Posaconazole injection is indicated for the treatment of invasive aspergillosis in adults and pediatric patients 13 years of age and older.

Posaconazole injection is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies (14.1)] as follows:    •   Posaconazole injection: adults and pediatric patients 2 years of age and older

Posaconazole injection ●  Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes [see Dosage and Administration (2.4)]. ●  If a central venous catheter is not available, posaconazole injection may be administered through a peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single-dose in advance of central venous line      placement or to bridge the period during which a central venous line is replaced or is in use for other intravenous treatment.●  When multiple dosing is required, the infusion should be done via a central venous line.●  Do NOT administer posaconazole injection as an intravenous bolus injection.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 1: Dosing Regimens in Adult Patients </span> </caption> <colgroup> <col width="22%"/> <col width="39%"/> <col width="37%"/> </colgroup> <thead> <tr class="First Last"> <th class="Lrule Rrule Toprule">Indication<br/> </th><th class="Lrule Rrule Toprule">Dose and Frequency<br/> </th><th class="Lrule Rrule Toprule">Duration of Therapy<br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle">Treatment of<br/>invasive<br/>Aspergillosis<br/> </td><td class="Rrule" valign="middle"><span class="Bold">Posaconazole Injection:</span> <br/> <span class="Underline">Loading dose:</span> <br/>300 mg posaconazole injection intravenously twice a day on the first day.<br/> <br/> <span class="Underline">Maintenance dose:</span> <br/>300 mg posaconazole injection intravenously once a day, starting on the second day.<br/> <br/> </td><td class="Rrule" valign="middle"> <br/> <span class="Underline">Loading dose:</span> <br/>1 day<br/> <br/> <br/> <span class="Underline">Maintenance dose:</span> <br/>Recommended total duration of therapy<br/>is 6 to 12 weeks.<br/> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Prophylaxis of invasive <span class="Italics">Aspergillus </span>and <span class="Italics">Candida </span>infections<br/> </td><td class="Rrule" valign="top"><span class="Bold">Posaconazole Injection:</span> <br/> <span class="Underline">Loading dose</span>: 300 mg posaconazole injection intravenously twice a day on the first day.<br/> <br/> <span class="Underline">Maintenance dose</span>: 300 mg posaconazole injection intravenously once a day thereafter. <br/> </td><td class="Rrule" valign="top"> <br/> <span class="Underline">Loading dose:</span> <br/>1 day<br/> <br/> <span class="Underline">Maintenance dose:</span> <br/>Duration of therapy is based on recovery from neutropenia or immunosuppression. <br/> </td> </tr> </tbody> </table></div>

The recommended dosing regimen of posaconazole injection for pediatric patients 2 to less than 18 years of age is shown in Table 2 [see Clinical Pharmacology (12.3)]. 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 2: Posaconazole Injection Dosing Regimens for Pediatric Patients (ages 2 to less than 18 years of age) </span> </caption> <colgroup> <col width="24.82%"/> <col width="23.36%"/> <col width="24.54%"/> <col width="27.28%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" colspan="2" valign="top"> <br/> </td><td class="Rrule" valign="top"><span class="Bold"><span class="Underline">Recommended Pediatric Dosage and Formulation</span></span> <br/> </td><td class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold"><span class="Underline">Indication</span></span> <br/> </td><td class="Rrule" valign="top"><span class="Bold"><span class="Underline">Weight</span></span><span class="Bold"><span class="Underline">/Age</span></span> <br/> </td><td class="Rrule" valign="top"><span class="Bold"><span class="Underline">Injection</span></span> <br/> </td><td class="Rrule" valign="top"><span class="Bold"><span class="Underline">Duration of therapy</span></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="2" valign="top">Prophylaxis of<br/>invasive <span class="Italics">Aspergillus</span> <br/>and <span class="Italics">Candida </span>infections<br/> </td><td class="Rrule" valign="top">Less than or equal to 40 kg (2 to less than 18 years of age)<br/> <br/> </td><td class="Rrule" rowspan="2" valign="top"><span class="Underline">Loading dose:</span> <br/>6 mg/kg up to a maximum of 300 mg twice daily on the first day<br/> <br/> <span class="Underline">Maintenance dose:</span> <br/>6 mg/kg up to a maximum of 300 mg once daily<br/> <br/> </td><td class="Rrule" rowspan="2" valign="top">Duration of therapy is based on recovery from neutropenia or immunosuppression.<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Greater than 40 kg <br/>(2 to less than 18<br/>years of age)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Treatment of<br/>invasive<br/>Aspergillosis<br/> </td><td class="Rrule" valign="top">13 to less than 18<br/>years of age<br/>regardless of<br/>weight.<br/> </td><td class="Rrule" valign="top"><span class="Underline">Loading dose:</span> <br/>300 mg posaconazole injection intravenously twice a day on the first day.<br/> <br/> <span class="Underline">Maintenance dose:</span> <br/>300 mg posaconazole injection intravenously once a day, starting on the second day.<br/> <br/>   </td><td class="Rrule" valign="top"><span class="Underline">Loading dose:</span> <br/>1 day<br/> <br/> <br/> <br/> <span class="Underline">Maintenance dose:</span> <br/>Recommended total duration of therapy is 6 to 12 weeks.<br/> </td> </tr> </tbody> </table></div>

Preparation:

Intravenous Line Compatibility:

A study was conducted to evaluate physical compatibility of posaconazole injection with injectable drug products and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined through visual observations, measurement of particulate matter and turbidity. Compatible diluents and drug products are listed in Tables 5 and 6 below. Any diluents or drug products not listed in the tables below should not be co-administered through the same intravenous line (or cannula).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 5: Compatible Diluents </span> </caption> <colgroup> <col width="100%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle">0.45% sodium chloride<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">0.9% sodium chloride<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">5% dextrose in water<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">5% dextrose and 0.45% sodium chloride<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">5% dextrose and 0.9% sodium chloride<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle">5% dextrose and 20 mEq potassium chloride<br/> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 6: Compatible Drugs </span> </caption> <colgroup> <col width="100%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle">Amikacin sulfate<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Caspofungin<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Ciprofloxacin<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Daptomycin<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Dobutamine hydrochloride<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Famotidine<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Filgrastim<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Gentamicin sulfate<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Hydromorphone hydrochloride<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Levofloxacin<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Lorazepam<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Meropenem<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Micafungin<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Morphine sulfate<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Norepinephrine bitartrate<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Potassium chloride<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle">Vancomycin hydrochloride<br/> </td> </tr> </tbody> </table></div>

Incompatible Diluents:

Posaconazole injection must not be diluted with the following diluents:

Lactated Ringer’s solution

5% dextrose with Lactated Ringer’s solution

4.2% sodium bicarbonate Administration:

Posaconazole Injection

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

Posaconazole injection (300 mg per vial) is available as a clear, colorless to yellow sterile liquid in a single-dose vial.

{ "type": "p", "children": [], "text": "Posaconazole injection (300 mg per vial) is available as a clear, colorless to yellow sterile liquid in a single-dose vial." }

Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.

Posaconazole is contraindicated with sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].

Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].

Coadministration of posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Warnings and Precautions (5.11) and Drug Interactions (7.16)].

Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole.

Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18 to 85 years of age) administered Noxafil oral suspension 400 mg twice daily with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.

Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)].

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.

Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11-deoxycortisol), has been reported with posaconazole use in the postmarket setting. Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldosteronism may include discontinuation of posaconazole, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists. 

Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the Noxafil oral suspension 800 mg daily (400 mg twice daily or 200 mg four times a day) in clinical trials.

Liver tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.

Posaconazole injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the posaconazole injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy [see Dosage and Administration (2.9) and Use in Specific Populations (8.6)].

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].

Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.10)].

Concomitant administration of posaconazole, a strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of posaconazole during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications (4.6)]. Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax [see Drug Interactions (7.16)]. Refer to the venetoclax prescribing information for dosing instructions.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trial Experience in Adults

Clinical Trial Experience with Posaconazole Injection and Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis

The safety of posaconazole injection and Noxafil delayed-release tablet was assessed in a randomized, doubleblind, active-controlled clinical study of posaconazole injection and Noxafil delayed-release tablets versus voriconazole for treatment of invasive aspergillosis (Aspergillosis Treatment Study). A total of 575 (288 in posaconazole arm, 287 in voriconazole arm) adult and pediatric patients 13 years of age and older with proven, probable or possible invasive aspergillosis were included. The median duration of treatment was 67 days for posaconazole injection or Noxafil delayed-release tablet and 64 days for voriconazole, with 55% to 60% of subjects starting treatment with the IV formulation of either drug. The median duration of the first instance of IV treatment (before switching to oral treatment or discontinuing or completing study treatment) was 9 days for both groups. Table 7 presents adverse reactions reported at an incidence of ≥10% in either one of the groups in Aspergillosis Treatment Study.   Adverse reactions leading to treatment discontinuation were reported for 33.9% of subjects. The most commonly reported adverse reactions (>2% of subjects) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the posaconazole arm, and septic shock and acute myeloid leukemia in the voriconazole arm. 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 7: Posaconazole Invasive Aspergillosis Treatment Study: Adverse Reactions in at Least 10% of Subjects Treated with Posaconazole Injection or Noxafil Delayed-Release Tablets </span> </caption> <colgroup> <col width="35%"/> <col width="31%"/> <col width="32%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">System</span><span class="Bold"> </span><span class="Bold">Organ</span><span class="Bold"> </span><span class="Bold">Class</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Posaconazole injection</span> <span class="Bold">or tablet <br/> (N = 288), n (%)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Voriconazole</span><span class="Bold"> </span><span class="Bold">injection</span><span class="Bold"> </span><span class="Bold">or oral <br/> (N = 287), n (%)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Italics">Blood</span><span class="Italics"> and lymphatic system disorders</span> <br/> </td><td class="Rrule" valign="middle"> <br/> </td><td class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Anemia<br/> </td><td align="center" class="Rrule" valign="middle">25 (8.7)<br/> </td><td align="center" class="Rrule" valign="middle">29 (10.1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Febrile neutropenia<br/> </td><td align="center" class="Rrule" valign="middle">42 (14.6)<br/> </td><td align="center" class="Rrule" valign="middle">38 (13.2)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Italics">Gastrointestinal</span><span class="Italics"> </span><span class="Italics">disorders</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Abdominal pain<br/> </td><td align="center" class="Rrule" valign="middle">29 (10.1)<br/> </td><td align="center" class="Rrule" valign="middle">24 (8.4)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Constipation<br/> </td><td align="center" class="Rrule" valign="middle">32 (11.1)<br/> </td><td align="center" class="Rrule" valign="middle">23 (8.0)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Diarrhea<br/> </td><td align="center" class="Rrule" valign="middle">52 (18.1)<br/> </td><td align="center" class="Rrule" valign="middle">52 (18.1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Nausea<br/> </td><td align="center" class="Rrule" valign="middle">65 (22.6)<br/> </td><td align="center" class="Rrule" valign="middle">51 (17.8)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Vomiting<br/> </td><td align="center" class="Rrule" valign="middle">52 (18.1)<br/> </td><td align="center" class="Rrule" valign="middle">39 (13.6)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Italics">General</span><span class="Italics"> disorders and administration site conditions</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Edema peripheral<br/> </td><td align="center" class="Rrule" valign="middle">32 (11.1)<br/> </td><td align="center" class="Rrule" valign="middle">24 (8.4)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Pyrexia<br/> </td><td align="center" class="Rrule" valign="middle">81 (28.1)<br/> </td><td align="center" class="Rrule" valign="middle">72 (25.1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Italics">Infections</span><span class="Italics"> </span><span class="Italics">and</span><span class="Italics"> </span><span class="Italics">infestations</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Pneumonia<br/> </td><td align="center" class="Rrule" valign="middle">36 (12.5)<br/> </td><td align="center" class="Rrule" valign="middle">26 (9.1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Italics">Investigations</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Alanine aminotransferase increased<br/> </td><td align="center" class="Rrule" valign="middle">42 (14.6)<br/> </td><td align="center" class="Rrule" valign="middle">37 (12.9)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Aspartate aminotransferase increased<br/> </td><td align="center" class="Rrule" valign="middle">38 (13.2)<br/> </td><td align="center" class="Rrule" valign="middle">36 (12.5)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Blood alkaline phosphatase increased<br/> </td><td align="center" class="Rrule" valign="middle">21 (7.3)<br/> </td><td align="center" class="Rrule" valign="middle">29 (10.1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Italics">Metabolism and</span><span class="Italics"> nutrition disorders</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Hypokalemia<br/> </td><td align="center" class="Rrule" valign="middle">82 (28.5)<br/> </td><td align="center" class="Rrule" valign="middle">49 (17.1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Hypomagnesemia<br/> </td><td align="center" class="Rrule" valign="middle">29 (10.1)<br/> </td><td align="center" class="Rrule" valign="middle">18 (6.3)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Italics">Nervous</span><span class="Italics"> system disorders</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Headache<br/> </td><td align="center" class="Rrule" valign="middle">35 (12.2)<br/> </td><td align="center" class="Rrule" valign="middle">25 (8.7)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Italics">Respiratory,</span><span class="Italics"> </span><span class="Italics">thoracic</span><span class="Italics"> </span><span class="Italics">and</span><span class="Italics"> </span><span class="Italics">mediastinal</span><span class="Italics"> </span><span class="Italics">disorders</span> <br/> </td><td class="Rrule" valign="middle"> <br/> </td><td class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Cough<br/> </td><td align="center" class="Rrule" valign="middle">30 (10.4)<br/> </td><td align="center" class="Rrule" valign="middle">24 (8.4)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Epistaxis<br/> </td><td align="center" class="Rrule" valign="middle">32 (11.1)<br/> </td><td align="center" class="Rrule" valign="middle">17 (5.9)<br/> </td> </tr> </tbody> </table></div>

