n<dd>enough disposable oral syringes (amber color) and caps for daily dosing</dd>\n<dt>•</dt>\n<dd>1 carrying case</dd>\n</dl>\n</td>\n</tr>\n</tbody>\n</table></div>" }

You will also need:

{ "type": "p", "children": [], "text": "You will also need:" }

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<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="40%"/> <col width="60%"/> <tbody class="Headless"> <tr> <td valign="top"> <p class="First">Figure 1: Opening the bottle<br/> <a name="id3756"></a><img alt="Figure" src="/dailymed/image.cfm?name=sirolimus-05.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84"/></p> </td><td valign="middle"> <p class="First">1. Open the solution bottle.</p> <dl> <dt>•</dt> <dd>Remove the safety cap by squeezing the tabs on each side of the cap and twisting counterclockwise (Figure 1). </dd> </dl> </td> </tr> <tr> <td valign="top"> <p class="First">Figure 2: Inserting adapter<br/> <a name="id3763"></a><img alt="Figure" src="/dailymed/image.cfm?name=sirolimus-06.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84"/></p> </td><td valign="top"> <p class="First">2. The <span class="Bold">first time</span> you use a bottle of sirolimus oral solution:</p> <dl> <dt>•</dt> <dd>Insert the oral syringe adapter (plastic tube with stopper) tightly into the bottle until it is even with the top of the bottle (Figure 2).</dd> <dt>•</dt> <dd>Do not remove the oral syringe adapter from the bottle once inserted.</dd> </dl> </td> </tr> <tr> <td valign="top"> <p class="First">Figure 3: Inserting syringe<br/> <a name="id3772"></a><img alt="Figure" src="/dailymed/image.cfm?name=sirolimus-07.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84"/></p> </td><td valign="top"> <p class="First">3. Use a new disposable amber oral syringe for each dose of sirolimus oral solution.</p> <dl> <dt>•</dt> <dd>Fully push down (depress) on the plunger of the disposable amber oral syringe.</dd> <dt>•</dt> <dd>Then, tightly insert the oral syringe into the opening in the adapter (Figure 3).</dd> </dl> </td> </tr> <tr> <td valign="top"> <p class="First">Figure 4: Withdrawing solution<br/> <a name="id3780"></a><img alt="Figure" src="/dailymed/image.cfm?name=sirolimus-08.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84"/></p> </td><td valign="top"> <p class="First">4. Withdraw the prescribed amount of sirolimus oral solution:</p> <dl> <dt>•</dt> <dd>Gently pull back the plunger of the syringe until the level of the oral solution is even with the marking on the syringe for your prescribed dose.</dd> <dt>•</dt> <dd>Always keep the bottle in an upright position. </dd> <dt>•</dt> <dd>If bubbles form within the oral solution in the syringe, empty the syringe into the bottle and repeat step 4 (Figure 4).</dd> <dt>•</dt> <dd>You may need to repeat step 4 more than once to draw up your prescribed dose.</dd> </dl> </td> </tr> <tr> <td valign="top"> <p class="First">Figure 5: Capping syringe<br/> <a name="id3790"></a><img alt="Figure" src="/dailymed/image.cfm?name=sirolimus-09.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84"/><br/>Figure 6: Placing syringe in carrying case<br/> <a name="id3793"></a><img alt="Figure" src="/dailymed/image.cfm?name=sirolimus-10.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84"/></p> </td><td valign="top"> <p class="First">5. If your doctor tells you to carry your medicine with you:</p> <dl> <dt>•</dt> <dd>Each dose of sirolimus oral solution should be placed in an oral syringe. Place a cap securely on each syringe. The cap should snap into place (Figure 5).</dd> <dt>•</dt> <dd>Place the capped syringe in the enclosed carrying case (Figure 6). If you need more than 1 carrying case, talk with your doctor or pharmacist.</dd> <dt>•</dt> <dd>See <a href="#Ref_MG4">'How should I store sirolimus</a>' for storage instructions.</dd> </dl> </td> </tr> <tr> <td valign="top"> <p class="First">Figure 7: Emptying syringe into glass<br/> <a name="id3803"></a><img alt="Figure" src="/dailymed/image.cfm?name=sirolimus-11.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84"/></p> </td><td valign="top"> <p class="First">6. Taking a dose of sirolimus oral solution:</p> <dl> <dt>•</dt> <dd>Choose a clean flat work surface. Place a clean paper towel on the work surface. Wash and dry your hands.</dd> <dt>•</dt> <dd>Empty the syringe into a glass or plastic cup containing at least 2 ounces (1/4 cup, 60 mL) of water or orange juice, stir vigorously for 1 minute and drink right away (Figure 7).</dd> <dt>•</dt> <dd>If more than 1 syringe is needed for your prescribed dose, empty the oral solution from each syringe into the same glass or plastic cup of water or orange juice.</dd> <dt>•</dt> <dd>Refill the container with at least 4 ounces (1/2 cup, 120 mL) of water or orange juice, stir vigorously again and drink the rinse solution. Do not mix sirolimus oral solution with apple juice, grapefruit juice, or other liquids. Only glass or plastic cups should be used to mix sirolimus oral solution.</dd> <dt>•</dt> <dd>The syringe and cap should be used only one time and then thrown away.</dd> <dt>•</dt> <dd>Throw away the paper towel and clean the work surface. Wash your hands.</dd> </dl> </td> </tr> <tr> <td valign="top"></td><td valign="top"> <p class="First">7. Always store the bottles of medication in the refrigerator.