The most frequently reported adverse reactions in the posaconazole-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%).

Clinical Trial Experience with Posaconazole Injection for Prophylaxis

Multiple doses of posaconazole injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, posaconazole injection was administered via central venous catheter.

The safety of posaconazole injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole injection when given as antifungal prophylaxis (Posaconazole Injection Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18 to 82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single-dose of 200 mg posaconazole injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days.

Table 8 presents adverse reactions observed in patients treated with posaconazole injection 300 mg daily dose in the Posaconazole Injection Study. Each patient received a loading dose, 300 mg twice on Day 1. Following posaconazole intravenous therapy, patients received Noxafil oral suspension to complete 28 days of total posaconazole therapy.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 8: Posaconazole Injection Study: Adverse Reactions in at Least 10% of Subjects Treated with Posaconazole Injection 300 mg Daily Dose</span> </caption> <colgroup> <col width="56.36%"/> <col width="11.74%"/> <col width="10.08%"/> <col width="10.9%"/> <col width="10.92%"/> </colgroup> <thead> <tr class="First Last"> <th class="Lrule Rrule Toprule"><span class="Bold"><span class="Italics">Body System</span></span> <br/> </th><th align="center" class="Lrule Rrule Toprule" colspan="2"><span class="Bold">Posaconazole Injection Treatment Phase</span> <br/> <span class="Bold">n=237 (%)*</span> <br/> </th><th align="center" class="Lrule Rrule Toprule" colspan="2"><span class="Bold">Posaconazole Injection Treatment Phase or Subsequent Noxafil Oral Suspension Treatment Phase</span> <br/> <span class="Bold">n=237 (%)</span><span class="Sup">†</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle">Subjects Reporting any Adverse Reaction<br/> </td><td align="center" class="Rrule" valign="middle">220<br/> </td><td align="center" class="Rrule" valign="middle">(93)<br/> </td><td align="center" class="Rrule" valign="middle">235<br/> </td><td align="center" class="Rrule" valign="middle">(99)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="middle"><span class="Italics">Blood and Lymphatic System Disorder</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Anemia<br/> </td><td align="center" class="Rrule" valign="middle">16<br/> </td><td align="center" class="Rrule" valign="middle">(7)<br/> </td><td align="center" class="Rrule" valign="middle">23<br/> </td><td align="center" class="Rrule" valign="middle">(10)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Thrombocytopenia<br/> </td><td align="center" class="Rrule" valign="middle">17<br/> </td><td align="center" class="Rrule" valign="middle">(7)<br/> </td><td align="center" class="Rrule" valign="middle">25<br/> </td><td align="center" class="Rrule" valign="middle">(11)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="middle">Gastrointestinal Disorders<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Abdominal Pain Upper<br/> </td><td align="center" class="Rrule" valign="middle">15<br/> </td><td align="center" class="Rrule" valign="middle">(6)<br/> </td><td align="center" class="Rrule" valign="middle">25<br/> </td><td align="center" class="Rrule" valign="middle">(11)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Abdominal Pain<br/> </td><td align="center" class="Rrule" valign="middle">30<br/> </td><td align="center" class="Rrule" valign="middle">(13)<br/> </td><td align="center" class="Rrule" valign="middle">41<br/> </td><td align="center" class="Rrule" valign="middle">(17)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Constipation<br/> </td><td align="center" class="Rrule" valign="middle">18<br/> </td><td align="center" class="Rrule" valign="middle">(8)<br/> </td><td align="center" class="Rrule" valign="middle">31<br/> </td><td align="center" class="Rrule" valign="middle">(13)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Diarrhea<br/> </td><td align="center" class="Rrule" valign="middle">75<br/> </td><td align="center" class="Rrule" valign="middle">(32)<br/> </td><td align="center" class="Rrule" valign="middle">93<br/> </td><td align="center" class="Rrule" valign="middle">(39)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Nausea<br/> </td><td align="center" class="Rrule" valign="middle">46<br/> </td><td align="center" class="Rrule" valign="middle">(19)<br/> </td><td align="center" class="Rrule" valign="middle">70<br/> </td><td align="center" class="Rrule" valign="middle">(30)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Vomiting<br/> </td><td align="center" class="Rrule" valign="middle">29<br/> </td><td align="center" class="Rrule" valign="middle">(12)<br/> </td><td align="center" class="Rrule" valign="middle">45<br/> </td><td align="center" class="Rrule" valign="middle">(19)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="middle"><span class="Italics">General Disorders and Administration Site Conditions</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Fatigue<br/> </td><td align="center" class="Rrule" valign="middle">19<br/> </td><td align="center" class="Rrule" valign="middle">(8)<br/> </td><td align="center" class="Rrule" valign="middle">24<br/> </td><td align="center" class="Rrule" valign="middle">(10)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Chills<br/> </td><td align="center" class="Rrule" valign="middle">28<br/> </td><td align="center" class="Rrule" valign="middle">(12)<br/> </td><td align="center" class="Rrule" valign="middle">38<br/> </td><td align="center" class="Rrule" valign="middle">(16)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Edema Peripheral<br/> </td><td align="center" class="Rrule" valign="middle">28<br/> </td><td align="center" class="Rrule" valign="middle">(12)<br/> </td><td align="center" class="Rrule" valign="middle">35<br/> </td><td align="center" class="Rrule" valign="middle">(15)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Pyrexia<br/> </td><td align="center" class="Rrule" valign="middle">49<br/> </td><td align="center" class="Rrule" valign="middle">(21)<br/> </td><td align="center" class="Rrule" valign="middle">73<br/> </td><td align="center" class="Rrule" valign="middle">(31)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="middle"><span class="Italics">Metabolism and Nutrition Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Decreased appetite<br/> </td><td align="center" class="Rrule" valign="middle">23<br/> </td><td align="center" class="Rrule" valign="middle">(10)<br/> </td><td align="center" class="Rrule" valign="middle">29<br/> </td><td align="center" class="Rrule" valign="middle">(12)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Hypokalemia<br/> </td><td align="center" class="Rrule" valign="middle">51<br/> </td><td align="center" class="Rrule" valign="middle">(22)<br/> </td><td align="center" class="Rrule" valign="middle">67<br/> </td><td align="center" class="Rrule" valign="middle">(28)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Hypomagnesemia<br/> </td><td align="center" class="Rrule" valign="middle">25<br/> </td><td align="center" class="Rrule" valign="middle">(11)<br/> </td><td align="center" class="Rrule" valign="middle">30<br/> </td><td align="center" class="Rrule" valign="middle">(13)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="middle"><span class="Italics">Nervous System Disorders</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Headache<br/> </td><td align="center" class="Rrule" valign="middle">33<br/> </td><td align="center" class="Rrule" valign="middle">(14)<br/> </td><td align="center" class="Rrule" valign="middle">49<br/> </td><td align="center" class="Rrule" valign="middle">(21)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="middle"><span class="Italics">Respiratory, Thoracic and Mediastinal Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Cough<br/> </td><td align="center" class="Rrule" valign="middle">21<br/> </td><td align="center" class="Rrule" valign="middle">(9)<br/> </td><td align="center" class="Rrule" valign="middle">31<br/> </td><td align="center" class="Rrule" valign="middle">(13)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Dyspnea<br/> </td><td align="center" class="Rrule" valign="middle">16<br/> </td><td align="center" class="Rrule" valign="middle">(7)<br/> </td><td align="center" class="Rrule" valign="middle">24<br/> </td><td align="center" class="Rrule" valign="middle">(10)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Epistaxis<br/> </td><td align="center" class="Rrule" valign="middle">34<br/> </td><td align="center" class="Rrule" valign="middle">(14)<br/> </td><td align="center" class="Rrule" valign="middle">40<br/> </td><td align="center" class="Rrule" valign="middle">(17)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="middle"><span class="Italics">Skin and Subcutaneous Tissue Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Petechiae<br/> </td><td align="center" class="Rrule" valign="middle">20<br/> </td><td align="center" class="Rrule" valign="middle">(8)<br/> </td><td align="center" class="Rrule" valign="middle">24<br/> </td><td align="center" class="Rrule" valign="middle">(10)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Rash<br/> </td><td align="center" class="Rrule" valign="middle">35<br/> </td><td align="center" class="Rrule" valign="middle">(15)<br/> </td><td align="center" class="Rrule" valign="middle">56<br/> </td><td align="center" class="Rrule" valign="middle">(24)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="middle"><span class="Italics">Vascular Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Hypertension<br/> </td><td align="center" class="Rrule" valign="middle">20<br/> </td><td align="center" class="Rrule" valign="middle">(8)<br/> </td><td align="center" class="Rrule" valign="middle">26<br/> </td><td align="center" class="Rrule" valign="middle">(11)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="5" valign="middle"><span class="Sup">*</span>Adverse reactions reported in patients with an onset during the posaconazole intravenous dosing phase of the study.<br/> <span class="Sup">†</span>Adverse reactions reported with an onset at any time during the study in patients who were treated for up to 28 days of posaconazole therapy.<br/> </td> </tr> </tbody> </table></div>

The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil oral suspension.

Clinical Trial Experience in Pediatrics

Clinical Trial Experience in Pediatric Patients (2 to less than 18 Years of Age)

The safety of posaconazole injection and Noxafil PowderMix for delayed-release oral suspension for prophylaxis of invasive fungal infections has been assessed in an open label uncontrolled dose-ranging PK and safety study (posaconazole injection/ Noxafil PowderMix for delayed-release oral suspension Pediatric Study 1, NCT02452034); hereinafter referred to as Noxafil Pediatric Study) in 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia. Posaconazole injection and Noxafil PowderMix for delayed-release oral suspension was administered at daily doses of up to 6 mg/kg (twice daily on day 1) in three dose cohorts. All 115 subjects initially received posaconazole injection for at least 7 days, and 63 subjects were transitioned to Noxafil PowderMix for delayed-release oral suspension. The mean overall treatment duration for all treated subjects was 20.6 days with 14.3 days (range: 1 to 28 days) on posaconazole injection and 11.6 days (range: 2 to 18 days) on Noxafil PowderMix for delayed-release oral suspension [see Clinical Pharmacology (12.3)].

Table 15 presents adverse reactions observed in greater than or equal to 10% of pediatric patients treated with posaconazole in the posaconazole Pediatric Study.

Reported adverse reaction profile of posaconazole in pediatric patients was consistent with the safety profile of posaconazole in adults. The most common adverse reactions (occurring in greater than 20% of pediatric patients receiving 6 mg/kg posaconazole injection and Noxafil PowderMix for delayed-release oral suspension daily dose) were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 15: Adverse Reactions in at Least 10% of Pediatric Patients Treated with Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension</span> </caption> <colgroup> <col width="34.96%"/> <col width="31.7%"/> <col width="33.34%"/> </colgroup> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule Toprule"><span class="Bold">Adverse Reaction</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"><span class="Bold">Posaconazole Injection and</span> <br/> <span class="Bold">Noxafil PowderMix for</span> <br/> <span class="Bold">Delayed-Release Oral</span> <br/> <span class="Bold">Suspension</span> <br/> <span class="Bold">6 mg/kg Dose Cohort</span> <br/> <span class="Bold">n=49 (%)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"><span class="Bold">Posaconazole Injection </span><span class="Bold">and</span> <br/> <span class="Bold">Noxafil PowderMix for</span> <br/> <span class="Bold">Delayed-Release Oral</span> <br/> <span class="Bold">Suspension</span> <br/> <span class="Bold">All Dose Cohorts</span> <br/> <span class="Bold">n=115 (%)</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle">Pyrexia <br/> </td><td align="center" class="Rrule" valign="middle">16 (33)<br/> </td><td align="center" class="Rrule" valign="middle">50 (43)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Febrile neutropenia <br/> </td><td align="center" class="Rrule" valign="middle">15 (31)<br/> </td><td align="center" class="Rrule" valign="middle">25 (22)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Vomiting <br/> </td><td align="center" class="Rrule" valign="middle">12 (24)<br/> </td><td align="center" class="Rrule" valign="middle">30 (26)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Mucosal inflammation <br/> </td><td align="center" class="Rrule" valign="middle">11 (22)<br/> </td><td align="center" class="Rrule" valign="middle">32 (28)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Pruritus <br/> </td><td align="center" class="Rrule" valign="middle">11 (22)<br/> </td><td align="center" class="Rrule" valign="middle">18 (16)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Hypertension <br/> </td><td align="center" class="Rrule" valign="middle">10 (20)<br/> </td><td align="center" class="Rrule" valign="middle">20 (17)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Hypokalemia <br/> </td><td align="center" class="Rrule" valign="middle">10 (20)<br/> </td><td align="center" class="Rrule" valign="middle">16 (14)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Stomatitis <br/> </td><td align="center" class="Rrule" valign="middle">10 (20)<br/> </td><td align="center" class="Rrule" valign="middle">13 (11)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Diarrhea <br/> </td><td align="center" class="Rrule" valign="middle">9 (18)<br/> </td><td align="center" class="Rrule" valign="middle">25 (22)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Nausea <br/> </td><td align="center" class="Rrule" valign="middle">9 (18)<br/> </td><td align="center" class="Rrule" valign="middle">18 (16)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Abdominal pain <br/> </td><td align="center" class="Rrule" valign="middle">8 (16)<br/> </td><td align="center" class="Rrule" valign="middle">20 (17)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Decreased appetite <br/> </td><td align="center" class="Rrule" valign="middle">7 (14)<br/> </td><td align="center" class="Rrule" valign="middle">17 (15)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Rash <br/> </td><td align="center" class="Rrule" valign="middle">7 (14)<br/> </td><td align="center" class="Rrule" valign="middle">18 (16)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Alanine aminotransferase increased<br/> </td><td align="center" class="Rrule" valign="middle">6 (12)<br/> </td><td align="center" class="Rrule" valign="middle">8 (7)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Headache  <br/> </td><td align="center" class="Rrule" valign="middle">6 (12)<br/> </td><td align="center" class="Rrule" valign="middle">16 (14)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Aspartate aminotransferase increased<br/> </td><td align="center" class="Rrule" valign="middle">5 (10)<br/> </td><td align="center" class="Rrule" valign="middle">8 (7)<br/> </td> </tr> </tbody> </table></div>

The number of patients receiving posaconazole in the posaconazole Pediatric Study who had changes in liver tests from Grade 0, 1, or 2 at baseline to Grade 3 or 4 is presented in Table 16.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 16: Posaconazole Pediatric Study: Changes in Liver Tests from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4</span> </caption> <colgroup> <col width="50.44%"/> <col width="49.56%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Number (%) of Patients with Change*</span> <br/> <span class="Bold">Pediatric Study 1</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Laboratory Parameter<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Posaconazole</span><span class="Bold"> Injection and Noxafil PowderMix for Delayed-Release Oral Suspension (6 mg/kg daily)</span> <br/> <span class="Bold">n=49 (%)</span><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">          AST<br/> </td><td align="center" class="Rrule" valign="middle">2/49 (4)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">          ALT<br/> </td><td align="center" class="Rrule" valign="middle">3/49 (6)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">          Bilirubin<br/> </td><td align="center" class="Rrule" valign="middle">0/48 (0)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">          Alkaline Phosphatase<br/> </td><td align="center" class="Rrule" valign="middle">0/48 (0)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="2" valign="top">*Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation. <br/>CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase<br/> </td> </tr> </tbody> </table></div>

The following adverse reaction has been identified during the post-approval use of posaconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Endocrine Disorders: Pseudoaldosteronism

Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3)].

Tacrolimus: Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications (4.3) and Warnings and Precautions (5.2)].

Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 [see Contraindications (4.4) and Clinical Pharmacology (12.3)].

Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids [see Contraindications (4.5)].

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].

Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3)].  It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.

Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see Clinical Pharmacology (12.3)]. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.

Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see Clinical Pharmacology (12.3)].

Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.

Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.

Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions [see Warnings and Precautions (5.8)]. Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.

Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.

Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.

Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities [see Contraindications (4.6), Warnings and Precautions (5.11)]. Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

Risk Summary

Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses 5 times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of ≥ 3 times the clinical exposure caused an increase in resorptions in these rabbits (see Data). Based on animal 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. 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

Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.

Risk Summary

There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition.

The safety and effectiveness of posaconazole injection for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 2 and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy.

The safety and effectiveness of posaconazole injection for the treatment of invasive aspergillosis have been established in pediatric patients aged 13 years and older.

Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 2 years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].

The safety and effectiveness of posaconazole have not been established in pediatric patients younger than 2 years of age.

No overall differences in the safety of posaconazole injection were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of posaconazole in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].

Of the 279 patients treated with posaconazole injection in the Posaconazole Injection Study, 52 (19%) were greater than 65 years of age. Of the 288 patients randomized to posaconazole injection in the Aspergillosis Treatment Study, 85 (29%) were ≥65 years of age. 

No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

Posaconazole injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the posaconazole injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy [see Dosage and Administration (2.9) and Warnings and Precautions (5.6)].

After a single oral dose of Noxafil oral suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.

It is recommended that no dose adjustment of Noxafil oral suspension, Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, and posaconazole injection is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2) and Warnings and Precautions (5.5)]. However, a specific study has not been conducted with Noxafil delayed-release tablets, Noxafil PowderMix for delayed-release oral suspension, and posaconazole injection.

The pharmacokinetics of posaconazole are comparable in males and females. No adjustment in the dosage of posaconazole is necessary based on gender.

The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of posaconazole is necessary based on race.

Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections.

There is no experience with overdosage of posaconazole injection. During the clinical trials, some patients received Noxafil oral suspension up to 1,600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1,200 mg twice daily Noxafil oral suspension for 3 days. No related adverse reactions were noted by the investigator.

{ "type": "p", "children": [], "text": "There is no experience with overdosage of posaconazole injection.\nDuring the clinical trials, some patients received Noxafil oral suspension up to 1,600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1,200 mg twice daily Noxafil oral suspension for 3 days. No related adverse reactions were noted by the investigator." }

Posaconazole is not removed by hemodialysis.

{ "type": "p", "children": [], "text": "Posaconazole is not removed by hemodialysis." }

Posaconazole injection is an azole antifungal agent available as concentrated solution to be diluted before intravenous administration. 

{ "type": "p", "children": [], "text": "Posaconazole injection is an azole antifungal agent available as concentrated solution to be diluted before intravenous administration. " }

Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5­-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-­hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an molecular formula of C37H42F2N8O4 and a molecular weight of 700.78. The chemical structure is:  

{ "type": "p", "children": [], "text": "Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5­-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-­hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an molecular formula of C37H42F2N8O4 and a molecular weight of 700.78. The chemical structure is:  " }

Posaconazole is a white to off-white crystalline powder with a low aqueous solubility. Posaconazole Injection

{ "type": "p", "children": [], "text": " Posaconazole is a white to off-white crystalline powder with a low aqueous solubility.\n\nPosaconazole Injection\n\n" }

Posaconazole injection is available as a clear colorless to yellow, sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.0033 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6 and water for injection.

{ "type": "p", "children": [], "text": "Posaconazole injection is available as a clear colorless to yellow, sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.0033 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6 and water for injection." }

Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].

Exposure Response Relationship Treatment of Invasive Aspergillosis:

Across a range of posaconazole plasma minimum concentrations (Cmin, range: 244 to 5,663 ng/mL) following administration of posaconazole injection and Noxafil delayed-release tablets in patients treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole Cmin and treatment efficacy [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. Similarly, across a range of population pharmacokinetic model-predicted steady-state plasma average concentrations (Cavg, range: 589 to 6,315 ng/mL), there was no association between posaconazole Cavg and treatment efficacy.

General Pharmacokinetic Characteristics Posaconazole Injection Posaconazole injection exhibits dose proportional pharmacokinetics after single-doses between 200 and 300 mg in healthy volunteers and patients. The mean pharmacokinetic parameters after single-doses with posaconazole injection in healthy volunteers and patients are shown in Table 18.  

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 18: Summary of Mean Pharmacokinetic Parameters (%CV) in Healthy Volunteers (30-minute infusion via peripheral venous line) and Patients (90 minute infusion via central venous line) after Dosing with Posaconazole Injection on Day 1 </span> </caption> <colgroup> <col width="11.56%"/> <col width="13.7%"/> <col width="5.5%"/> <col width="13.58%"/> <col width="14.88%"/> <col width="14.18%"/> <col width="12.12%"/> <col width="14.48%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Dose (mg)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">n</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">AUC<span class="Sub">0-∞</span></span> <br/> <span class="Bold">(ng·hr/mL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">AUC<span class="Sub">0-12</span></span> <br/> <span class="Bold">(ng·hr/mL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">C<span class="Sub">max</span> (ng/mL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">t<span class="Sub">1/2</span> (hr)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">CL</span> <br/> <span class="Bold">(L/hr)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="2" valign="middle">Healthy Volunteers<br/> </td><td align="center" class="Rrule" valign="middle">200<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">35,400 (50)<br/> </td><td align="center" class="Rrule" valign="middle">8,840 (20)<br/> </td><td align="center" class="Rrule" valign="middle">2,250 (29)<br/> </td><td align="center" class="Rrule" valign="middle">23.6 (23)<br/> </td><td align="center" class="Rrule" valign="middle">6.5 (32)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">300<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">46,400 (26)<br/> </td><td align="center" class="Rrule" valign="middle">13,000 (13)<br/> </td><td align="center" class="Rrule" valign="middle">2,840 (30)<br/> </td><td align="center" class="Rrule" valign="middle">24.6 (20)<br/> </td><td align="center" class="Rrule" valign="middle">6.9 (27)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="2" valign="middle">Patients<br/> </td><td align="center" class="Rrule" valign="middle">200<br/> </td><td align="center" class="Rrule" valign="middle">30<br/> </td><td align="center" class="Rrule" valign="middle">N/D<br/> </td><td align="center" class="Rrule" valign="middle">5,570 (32)<br/> </td><td align="center" class="Rrule" valign="middle">954 (44)<br/> </td><td align="center" class="Rrule" valign="middle">N/D<br/> </td><td align="center" class="Rrule" valign="middle">N/D<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">300<br/> </td><td align="center" class="Rrule" valign="middle">22<br/> </td><td align="center" class="Rrule" valign="middle">N/D<br/> </td><td align="center" class="Rrule" valign="middle">8,240 (26)<br/> </td><td align="center" class="Rrule" valign="middle">1,590 (62)<br/> </td><td align="center" class="Rrule" valign="middle">N/D<br/> </td><td align="center" class="Rrule" valign="middle">N/D<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="8" valign="top">AUC<span class="Sub">0-∞</span> = Area under the plasma concentration-time curve from time zero to infinity; AUC<span class="Sub">0-12</span> = Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; C<span class="Sub">max</span> = maximum observed concentration; t<span class="Sub">1/2</span> = terminal phase half-life; CL = total body clearance; N/D = Not Determined<br/> </td> </tr> </tbody> </table></div>