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col width=\"40%\"/>\n<col width=\"60%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td valign=\"top\">\n<p class=\"First\">Figure 1: Opening the bottle<br/>\n<a name=\"id3756\"></a><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=sirolimus-05.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84\"/></p>\n</td><td valign=\"middle\">\n<p class=\"First\">1. Open the solution bottle.</p>\n<dl>\n<dt>•</dt>\n<dd>Remove the safety cap by squeezing the tabs on each side of the cap and twisting counterclockwise (Figure 1). </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">Figure 2: Inserting adapter<br/>\n<a name=\"id3763\"></a><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=sirolimus-06.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84\"/></p>\n</td><td valign=\"top\">\n<p class=\"First\">2. The <span class=\"Bold\">first time</span> you use a bottle of sirolimus oral solution:</p>\n<dl>\n<dt>•</dt>\n<dd>Insert the oral syringe adapter (plastic tube with stopper) tightly into the bottle until it is even with the top of the bottle (Figure 2).</dd>\n<dt>•</dt>\n<dd>Do not remove the oral syringe adapter from the bottle once inserted.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">Figure 3: Inserting syringe<br/>\n<a name=\"id3772\"></a><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=sirolimus-07.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84\"/></p>\n</td><td valign=\"top\">\n<p class=\"First\">3. Use a new disposable amber oral syringe for each dose of sirolimus oral solution.</p>\n<dl>\n<dt>•</dt>\n<dd>Fully push down (depress) on the plunger of the disposable amber oral syringe.</dd>\n<dt>•</dt>\n<dd>Then, tightly insert the oral syringe into the opening in the adapter (Figure 3).</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">Figure 4: Withdrawing solution<br/>\n<a name=\"id3780\"></a><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=sirolimus-08.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84\"/></p>\n</td><td valign=\"top\">\n<p class=\"First\">4. Withdraw the prescribed amount of sirolimus oral solution:</p>\n<dl>\n<dt>•</dt>\n<dd>Gently pull back the plunger of the syringe until the level of the oral solution is even with the marking on the syringe for your prescribed dose.</dd>\n<dt>•</dt>\n<dd>Always keep the bottle in an upright position. </dd>\n<dt>•</dt>\n<dd>If bubbles form within the oral solution in the syringe, empty the syringe into the bottle and repeat step 4 (Figure 4).</dd>\n<dt>•</dt>\n<dd>You may need to repeat step 4 more than once to draw up your prescribed dose.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">Figure 5: Capping syringe<br/>\n<a name=\"id3790\"></a><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=sirolimus-09.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84\"/><br/>Figure 6: Placing syringe in carrying case<br/>\n<a name=\"id3793\"></a><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=sirolimus-10.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84\"/></p>\n</td><td valign=\"top\">\n<p class=\"First\">5. If your doctor tells you to carry your medicine with you:</p>\n<dl>\n<dt>•</dt>\n<dd>Each dose of sirolimus oral solution should be placed in an oral syringe. Place a cap securely on each syringe. The cap should snap into place (Figure 5).</dd>\n<dt>•</dt>\n<dd>Place the capped syringe in the enclosed carrying case (Figure 6). If you need more than 1 carrying case, talk with your doctor or pharmacist.</dd>\n<dt>•</dt>\n<dd>See <a href=\"#Ref_MG4\">'How should I store sirolimus</a>' for storage instructions.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">Figure 7: Emptying syringe into glass<br/>\n<a name=\"id3803\"></a><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=sirolimus-11.jpg&amp;setid=384cb547-55a4-47fc-a0a6-054c18a51b84\"/></p>\n</td><td valign=\"top\">\n<p class=\"First\">6. Taking a dose of sirolimus oral solution:</p>\n<dl>\n<dt>•</dt>\n<dd>Choose a clean flat work surface. Place a clean paper towel on the work surface. Wash and dry your hands.</dd>\n<dt>•</dt>\n<dd>Empty the syringe into a glass or plastic cup containing at least 2 ounces (1/4 cup, 60 mL) of water or orange juice, stir vigorously for 1 minute and drink right away (Figure 7).</dd>\n<dt>•</dt>\n<dd>If more than 1 syringe is needed for your prescribed dose, empty the oral solution from each syringe into the same glass or plastic cup of water or orange juice.</dd>\n<dt>•</dt>\n<dd>Refill the container with at least 4 ounces (1/2 cup, 120 mL) of water or orange juice, stir vigorously again and drink the rinse solution. Do not mix sirolimus oral solution with apple juice, grapefruit juice, or other liquids. Only glass or plastic cups should be used to mix sirolimus oral solution.</dd>\n<dt>•</dt>\n<dd>The syringe and cap should be used only one time and then thrown away.</dd>\n<dt>•</dt>\n<dd>Throw away the paper towel and clean the work surface. Wash your hands.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td valign=\"top\"></td><td valign=\"top\">\n<p class=\"First\">7. Always store the bottles of medication in the refrigerator.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