Table 19 displays the pharmacokinetic parameters of posaconazole in patients following administration of posaconazole injection 300 mg taken once a day for 10 or 14 days following twice daily dosing on Day 1.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 19: Arithmetic Mean (%CV) of PK Parameters in Serial PK-Evaluable Patients Following Dosing of Posaconazole Injection (300 mg)* </span> </caption> <colgroup> <col width="8.84%"/> <col width="5.88%"/> <col width="16.66%"/> <col width="21.42%"/> <col width="17.84%"/> <col width="14.1%"/> <col width="15.26%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Day</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">N</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">C<span class="Sub">max</span></span> <br/> <span class="Bold">(ng/mL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">T<span class="Sub">max</span></span><span class="Bold"><span class="Sup">†</span></span> <br/> <span class="Bold">(hr)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">AUC<span class="Sub">0-24</span></span> <br/> <span class="Bold">(ng*hr/mL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Cav </span> <br/> <span class="Bold">(ng/mL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">C<span class="Sub">min</span></span> <br/> <span class="Bold">(ng/mL)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">10/14<br/> </td><td align="center" class="Rrule" valign="middle">49<br/> </td><td align="center" class="Rrule" valign="middle">3,280 (74)<br/> </td><td align="center" class="Rrule" valign="middle">1.5 (0.98 to 4)<br/> </td><td align="center" class="Rrule" valign="middle">36,100 (35)<br/> </td><td align="center" class="Rrule" valign="middle">1,500 (35)<br/> </td><td align="center" class="Rrule" valign="middle">1,090 (44)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top">AUC<span class="Sub">0-24</span> = area under the concentration-time curve over the dosing interval (i.e. 24 hours); Cav= time-averaged concentrations (i.e., AUC<span class="Sub">0-24h</span>/24hr);<br/>C<span class="Sub">min</span> = POS trough level immediately before a subject received the dose of POS on the day specified in the protocol; C<span class="Sub">max</span> = observed maximum plasma concentration; CV = coefficient of variation, expressed as a percent (%); Day = study day on treatment; T<span class="Sub">max</span> = time of observed maximum plasma concentration.<br/> <span class="Sup">*</span>  300 mg dose administered over 90 minutes once a day following twice daily dosing on Day 1<br/> <span class="Sup">†</span>  Median (minimum-maximum)<br/> </td> </tr> </tbody> </table></div>

Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226 to 295 L between studies and dose levels.

Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin. Metabolism: 

Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.

Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers </span> </caption> <colgroup> <col width="21.06%"/> <col width="19.92%"/> <col width="19.52%"/> <col width="19.74%"/> <col width="19.76%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="2" valign="middle"><span class="Bold">Coadministered Drug (Postulated Mechanism of Interaction)</span> <br/> </td><td align="center" class="Rrule" rowspan="2" valign="middle"><span class="Bold">Coadministered Drug Dose/Schedule</span> <br/> </td><td align="center" class="Rrule" rowspan="2" valign="middle"><span class="Bold">Posaconazole Dose/Schedule</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Effect on Bioavailability of Posaconazole</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Change in Mean C<span class="Sub">max</span></span>(ratio estimate<span class="Sup">*</span>; 90% CI of the ratio estimate)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Change in Mean AUC </span>(ratio estimate<span class="Sup">*</span>; 90% CI of the ratio estimate)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Efavirenz (UDP-G Induction) <br/> </td><td align="center" class="Rrule" valign="middle">400 mg once daily × 10 and 20 days<br/> </td><td align="center" class="Rrule" valign="middle">400 mg (oral suspension) twice daily × 10 and 20 days<br/> </td><td align="center" class="Rrule" valign="middle">↓ 45% <br/>(0.55; 0.47-0.66)<br/> </td><td align="center" class="Rrule" valign="middle">  ↓ 50%<br/> (0.50; 0.43-0.60)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Fosamprenavir (unknown mechanism) <br/> </td><td align="center" class="Rrule" valign="middle">700 mg twice daily x 10 days<br/> </td><td align="center" class="Rrule" valign="middle">200 mg once daily on the 1<span class="Sup">st</span> day, 200 mg twice daily on the 2<span class="Sup">nd</span> day, then 400 mg twice daily x 8 Days<br/> </td><td align="center" class="Rrule" valign="middle">↓ 21% <br/>0.79 (0.71-0.89)<br/> </td><td align="center" class="Rrule" valign="middle">↓ 23% <br/>0.77 <br/>(0.68-0.87)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Rifabutin (UDP-G Induction) <br/> </td><td align="center" class="Rrule" valign="middle">300 mg once daily x 17 days<br/> </td><td align="center" class="Rrule" valign="middle">200 mg (tablets) once daily × 10 days<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="middle">↓ 43% <br/>(0.57; 0.43-0.75)<br/> </td><td align="center" class="Rrule" valign="middle">↓ 49% <br/>(0.51; 0.37-0.71)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Phenytoin (UDP-G Induction) <br/> </td><td align="center" class="Rrule" valign="middle">200 mg once daily x 10 days<br/> </td><td align="center" class="Rrule" valign="middle">200 mg (tablets) once daily × 10 days<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="middle">  ↓ 41% <br/>(0.59; 0.44-0.79)<br/> </td><td align="center" class="Rrule" valign="middle">↓ 50% <br/>(0.50; 0.36-0.71)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="5" valign="top"><span class="Sup">*</span> Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for C<span class="Sub">max</span> or AUC. <br/> <span class="Sup">† </span>The tablet refers to a non-commercial tablet formulation without polymer. <br/> </td> </tr> </tbody> </table></div>

In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 28 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and Patients </span> </caption> <colgroup> <col width="16.54%"/> <col width="20.78%"/> <col width="24.18%"/> <col width="19.52%"/> <col width="18.98%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="2" valign="middle"><span class="Bold">Coadministered Drug </span>(Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)<br/> </td><td align="center" class="Rrule" rowspan="2" valign="middle"><span class="Bold">Coadministered Drug Dose/Schedule</span> <br/> </td><td align="center" class="Rrule" rowspan="2" valign="middle"><span class="Bold">Posaconazole Dose/Schedule</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Effect on Bioavailability of Coadministered Drugs</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Change in Mean C<span class="Sub">max </span></span>(ratio estimate<span class="Sup">*</span>; 90% CI of the ratio estimate)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Change in Mean AUC </span>(ratio estimate<span class="Sup">*</span>; 90% CI of the ratio estimate)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Sirolimus<br/> </td><td align="center" class="Rrule" valign="top">2-mg single oral dose<br/> </td><td align="center" class="Rrule" valign="top">400 mg (oral suspension) twice daily x 16 days<br/> </td><td align="center" class="Rrule" valign="top">↑  572%<br/>(6.72; 5.62-8.03)<br/> </td><td align="center" class="Rrule" valign="top">↑  788%<br/>(8.88; 7.26-10.9)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Cyclosporine<br/> <br/> </td><td align="center" class="Rrule" valign="top">Stable maintenance dose in heart transplant recipients<br/> </td><td align="center" class="Rrule" valign="top">200 mg (tablets) once daily x 10 days<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top">↑ cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Tacrolimus<br/> </td><td align="center" class="Rrule" valign="top">0.05-mg/kg single oral dose<br/> </td><td align="center" class="Rrule" valign="top">400 mg (oral suspension) twice daily × 7 days<br/> </td><td align="center" class="Rrule" valign="top">↑ 121%<br/>(2.21; 2.01-2.42)<br/> </td><td align="center" class="Rrule" valign="top">↑ 358%<br/>(4.58; 4.03-5.19)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" rowspan="4" valign="top">Simvastatin<br/> </td><td align="center" class="Rrule" rowspan="4" valign="top">40-mg single oral dose<br/> </td><td align="center" class="Rrule" rowspan="2" valign="top">100 mg (oral suspension)<br/>once daily x 13 days<br/> </td><td align="center" class="Rrule" valign="top">Simvastatin<br/>↑  841%<br/>(9.41, 7.13-12.44)<br/> </td><td align="center" class="Rrule" valign="top">Simvastatin<br/>↑  931%<br/>(10.31, 8.40-12.67)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Simvastatin Acid      ↑ 817%<br/>(9.17, 7.36-11.43)<br/> <br/> </td><td align="center" class="Rrule" valign="top">Simvastatin Acid      ↑ 634%<br/>(7.34, 5.82-9.25)<br/> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" rowspan="2" valign="top">200 mg (oral suspension)<br/>once daily x 13 days<br/> </td><td align="center" class="Rrule" valign="top">Simvastatin<br/>↑  1041%<br/>(11.41, 7.99-16.29) <br/> </td><td align="center" class="Rrule" valign="top">Simvastatin<br/>↑  960%<br/>(10.60, 8.63-13.02) <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Simvastatin Acid       ↑ 851%<br/>(9.51, 8.15-11.10) <br/> </td><td align="center" class="Rrule" valign="top">Simvastatin Acid       ↑ 748%<br/>(8.48, 7.04-10.23) <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" rowspan="3" valign="top">Midazolam<br/> </td><td align="center" class="Rrule" valign="top">0.4-mg single <br/>intravenous dose<span class="Sup">‡</span> <br/> </td><td align="center" class="Rrule" valign="top">200 mg (oral suspension)<br/>twice daily x 7 days <br/> </td><td align="center" class="Rrule" valign="top">↑ 30% <br/>(1.3; 1.13-1.48) <br/> </td><td align="center" class="Rrule" valign="top">↑ 362% <br/>(4.62; 4.02-5.3) <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">0.4-mg single <br/>intravenous dose<span class="Sup">‡</span> <br/> </td><td align="center" class="Rrule" valign="top">400 mg (oral suspension)<br/>twice daily x 7 days <br/> </td><td align="center" class="Rrule" valign="top">↑ 62% <br/>(1.62; 1.41-1.86) <br/> </td><td align="center" class="Rrule" valign="top">↑ 524% <br/>(6.24; 5.43-7.16) <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">2-mg single oral dose<span class="Sup">‡</span> <br/> </td><td align="center" class="Rrule" valign="top">200 mg (oral suspension)<br/>once daily x 7 days <br/> </td><td align="center" class="Rrule" valign="top">↑ 169% <br/>(2.69; 2.46-2.93) <br/> </td><td align="center" class="Rrule" valign="top">↑ 470% <br/>(5.70; 4.82-6.74) <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top">2-mg single oral dose<span class="Sup">‡</span> <br/> </td><td align="center" class="Rrule" valign="top">400 mg (oral suspension)<br/>twice daily x 7 days <br/> </td><td align="center" class="Rrule" valign="top">↑ 138% <br/>(2.38; 2.13-2.66) <br/> </td><td align="center" class="Rrule" valign="top">↑ 397% <br/>(4.97; 4.46-5.54) <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Rifabutin<br/> </td><td align="center" class="Rrule" valign="top">300 mg once daily x 17 days <br/> </td><td align="center" class="Rrule" valign="top">200 mg (tablets) once daily × 10 days<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="top">↑ 31%<br/>(1.31; 1.10-1.57)<br/> </td><td align="center" class="Rrule" valign="top">↑ 72%<br/>(1.72;1.51-1.95)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Phenytoin<br/> </td><td align="center" class="Rrule" valign="top">200 mg once daily PO x 10 days<br/> </td><td align="center" class="Rrule" valign="top">200 mg (tablets) once daily x 10 days<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="top">↑  16%<br/>(1.16; 0.85-1.57)<br/> </td><td align="center" class="Rrule" valign="top">↑  16%<br/>(1.16; 0.84-1.59)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Ritonavir<br/> </td><td align="center" class="Rrule" valign="top">100 mg once daily x 14 days<br/> </td><td align="center" class="Rrule" valign="top">400 mg (oral suspension) twice daily x 7 days<br/> </td><td align="center" class="Rrule" valign="top">↑ 49%<br/>(1.49; 1.04-2.15)<br/> </td><td align="center" class="Rrule" valign="top">↑ 80%<br/>(1.8;1.39-2.31)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Atazanavir<br/> </td><td align="center" class="Rrule" valign="top">300 mg once daily x 14 days<br/> </td><td align="center" class="Rrule" valign="top">400 mg (oral suspension)<br/>twice daily x 7 days<br/> </td><td align="center" class="Rrule" valign="top">↑ 155%<br/>(2.55; 1.89-3.45)<br/> </td><td align="center" class="Rrule" valign="top">↑ 268%<br/>(3.68; 2.89-4.70)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Atazanavir/<br/>ritonavir boosted<br/>regimen<br/> </td><td align="center" class="Rrule" valign="top">300 mg/100 mg once daily x<br/>14 days<br/> </td><td align="center" class="Rrule" valign="top">400 mg (oral suspension)<br/>twice daily x 7 days <br/> </td><td align="center" class="Rrule" valign="top">↑  53% <br/>(1.53; 1.13-2.07)<br/> </td><td align="center" class="Rrule" valign="top">↑ 146%<br/>(2.46; 1.93-3.13)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="5" valign="middle"><span class="Sup">*</span> Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C<span class="Sub">max</span> or AUC. <br/> <span class="Sup">†</span> The tablet refers to a non-commercial tablet formulation without polymer. <br/> <span class="Sup">‡</span> The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole. <br/> </td> </tr> </tbody> </table></div>

Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg once daily.

  Excretion:

Following administration of Noxafil oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug). 

Posaconazole injection is eliminated with a mean terminal half-life (t½) of 27 hours and a total body clearance (CL) of 7.3 L/h.

Noxafil delayed-release tablet is eliminated with a mean half-life (t½) ranging between 26 to 31 hours.

Noxafil oral suspension is eliminated with a mean half-life (t½) of 35 hours (range: 20­ to 66 hours). Specific Populations   

No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment).

Race/Ethnicity:

In a population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure.

Patients Weighing More Than 120 kg:

Weight has a clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)].

Pediatric Patients

The mean pharmacokinetic parameters after multiple-dose administration of posaconazole injection and Noxafil PowderMix for delayed-release oral suspension in neutropenic pediatric patients 2 to less than 18 years of age are shown in Table 29. Patients were enrolled into 2 age groups and received posaconazole injection and Noxafil PowderMix for delayed-release oral suspension doses at 6 mg/kg (0.6 to 1 times the recommended dose) with a maximum 300 mg dose once daily (twice daily on Day 1) [see Adverse Reactions (6.1)].

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 29: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters (% Geometric CV) After Multiple Dosing with Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension 6 mg/kg* in Pediatric Patients with Neutropenia or Expected Neutropenia</span> </caption> <colgroup> <col width="11.74%"/> <col width="11.18%"/> <col width="9.82%"/> <col width="13.12%"/> <col width="11.82%"/> <col width="11.82%"/> <col width="8.32%"/> <col width="12.82%"/> <col width="9.38%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold">Age Group</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Dose Type</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">N</span><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">AUC<span class="Sub">0-24hr</span></span> <br/> <span class="Bold">(ng·hr/mL)</span><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Cav</span><span class="Sup">†</span> <br/> <span class="Bold">(ng/mL)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">C<span class="Sub">max</span></span> <br/> <span class="Bold">(ng/mL)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">C<span class="Sub">min</span></span> <br/> <span class="Bold">(ng/mL)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">T<span class="Sub">max</span><span class="Sup">‡</span> <br/> (hr)</span><span class="Bold"> </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">CL/F</span><span class="Sup">§</span> <br/> <span class="Bold">(L/hr)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="2" valign="top">2 to &lt;7<br/>years<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">IV<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">17<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">31,100<br/>(48.9)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1,300<br/>(48.9)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">3,060<br/>(54.1)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">626<br/>(104.8)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1.75<br/>(1.57-1.83)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">3.27<br/>(49.3)<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">PFS<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">7<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">23,000<br/>(47.3)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">960 (47.3)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1,510<br/>(43.4)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">542<br/>(68.8)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">4.00<br/>(2.17-7.92)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">4.60<br/>(35.2)<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="2" valign="top">7 to 17<br/>years<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">IV<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">24<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">44,200<br/>(41.5)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1,840<br/>(41.5)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">3,340<br/>(39.4)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1,160<br/>(60.4)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1.77<br/>(1.33-6.00)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">4.76<br/>(55.7)<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">PFS<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">12<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">25,000<br/>(184.3)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1,040<br/>(184.3)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">1,370<br/>(178.5)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">713<br/>(300.6)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">2.78<br/>(0.00-4.00)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">8.39<br/>(190.3)<span class="Bold"></span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="9" valign="top">IV= posaconazole injection; PFS= Noxafil PowderMix for delayed-release oral suspension; AUC<span class="Sub">0-24 </span>= Area under the plasma concentration-time curve from time zero to 24 hr; C<span class="Sub">max </span>= maximum observed concentration; C<span class="Sub">min</span> = minimum observed plasma concentration; T<span class="Sub">max</span> = time of maximum observed concentration; CL /F = apparent total body clearance<br/> <span class="Sup">*</span> 0.6 to 1 times the recommended dose<br/> <span class="Sup">† </span>Cav = time-averaged concentrations (i.e., AUC<span class="Sub">0-24hr </span>/24hr)<br/> <span class="Sup">‡ </span>Median (minimum-maximum)<br/> <span class="Sup">§</span> Clearance (CL for IV and CL/F for PFS)<span class="Bold"></span> <br/> </td> </tr> </tbody> </table></div>

Based on a population pharmacokinetic model evaluating posaconazole pharmacokinetics and predicting exposures in pediatric patients, the exposure of steady-state posaconazole average concentration greater than or equal to 700 ng/mL in approximately 90% of patients is attained with the recommended dose of posaconazole injection and Noxafil PowderMix for delayed-release oral suspension.

The population pharmacokinetic analysis of posaconazole in pediatric patients suggests that age, sex, renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics of posaconazole.

Mechanism of Action:

Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole. Resistance:

Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.

  Antimicrobial Activity:

Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Microorganisms:

Aspergillus spp. and Candida spp. Susceptibility Testing: 

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Carcinogenesis No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9-  or 3.5-times the exposure achieved with a 400-mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400-mg twice daily oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with a 400-mg twice daily oral suspension regimen.

Mutagenesis Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study.

Impairment of Fertility Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 x the 400-mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 x the 400-mg twice daily oral suspension regimen).

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5­-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in a separate study of 10-week-old dogs dosed with intravenous posaconazole for 13 weeks with a 9-week recovery period or a follow-up study of 31-week-old dogs dosed for 3 months.

Aspergillosis Treatment Study (NCT01782131) was a randomized, double-blind, controlled trial which evaluated the safety and efficacy of posaconazole injection and Noxafil delayed-release tablets versus voriconazole for primary treatment of invasive fungal disease caused by Aspergillus species. Eligible patients had proven, probable, or possible invasive fungal infections per the European Organization for Research and Treatment of Cancer/Mycoses Study Group, EORTC/MSG criteria. Patients were stratified by risk for mortality or poor outcome where high risk included a history of allogeneic bone marrow transplant, liver transplant, or relapsed leukemia undergoing salvage chemotherapy. The median age of patients was 57 years (range 14 to 91 years), with 27.8% of patients aged ≥65 years; 5 patients were pediatric patients 14 to16 years of age, of whom 3 were treated with posaconazole and 2 with voriconazole. The majority of patients were male (59.8%) and white (67.1%). With regard to risk factors for invasive aspergillosis, approximately two-thirds of the patients in the study had a recent history of neutropenia, while approximately 20% with a history of an allogeneic stem cell transplant. Over 80% of subjects in each treatment group had infection limited to the lower respiratory tract (primarily lung), while approximately 11% to 13% also had infection in another organ. Invasive aspergillosis was proven or probable in 58.1% of patients as classified by independent adjudicators blinded to study treatment assignment. At least one Aspergillus species was identified in 21% of the patients; A. fumigatus and A. flavus were the most common pathogens identified.

Patients randomized to receive posaconazole were given a dose of 300 mg once daily (twice daily on Day 1) IV or tablet. Patients randomized to receive voriconazole were given a dose of 6 mg/kg twice daily Day 1 followed by 4 mg/kg twice daily IV, or oral 300 mg twice daily Day 1 followed by 200 mg twice daily. The recommended initial route of administration was IV; however, patients could begin oral therapy if clinically stable and able to tolerate oral dosing. The transition from IV to oral therapy occurred when the patient was clinically stable. The protocol recommended duration of therapy was 84 days with a maximum allowed duration of 98 days. Median treatment duration was 67 days for posaconazole patients and 64 days for voriconazole patients. Overall, 55% to 60% of patients began treatment with the IV formulation with a median duration of 9 days for the initial IV dosing.

The Intent to Treat (ITT) population included all patients randomized and receiving at least one dose of study treatment. All-cause mortality through Day 42 in the overall population (ITT) was 15.3% for posaconazole patients compared to 20.6% for voriconazole patients for an adjusted treatment difference of -5.3% with a 95% confidence interval of -11.6 to 1.0%. Consistent results were seen in patients with proven or probable invasive aspergillosis per EORTC criteria (see Table 30).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 30: Posaconazole Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: All-Cause Mortality Through Day 42</span> </caption> <colgroup> <col width="25%"/> <col width="12.5%"/> <col width="12.5%"/> <col width="12.5%"/> <col width="12.5%"/> <col width="25%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Posaconazole Injection and Delayed-ReleaseTablets</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Voriconazole</span> <br/> </td><td class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Population<br/> </td><td align="center" class="Rrule" valign="middle">N<br/> </td><td align="center" class="Rrule" valign="middle">n (%)<br/> </td><td align="center" class="Rrule" valign="middle">N<br/> </td><td align="center" class="Rrule" valign="middle">n (%)<br/> </td><td align="center" class="Rrule" valign="middle">Difference* (95% CI)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Intent to Treat<br/> </td><td align="center" class="Rrule" valign="middle">288<br/> </td><td align="center" class="Rrule" valign="middle">44 (15.3)<br/> </td><td align="center" class="Rrule" valign="middle">287<br/> </td><td align="center" class="Rrule" valign="middle">59 (20.6)<br/> </td><td align="center" class="Rrule" valign="middle">-5.3 (-11.6, 1.0)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Proven/ProbableInvasive Aspergillosis<br/> </td><td align="center" class="Rrule" valign="middle">163<br/> </td><td align="center" class="Rrule" valign="middle">31 (19.0)<br/> </td><td align="center" class="Rrule" valign="middle">171<br/> </td><td align="center" class="Rrule" valign="middle">32 (18.7)<br/> </td><td align="center" class="Rrule" valign="middle">0.3 (-8.2, 8.8)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="6" valign="middle">* Adjusted treatment difference based on Miettinen and Nurminen’s method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme.<br/> </td> </tr> </tbody> </table></div>