How should I store sirolimus?

{ "type": "p", "children": [], "text": "How should I store sirolimus?" }

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

Keep sirolimus and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep sirolimus and all medicines 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." }

LAB-0687-6.0

{ "type": "p", "children": [], "text": "LAB-0687-6.0" }

Revised November 2024

{ "type": "p", "children": [], "text": "Revised November 2024" }

ALWAYS DISPENSE WITH MEDICATION GUIDE

{ "type": "p", "children": [], "text": "ALWAYS DISPENSE WITH MEDICATION GUIDE" }

NDC 59762-1205-460 mL bottle

{ "type": "p", "children": [], "text": "NDC 59762-1205-460 mL bottle" }

GREENSTONE® BRANDsirolimusoral solution

{ "type": "p", "children": [], "text": "GREENSTONE® BRANDsirolimusoral solution" }

1 mg/mL

{ "type": "p", "children": [], "text": "1 mg/mL" }

For oral use only.Each mL of sirolimus oral solution contains1 mg sirolimus.1.5%-2.5% ethanolAlso contains a mixture of propylene glycoland phosphatidylcholine derived from soylecithin (and other components) andpolysorbate 80.

{ "type": "p", "children": [], "text": "For oral use only.Each mL of sirolimus oral solution contains1 mg sirolimus.1.5%-2.5% ethanolAlso contains a mixture of propylene glycoland phosphatidylcholine derived from soylecithin (and other components) andpolysorbate 80." }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

ALWAYS DISPENSE WITHMEDICATION GUIDE

{ "type": "p", "children": [], "text": "ALWAYS DISPENSE WITHMEDICATION GUIDE" }

NDC 59762-1205-460 mL bottle

{ "type": "p", "children": [], "text": "NDC 59762-1205-460 mL bottle" }

GREENSTONE® BRAND

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sirolimusoral solution

{ "type": "p", "children": [], "text": "sirolimusoral solution" }

1 mg/mL

{ "type": "p", "children": [], "text": "1 mg/mL" }

For oral use only.

{ "type": "p", "children": [], "text": "For oral use only." }

Each mL of sirolimus oralsolution contains 1 mgsirolimus.

{ "type": "p", "children": [], "text": "Each mL of sirolimus oralsolution contains 1 mgsirolimus." }

1.5%-2.5% ethanol

{ "type": "p", "children": [], "text": "1.5%-2.5% ethanol" }

Also contains a mixture ofpropylene glycol andphosphatidylcholine derived fromsoy lecithin (and othercomponents) and polysorbate 80.

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Rx only

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ALWAYS DISPENSE WITH MEDICATION GUIDE

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NDC 59762-1205-660 mL patient kit

{ "type": "p", "children": [], "text": "NDC 59762-1205-660 mL patient kit" }

GREENSTONE® BRAND

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sirolimusoral solution

{ "type": "p", "children": [], "text": "sirolimusoral solution" }

1 mg/mL

{ "type": "p", "children": [], "text": "1 mg/mL" }

For oral use only.

{ "type": "p", "children": [], "text": "For oral use only." }

Each mL of sirolimus oral solution contains 1 mg sirolimus.

{ "type": "p", "children": [], "text": "Each mL of sirolimus oral solution contains 1 mg sirolimus." }

1.5%-2.5% ethanol

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Also contains a mixture of propylene glycol and phosphatidylcholinederived from soy lecithin (and other components) and polysorbate 80.

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Rx only

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Each sirolimus oral solution carton contains:

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Also contains: Package Insert and Medication Guide

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You will also need:

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