Global clinical response at Week 6 was assessed by a blinded, independent adjudication committee based upon prespecified clinical, radiologic, and mycologic criteria. In the subgroup of patients with proven or probable invasive aspergillosis per EORTC criteria, the global clinical response of success (complete or partial response) at Week 6 was seen in 44.8% for posaconazole-treated patients compared to 45.6% for voriconazole-treated patients (see Table 31).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 31: Posaconazole Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: Successful Global Clinical Response* at Week 6 </span> </caption> <colgroup> <col width="21.78%"/> <col width="7.28%"/> <col width="20%"/> <col width="8.2%"/> <col width="20%"/> <col width="22.72%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Posaconazole</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Voriconazole</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Population<br/> </td><td align="center" class="Rrule" valign="middle">N<br/> </td><td align="center" class="Rrule" valign="middle">Success<br/> </td><td align="center" class="Rrule" valign="middle">N<br/> </td><td align="center" class="Rrule" valign="middle">Success<br/> </td><td align="center" class="Rrule" valign="middle">Difference<span class="Sup">†</span>(95% CI)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Proven/ProbableInvasive Aspergillosis<br/> </td><td align="center" class="Rrule" valign="middle">163<br/> </td><td align="center" class="Rrule" valign="middle">73 (44.8)<br/> </td><td align="center" class="Rrule" valign="middle">171<br/> </td><td align="center" class="Rrule" valign="middle">78 (45.6)<br/> </td><td align="center" class="Rrule" valign="middle">-0.6 (-11.2, 10.1)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="6" valign="middle"><span class="Sup">*</span> Successful Global Clinical Response was defined as survival with a partial or complete response.<br/> <span class="Sup">†</span>Adjusted treatment difference based on Miettinen and Nurminen’s method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme.<br/> </td> </tr> </tbody> </table></div>

Two randomized, controlled studies were conducted using Noxafil as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems. The first study (Noxafil Oral Suspension Study 1) was a randomized, double-blind trial that compared Noxafil oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may have met more than one of these criteria). This assessed all patients while on study therapy plus 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (80 days, Noxafil oral suspension; 77 days, fluconazole). Table 32 contains the results from Noxafil Oral Suspension Study 1.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 32: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Noxafil Oral Suspension Study 1 </span> </caption> <colgroup> <col width="47.96%"/> <col width="26.04%"/> <col width="26%"/> </colgroup> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule Toprule"></th><th align="center" class="Lrule Rrule Toprule"><span class="Bold"> Posaconazole</span> <br/> <span class="Bold">n=301<span class="Italics"></span></span> <br/> </th><th align="center" class="Lrule Rrule Toprule"><span class="Bold">Fluconazole</span> <br/> <span class="Bold">n=299<span class="Italics"></span></span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold"><span class="Italics">On therapy plus 7 days</span></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Clinical Failure*</span> <br/> </td><td align="center" class="Rrule" valign="middle">50 (17%)<br/> </td><td align="center" class="Rrule" valign="middle">55 (18%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold">Failure due to:</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">       Proven/Probable IFI<br/> </td><td align="center" class="Rrule" valign="middle">7 (2%)<br/> </td><td align="center" class="Rrule" valign="middle">22 (7%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">             (<span class="Italics">Aspergillus</span>)<br/> </td><td align="center" class="Rrule" valign="middle">3 (1%)<br/> </td><td align="center" class="Rrule" valign="middle">17 (6%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">             (<span class="Italics">Candida</span>)<br/> </td><td align="center" class="Rrule" valign="middle">1 (&lt;1%)<br/> </td><td align="center" class="Rrule" valign="middle">3 (1%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">             (Other)<br/> </td><td align="center" class="Rrule" valign="middle">3 (1%)<br/> </td><td align="center" class="Rrule" valign="middle">2 (1%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">       All Deaths<br/>             Proven/probable fungal infection prior to death<br/> </td><td align="center" class="Rrule" valign="middle">22 (7%)<br/>2 (&lt;1%)<br/> </td><td align="center" class="Rrule" valign="middle">24 (8%)<br/>6 (2%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">       SAF<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="middle">27 (9%)<br/> </td><td align="center" class="Rrule" valign="middle">25 (8%)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold"><span class="Italics">Through 16 weeks</span></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">Clinical Failure*<span class="Sup">,‡</span></span> <br/> </td><td align="center" class="Rrule" valign="middle">99 (33%)<br/> </td><td align="center" class="Rrule" valign="middle">110 (37%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold">Failure due to:</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">       Proven/Probable IFI<br/> </td><td align="center" class="Rrule" valign="middle">16 (5%)<br/> </td><td align="center" class="Rrule" valign="middle">27 (9%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">             (<span class="Italics">Aspergillus</span>)<br/> </td><td align="center" class="Rrule" valign="middle">7 (2%)<br/> </td><td align="center" class="Rrule" valign="middle">21 (7%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">             (<span class="Italics">Candida</span>)<br/> </td><td align="center" class="Rrule" valign="middle">4 (1%)<br/> </td><td align="center" class="Rrule" valign="middle">4 (1%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">             (Other)<br/> </td><td align="center" class="Rrule" valign="middle">5 (2%)<br/> </td><td align="center" class="Rrule" valign="middle">2 (1%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">       All Deaths<br/>             Proven/probable fungal infection prior to death<br/> </td><td align="center" class="Rrule" valign="middle">58 (19%)<br/>10 (3%)<br/> </td><td align="center" class="Rrule" valign="middle">59 (20%)<br/>16 (5%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">       SAF<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="middle">26 (9%)<br/> </td><td align="center" class="Rrule" valign="middle">30 (10%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">       Event free lost to follow-up<span class="Sup">§</span> <br/> </td><td align="center" class="Rrule" valign="middle">24 (8%)<br/> </td><td align="center" class="Rrule" valign="middle">30 (10%)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Sup">*</span> Patients may have met more than one criterion defining failure.<br/> <span class="Sup">†</span> Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage &gt;4 consecutive days).<br/> <span class="Sup">‡</span> 95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%).<br/> <span class="Sup">§</span> Patients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. These patients were considered failures.<br/> </td> </tr> </tbody> </table></div>

The second study (Noxafil Oral Suspension Study 2) was a randomized, open-label study that compared Noxafil oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Noxafil Oral Suspension Study 1, efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). This study assessed patients while on treatment plus 7 days and 100 days postrandomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 33 contains the results from Noxafil Oral Suspension Study 2.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 33: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Noxafil Oral Suspension Study 2  </span> </caption> <colgroup> <col width="40.54%"/> <col width="28.2%"/> <col width="31.26%"/> </colgroup> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule Toprule"></th><th align="center" class="Lrule Rrule Toprule"><span class="Bold"> Posaconazole</span> <br/> <span class="Bold">n=304 </span> <br/> </th><th align="center" class="Lrule Rrule Toprule"><span class="Bold">Fluconazole/Itraconazole n=298 </span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold"><span class="Italics">On therapy plus 7 days</span></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Clinical Failure<span class="Sup">*,†</span></span> <br/> </td><td align="center" class="Rrule" valign="middle">82 (27%)<br/> </td><td align="center" class="Rrule" valign="middle">126 (42%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold">Failure due to:</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">        Proven/Probable IFI<br/> </td><td align="center" class="Rrule" valign="middle">7 (2%)<br/> </td><td align="center" class="Rrule" valign="middle">25 (8%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">                (<span class="Italics">Aspergillus</span>)<br/> </td><td align="center" class="Rrule" valign="middle">2 (1%)<br/> </td><td align="center" class="Rrule" valign="middle">20 (7%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">                (<span class="Italics">Candida</span>)<br/> </td><td align="center" class="Rrule" valign="middle">3 (1%)<br/> </td><td align="center" class="Rrule" valign="middle">2 (1%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">                (Other)<br/> </td><td align="center" class="Rrule" valign="middle">2 (1%)<br/> </td><td align="center" class="Rrule" valign="middle">3 (1%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">        All Deaths<br/>               Proven/probable fungal infection prior to death<br/> </td><td align="center" class="Rrule" valign="middle">17 (6%)<br/>1 (&lt;1%)<br/> </td><td align="center" class="Rrule" valign="middle">25 (8%)<br/>2 (1%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">        SAF<span class="Sup">‡</span> <br/> </td><td align="center" class="Rrule" valign="middle">67 (22%)<br/> </td><td align="center" class="Rrule" valign="middle">98 (33%)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold"><span class="Italics">Through 100 days postrandomization</span></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Clinical Failure<span class="Sup">†</span></span> <br/> </td><td align="center" class="Rrule" valign="middle">158 (52%)<br/> </td><td align="center" class="Rrule" valign="middle">191 (64%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold">Failure due to:</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">         Proven/Probable IFI<br/> </td><td align="center" class="Rrule" valign="middle">14 (5%)<br/> </td><td align="center" class="Rrule" valign="middle">33 (11%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">                (<span class="Italics">Aspergillus</span>)<br/> </td><td align="center" class="Rrule" valign="middle">2 (1%)<br/> </td><td align="center" class="Rrule" valign="middle">26 (9%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">                (<span class="Italics">Candida</span>)<br/> </td><td align="center" class="Rrule" valign="middle">10 (3%)<br/> </td><td align="center" class="Rrule" valign="middle">4 (1%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">                (Other)<br/> </td><td align="center" class="Rrule" valign="middle">2 (1%)<br/> </td><td align="center" class="Rrule" valign="middle">3 (1%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">         All Deaths<br/>                Proven/probable fungal infection prior to death<br/> </td><td align="center" class="Rrule" valign="middle">44 (14%)<br/>2 (1%)<br/> </td><td align="center" class="Rrule" valign="middle">64 (21%)<br/>16 (5%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">         SAF<span class="Sup">‡</span> <br/> </td><td align="center" class="Rrule" valign="middle">98 (32%)<br/> </td><td align="center" class="Rrule" valign="middle">125 (42%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">         Event free lost to follow-up<span class="Sup">§</span> <br/> </td><td align="center" class="Rrule" valign="middle">34 (11%)<br/> </td><td align="center" class="Rrule" valign="middle">24 (8%)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Sup">*</span> 95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%).<br/> <span class="Sup">†</span> Patients may have met more than one criterion defining failure.<br/> <span class="Sup">‡</span> Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage &gt;3 consecutive days).<br/> <span class="Sup">§</span> Patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures.<br/> </td> </tr> </tbody> </table></div>

In summary, 2 clinical studies of prophylaxis were conducted with the Noxafil oral suspension. As seen in the accompanying tables (Tables 32 and 33), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Noxafil Oral Suspension Study 1 (Table 32), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole–comparator -11.5% to 3.7%) while in Noxafil Oral Suspension Study 2 (Table 33) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole–comparator -22.9% to -7.8%). All-cause mortality was similar at 16 weeks for both treatment arms in Noxafil Oral Suspension Study 1 [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in Noxafil Oral Suspension Study 2 [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.

Posaconazole Injection Posaconazole injection is available as a clear, colorless to yellow sterile liquid in single-dose Type I glass vials closed with bromobutyl rubber stopper and aluminum seal and is supplied as follows.

300 mg per 16.7 mL (18 mg/mL):

16.7 mL Single-Dose Vial

Packaged Individually            NDC 55150-388-01

Posaconazole Injection Posaconazole injection vial should be stored refrigerated at 2 to 8°C (36 to 46°F). Storage conditions for the diluted solution are presented in another section of the prescribing information [see Dosage and Administration (2.4)].

The vial stopper is not made with natural rubber latex.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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Important Administration Instructions Instruct patients that if they miss a dose, they should take it as soon as they remember. However, if it is almost time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

{ "type": "p", "children": [], "text": "\nImportant Administration Instructions\n\n Instruct patients that if they miss a dose, they should take it as soon as they remember. However, if it is almost time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose." }

Drug Interactions

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

Advise patients to inform their physician immediately if they:

{ "type": "p", "children": [], "text": "Advise patients to inform their physician immediately if they:" }

{ "type": "ul", "children": [ "develop severe diarrhea or vomiting.", "are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.", "are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.", "are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole." ], "text": "" }

Serious and Potentially Serious Adverse Reactions

{ "type": "p", "children": [], "text": "\nSerious and Potentially Serious Adverse Reactions\n" }

Advise patients to inform their physician immediately if they:

{ "type": "p", "children": [], "text": "Advise patients to inform their physician immediately if they:" }

{ "type": "ul", "children": [ "notice a change in heart rate or heart rhythm or have a heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions.", "are pregnant, plan to become pregnant, or are nursing.", "have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu.", "have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole." ], "text": "" }

All brands listed are the trademarks of their respective owners and are not trademarks of Eugia Pharma Specialities Limited.

{ "type": "p", "children": [], "text": "All brands listed are the trademarks of their respective owners and are not trademarks of Eugia Pharma Specialities Limited.\n" }

Distributed by: Eugia US LLC 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032 India

{ "type": "p", "children": [], "text": "Distributed by:\nEugia US LLC\n 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520\n Manufactured by:\nEugia Pharma Specialities Limited\n Hyderabad - 500032 India" }

Posaconazole (POE-sa-KON-a-zole) Injection

{ "type": "p", "children": [], "text": "Posaconazole (POE-sa-KON-a-zole) Injection" }

What is posaconazole injection?

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

Posaconazole injection is prescription medicine used in adults and children to help prevent fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Posaconazole injection is used in people who have an increased chance of getting these infections due to a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a low white blood cell count due to chemotherapy for blood cancers (hematologic malignancy)

{ "type": "p", "children": [], "text": "Posaconazole injection is prescription medicine used in adults and children to help prevent fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Posaconazole injection is used in people who have an increased chance of getting these infections due to a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a low white blood cell count due to chemotherapy for blood cancers (hematologic malignancy)" }

Posaconazole injection is used for

{ "type": "p", "children": [], "text": "\nPosaconazole injection is used for\n" }

{ "type": "ul", "children": [ "prevention of fungal infections in adults and children 2 years of age and older.", " treatment of fungal infections in adults and children 13 years of age and older." ], "text": "" }

It is not known if posaconazole injection is safe and effective in children under 2 years of age.

{ "type": "p", "children": [], "text": "\n It is not known if posaconazole injection is safe and effective in children under 2 years of age." }

Who should not take posaconazole injection?

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

Do not take posaconazole injection if you: • are allergic to posaconazole, any of the ingredients in posaconazole injection, or other azole antifungal medicines. See the end of this leaflet for a complete list of ingredients in posaconazole injection. • are taking any of the following medicines:    o sirolimus    o pimozide    o quinidine    o certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)    o ergot alkaloids (ergotamine, dihydroergotamine) • have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.

{ "type": "p", "children": [], "text": "\nDo not take posaconazole injection if you:\n • are allergic to posaconazole, any of the ingredients in posaconazole injection, or other azole antifungal medicines. See the end of this leaflet for a complete list of ingredients in posaconazole injection. • are taking any of the following medicines:    o sirolimus    o pimozide    o quinidine    o certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)    o ergot alkaloids (ergotamine, dihydroergotamine) • have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased." }

Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. Do not start taking a new medicine without talking to your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. Do not start taking a new medicine without talking to your healthcare provider or pharmacist." }

What should I tell my healthcare provider before taking posaconazole injection?

{ "type": "p", "children": [], "text": "\nWhat should I tell my healthcare provider before taking posaconazole injection?\n" }

Before you take posaconazole injection, tell your healthcare provider if you: • are taking certain medicines that lower your immune system like cyclosporine or tacrolimus. • are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause a decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole injection. • are taking midazolam, a hypnotic and sedative medicine. • are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat cancer). • are taking venetoclax, a medicine used to treat cancer. • have or had liver problems. • have or had kidney problems. • have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems. • are pregnant or plan to become pregnant. It is not known if posaconazole injection will harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole injection or breastfeed. You should not do both.

{ "type": "p", "children": [], "text": "\nBefore you take posaconazole injection, tell your healthcare provider if you:\n • are taking certain medicines that lower your immune system like cyclosporine or tacrolimus. • are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause a decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole injection. • are taking midazolam, a hypnotic and sedative medicine. • are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat cancer). • are taking venetoclax, a medicine used to treat cancer. • have or had liver problems. • have or had kidney problems. • have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems. • are pregnant or plan to become pregnant. It is not known if posaconazole injection will harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole injection or breastfeed. You should not do both." }

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Posaconazole injection can affect the way other medicines work, and other medicines can affect the way posaconazole injection work, and can cause serious side effects.

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Posaconazole injection can affect the way other medicines work, and other medicines can affect the way posaconazole injection work, and can cause serious side effects." }

Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them with you to show your healthcare provider or pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.\n Know the medicines you take. Keep a list of them with you to show your healthcare provider or pharmacist when you get a new medicine." }

How will I take posaconazole injection? • Take posaconazole injection exactly as your healthcare provider tells you to take it. • Your healthcare provider will tell you how much posaconazole injection to take and when to take it. • Take posaconazole injection for as long as your healthcare provider tells you to take it. • If you take too much posaconazole, call your healthcare provider or go to the nearest hospital emergency room right away. • Posaconazole injection is usually given over 30 to 90 minutes through a plastic tube placed in your vein.

{ "type": "p", "children": [], "text": "\nHow will I take posaconazole injection?\n • Take posaconazole injection exactly as your healthcare provider tells you to take it. • Your healthcare provider will tell you how much posaconazole injection to take and when to take it. • Take posaconazole injection for as long as your healthcare provider tells you to take it. • If you take too much posaconazole, call your healthcare provider or go to the nearest hospital emergency room right away. • Posaconazole injection is usually given over 30 to 90 minutes through a plastic tube placed in your vein." }

What are the possible side effects of posaconazole injection?

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

Posaconazole injection may cause serious side effects, including:

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

• drug interactions with cyclosporine or tacrolimus. If you take posaconazole injection with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole injection. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of  breath.

{ "type": "p", "children": [], "text": "\n• drug interactions with cyclosporine or tacrolimus. If you take posaconazole injection with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole injection. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of  breath." }

• problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular. • changes in body salt (electrolytes) levels in your blood. Your healthcare provider should check your electrolytes while you are taking posaconazole.

{ "type": "p", "children": [], "text": "\n• problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.\n\n• changes in body salt (electrolytes) levels in your blood. Your healthcare provider should check your electrolytes while you are taking posaconazole. " }

• new or worsening high blood pressure and low potassium levels in your blood (pseudoaldosteronism). Your healthcare provider should check your blood pressure and potassium levels.

{ "type": "p", "children": [], "text": "\n• new or worsening high blood pressure and low potassium levels in your blood (pseudoaldosteronism). Your healthcare provider should check your blood pressure and potassium levels." }

• liver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of posaconazole injection. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole injection. Call your healthcare provider right away if you have any of the following symptoms of liver problems:

{ "type": "p", "children": [], "text": "\n• liver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of posaconazole injection. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole injection. Call your healthcare provider right away if you have any of the following symptoms of liver problems:" }

    o itchy skin                                 o feeling very tired     o nausea or vomiting                   o flu-like symptoms     o yellowing of your eyes or skin

{ "type": "p", "children": [], "text": "    o itchy skin                                 o feeling very tired     o nausea or vomiting                   o flu-like symptoms     o yellowing of your eyes or skin" }

• increased amounts of midazolam in your blood. If you take posaconazole injection with midazolam, posaconazole injection increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole injection. The most common side effects of posaconazole injection in adults include: •  diarrhea                  •  headache •  nausea                    •  coughing •  fever                       •  low potassium levels in the blood •  vomiting The most common side effects of posaconazole injection in children include: •  fever                                                                                               •  itching •  fever with low white blood cell count                           

{ "type": "p", "children": [], "text": "\n• increased amounts of midazolam in your blood. If you take posaconazole injection with midazolam, posaconazole injection increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole injection.\nThe most common side effects of posaconazole injection in adults include:\n•  diarrhea                  •  headache •  nausea                    •  coughing •  fever                       •  low potassium levels in the blood •  vomiting\nThe most common side effects of posaconazole injection in children include:\n•  fever                                                                                               •  itching •  fever with low white blood cell count                           " }

   (febrile neutropenia)                                                                       •  high blood pressure •  vomiting                                                                                          •  redness and sores of the lining of the mouth, lips,   

{ "type": "p", "children": [], "text": "   (febrile neutropenia)                                                                       •  high blood pressure •  vomiting                                                                                          •  redness and sores of the lining of the mouth, lips,   " }

    throat, stomach, and genitals (mucositis or

{ "type": "p", "children": [], "text": "    throat, stomach, and genitals (mucositis or " }

    stomatitis)                                                                                    •   low potassium levels in the blood Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

{ "type": "p", "children": [], "text": "    stomatitis)                                                                                    •   low potassium levels in the blood Tell your healthcare provider if you have any side effect that bothers you or that does not go away. " }

These are not all the possible side effects of posaconazole injection. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of posaconazole injection. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store posaconazole injection? Posaconazole injection •    Store posaconazole injection refrigerated at 36°F to 46°F (2°C to 8°C). Safely throw away medicine that is out of date or no longer needed.

{ "type": "p", "children": [], "text": "\nHow should I store posaconazole injection?\n\nPosaconazole injection\n •    Store posaconazole injection refrigerated at 36°F to 46°F (2°C to 8°C). Safely throw away medicine that is out of date or no longer needed. " }

Keep posaconazole injection and all medicines out of the reach of children. General information about the safe and effective use of posaconazole injection.

{ "type": "p", "children": [], "text": "\nKeep posaconazole injection and all medicines out of the reach of children. General information about the safe and effective use of posaconazole injection.\n" }

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

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

What are the ingredients in posaconazole injection?

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

Active ingredient: posaconazole

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

Inactive ingredients: Posaconazole injection: Betadex Sulfobutyl Ether Sodium (SBECD), edetate disodium, hydrochloric acid, sodium hydroxide, and water for injection. Distributed by: Eugia US LLC 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520

{ "type": "p", "children": [], "text": "\nInactive ingredients:\n\n\nPosaconazole injection: Betadex Sulfobutyl Ether Sodium (SBECD), edetate disodium, hydrochloric acid, sodium hydroxide, and water for injection.\n Distributed by:\nEugia US LLC\n 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520" }

Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032 India

{ "type": "p", "children": [], "text": "Manufactured by:\nEugia Pharma Specialities Limited\n Hyderabad - 500032 India" }

For more information, go to eugiaus.com or call 1-888-238-7880.

{ "type": "p", "children": [], "text": "For more information, go to eugiaus.com or call 1-888-238-7880." }

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

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

Revised: June 2025

{ "type": "p", "children": [], "text": "Revised: June 2025" }

Rx only                   NDC 55150-388-01 Posaconazole Injection 300 mg per 16.7 mL (18 mg/mL) For Intravenous Use Only Sterile Single-Dose VialDiscard Unused Portion

{ "type": "p", "children": [], "text": "\nRx only                   NDC 55150-388-01\nPosaconazole\nInjection\n300 mg per 16.7 mL\n(18 mg/mL)\nFor Intravenous Use Only\nSterile Single-Dose VialDiscard Unused Portion\n" }

Rx only                   NDC 55150-388-01 Posaconazole Injection 300 mg per 16.7 mL (18 mg/mL) For Intravenous Use Only Requires further dilutionprior to infusion.Sterile Single-Dose Vial Discard Unused Portion eugia

{ "type": "p", "children": [], "text": "\nRx only                   NDC 55150-388-01\nPosaconazole\nInjection\n300 mg per 16.7 mL\n(18 mg/mL)\nFor Intravenous Use Only\nRequires further dilutionprior to infusion.Sterile Single-Dose Vial\nDiscard Unused Portion\n\neugia\n" }

Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies (14.2)] as follows:

Posaconazole oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older.

Non-substitutable:

Posaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2, 2.3)].

Posaconazole oral suspension:

Table 1: Dosing Regimens in Adult Patients

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="18%"/> <col width="56%"/> <col width="26%"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Indication</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Dose and Frequency</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Duration of Therapy</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Prophylaxis of invasive <span class="Italics">Aspergillus</span> and <span class="Italics">Candida </span>infections</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Posaconazole Oral Suspension:</span> 200 mg (5 mL) three times a day.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Duration of therapy is based on recovery from neutropenia or immunosuppression.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oropharyngeal Candidiasis <br/>(OPC)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Posaconazole Oral Suspension:</span> </p> <p> <span class="Underline">Loading dose</span>: 100 mg (2.5 mL) twice a day on the first day.</p> <p> <span class="Underline">Maintenance dose</span>: 100 mg (2.5 mL) once a day thereafter. </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Underline">Loading dose</span>: <br/>1 day <br/> <span class="Underline">Maintenance dose</span>: <br/>13 days</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">OPC Refractory (rOPC) to Itraconazole and/or Fluconazole</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Posaconazole Oral Suspension:</span> 400 mg (10 mL) twice a day.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Duration of therapy is based on the severity of the patient’s underlying disease and clinical response.</p> </td> </tr> </tbody> </table></div>

The recommended dosing regimen of posaconazole oral suspension for pediatric patients ages 13 to less than 18 years of age is shown in Table 3[see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

Table 3: Posaconazole Oral Suspension Dosing Regimens for Pediatric Patients (ages 13 to less than 18 years of age)

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="20%"/> <col width="25%"/> <col width="28%"/> <col width="27%"/> <thead> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Indication</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Loading Dose (volume) and frequency</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Maintenance Dose (volume) and frequency</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Duration of Therapy</span></th> </tr> </thead> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Prophylaxis of invasive <span class="Italics">Aspergillus</span> and <span class="Italics">Candida </span>infections</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg (5 mL) three times a day</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg (5 mL) three times a day</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Duration of therapy is based on recovery from neutropenia or immunosuppression.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oropharyngeal Candidiasis (OPC)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100 mg (2.5 mL) twice daily on the first day.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100 mg (2.5 mL) once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13 days</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">OPC Refractory (rOPC) to Itraconazole and/or Fluconazole</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg (10 mL) twice daily </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg (10 mL) twice daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Duration of therapy is based on the severity of the patient’s underlying disease and clinical response.</p> </td> </tr> </tbody> </table></div>

Posaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2, 2.3)].

The pharmacokinetics of posaconazole oral suspension are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

Posaconazole oral suspension is available as a white to off-white, cherry brandy flavored suspension in 4-ounce (120 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL).

{ "type": "p", "children": [], "text": "Posaconazole oral suspension is available as a white to off-white, cherry brandy flavored suspension in 4-ounce (120 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL)." }

Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.

Posaconazole is contraindicated with sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].

Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].

Coadministration of posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Warnings and Precautions (5.11) and Drug Interactions (7.16)].

Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole.

Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18 to 85 years of age) administered posaconazole oral suspension 400 mg twice daily with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.

Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)].

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.

Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11-deoxycortisol), has been reported with posaconazole use in the postmarket setting. Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldosteronism may include discontinuation of posaconazole, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists.

Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the posaconazole oral suspension 800 mg daily (400 mg twice daily or 200 mg four times a day) in clinical trials.

Liver tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.

Due to the variability in exposure with posaconazole oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2.9) and Use in Specific Populations (8.6)].

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].

Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.10)].

Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole.

Concomitant administration of posaconazole, a strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of posaconazole during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications (4.6)]. Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients.

For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax [see Drug Interactions (7.16)]. Refer to the venetoclax prescribing information for dosing instructions.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trial Experience in Adults:

Clinical Trial Safety Experience with Posaconazole Oral Suspension:

The safety of posaconazole oral suspension has been assessed in 1,844 patients. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection, as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8 to 84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 14% black). Posaconazole therapy was given to 171 patients for ≥6 months, with 58 patients receiving posaconazole therapy for ≥12 months. Table 10 presents adverse reactions observed at an incidence of >10% in posaconazole prophylaxis studies. Table 11 presents adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.

Prophylaxis of Aspergillus and Candida: In the 2 randomized, comparative prophylaxis studies (Posaconazole Oral Suspension Study 1 and 2), the safety of posaconazole oral suspension 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients.

The most frequently reported adverse reactions (>30%) in the prophylaxis clinical trials were fever, diarrhea, and nausea.

The most common adverse reactions leading to discontinuation of posaconazole in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).

Table 10: Posaconazole Oral Suspension Study 1 and Study 2. Adverse Reactions in at Least 10% of the Posaconazole Oral Suspension or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)

<div class="scrollingtable"><table class="Noautorules" width="99.22%"> <col width="40%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="9%"/> <col width="10%"/> <col width="10%"/> <thead> <tr> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"><span class="Italics">Body System</span></span> <br/> </th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Posaconazole <br/>Oral Suspension</span> <br/> <span class="Bold">n=605 (%)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Fluconazole</span> <br/> <span class="Bold">n=539 (%)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Itraconazole</span> <br/> <span class="Bold">n=58 (%)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Percentages of sex-specific adverse reactions are based on the number of males/females.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Subjects Reporting any Adverse Reaction</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">595</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(98)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">531</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(99)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">58</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(100)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Body as a Whole - General Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fever</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">274</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(45)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">254</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(47)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">32</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(55)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">171</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(28)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">141</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(26)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(40)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rigors</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">122</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(20)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">87</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(29)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fatigue</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">101</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(17)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">98</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(18)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Edema Legs</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">93</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(15)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">67</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(12)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(19)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Anorexia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">92</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(15)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">94</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(17)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(28)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">64</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">56</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Edema</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">54</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">68</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(13)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(14)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Weakness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">51</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">52</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Cardiovascular Disorders, General</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypertension</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">106</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(18)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">88</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypotension</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">83</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(14)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">79</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(15)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(17)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Disorders of Blood and Lymphatic System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Anemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">149</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(25)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">124</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(23)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(28)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Neutropenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">141</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(23)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">122</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(23)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(40)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Disorders of the Reproductive System and Breast</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Vaginal Hemorrhage<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(12)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Gastrointestinal System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">256</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(42)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">212</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(39)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">35</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(60)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">232</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(38)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">198</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(37)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(52)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">174</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(29)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">173</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(32)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(41)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal Pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">161</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(27)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">147</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(27)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(36)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Constipation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">126</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(21)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">94</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(17)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(17)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyspepsia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">61</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">50</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(10)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Heart Rate and Rhythm Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tachycardia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">72</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(12)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">75</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(14)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Infection and Infestations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pharyngitis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">71</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(12)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">60</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(21)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Liver and Biliary System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Bilirubinemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">59</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">51</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(19)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Metabolic and Nutritional Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypokalemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">181</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(30)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">142</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(26)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(52)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypomagnesemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">110</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(18)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">84</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(19)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperglycemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">68</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">76</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(14)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypocalcemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">56</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">55</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Musculoskeletal System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Musculoskeletal Pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">95</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">82</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(15)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(16)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Arthralgia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">69</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">67</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(12)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Back Pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">63</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">66</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(12)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Platelet, Bleeding and Clotting Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Thrombocytopenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">175</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(29)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">146</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(27)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(34)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Petechiae</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">64</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">54</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(16)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Psychiatric Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">103</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(17)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">92</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(17)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(19)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Respiratory System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Coughing</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">146</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(24)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">130</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(24)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(24)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyspnea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">121</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(20)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">116</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(22)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(26)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Epistaxis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">82</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(14)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">73</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(14)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(21)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Italics">Skin and Subcutaneous Tissue Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rash</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">113</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(19)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">96</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(18)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(43)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Pruritus</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">69</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">62</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(12)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">(19)</p> </td> </tr> </tbody> </table></div>

HIV Infected Subjects with OPC: In 2 randomized comparative studies in OPC, the safety of posaconazole oral suspension at a dose of less than or equal to 400 mg once daily in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg once daily.

An additional 239 HIV-infected patients with refractory OPC received posaconazole oral suspension in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800 mg/day dose and the remainder received the less than or equal to 400 mg once daily dose.

In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, vomiting, and coughing.

The most common adverse reactions that led to treatment discontinuation of posaconazole in the Controlled OPC Pool included respiratory impairment (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of posaconazole were AIDS (7%) and respiratory impairment (3%).

Table 11: Adverse Reactions in at Least 10% of the Treated Population in OPC Studies with Posaconazole Oral Suspension

<div class="scrollingtable"><table class="Noautorules" width="99.22%"> <col width="20%"/> <col width="28%"/> <col width="23%"/> <col width="29%"/> <thead> <tr> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="4" valign="top"><span class="Bold">Body System</span> <br/> <span class="Bold">  </span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"><span class="Bold">Number (%) of Subjects</span></th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Controlled OPC Pool</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Refractory OPC Pool</span></th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Posaconazole Oral Suspension</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Fluconazole</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Posaconazole Oral <br/>Suspension</span></th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">n=557</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">n=262</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">n=239</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Number of subjects reporting adverse reactions at least once during the study, without regard to relationship to treatment. Subjects may have reported more than 1 event. <br/>OPC=oropharyngeal candidiasis</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Subjects Reporting any Adverse Reaction<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">356 (64)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">175 (67)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">221 (92)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Italics">Body as a Whole – General Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Fever</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">34 (6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22 (8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">82 (34)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44 (8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23 (9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">47 (20)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Anorexia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">46 (19)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Fatigue</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18 (3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12 (5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">31 (13)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Asthenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">31 (13)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Rigors</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (&lt;1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">29 (12)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27 (11)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Italics">Disorders of Blood and Lymphatic System</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Neutropenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21 (4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8 (3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">39 (16)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Anemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">34 (14)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Italics">Gastrointestinal System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">58 (10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">34 (13)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">70 (29)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">48 (9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30 (11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">70 (29)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">37 (7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18 (7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">67 (28)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Abdominal Pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27 (5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17 (6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">43 (18)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Italics">Infection and Infestations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Candidiasis, Oral</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (&lt;1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">28 (12)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Herpes Simplex</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16 (3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8 (3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">26 (11)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Pneumonia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17 (3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25 (10)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Italics">Metabolic and Nutritional Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Weight Decrease</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">33 (14)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Dehydration</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7 (3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27 (11)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Italics">Psychiatric Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8 (1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">39 (16)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Italics">Respiratory System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Coughing</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18 (3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11 (4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">60 (25)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Dyspnea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8 (1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8 (3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">28 (12)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Italics">Skin and Subcutaneous Tissue Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Rash</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15 (3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 (4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">36 (15)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">  Sweating Increased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23 (10)</p> </td> </tr> </tbody> </table></div>

Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%).

Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of posaconazole are listed below:

Clinical Laboratory Values: In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma concentrations of posaconazole.

For the prophylaxis studies, the number of patients with changes in liver tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in Table 12.

Table 12: Posaconazole Oral Suspension Study 1 and Study 2. Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4

<div class="scrollingtable"><table width="83.4%"> <col width="31%"/> <col width="31%"/> <col width="32%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule Toprule" colspan="3" valign="top"><span class="Bold">Number (%) of Patients with Change*</span></th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Posaconazole Oral Suspension Study 1</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Laboratory Parameter</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">Posaconazole Oral <br/>Suspension<br/>n=301</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">Fluconazole<br/>n=299</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  AST</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11/266 (4)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13/266 (5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  ALT</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">47/271 (17)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">39/272 (14)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Bilirubin</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">24/271 (9)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20/275 (7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Alkaline Phosphatase</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9/271 (3)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8/271 (3)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Posaconazole Oral Suspension Study 2</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Laboratory Parameter</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Posaconazole Oral <br/>Suspension<br/>(n=304)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Fluconazole/Itraconazole<br/>(n=298)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  AST</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9/286 (3)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5/280 (2)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  ALT</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18/289 (6)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13/284 (5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Bilirubin</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20/290 (7)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">25/285 (9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">  Alkaline Phosphatase</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4/281 (1)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1/276 (&lt;1)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="bottom"> <p class="First">*Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation. <br/>CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; <br/>ALT= Alanine Aminotransferase.</p> </td> </tr> </tbody> </table></div>

The number of patients treated for OPC with clinically significant liver test abnormalities at any time during the studies is provided in Table 13 (liver test abnormalities were present in some of these patients prior to initiation of the study drug).

Table 13: Posaconazole Oral Suspension Studies: Clinically Significant Laboratory Test Abnormalities without Regard to Baseline Value

<div class="scrollingtable"><table width="100%"> <col width="34%"/> <col width="23%"/> <col width="20%"/> <col width="22%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="top"><span class="Bold">Laboratory Test</span></th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Controlled</span></th><th align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Refractory</span></th> </tr> <tr> <th align="center" class="Botrule Rrule" valign="top"><span class="Bold">Posaconazole Oral Suspension</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">Fluconazole</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">Posaconazole Oral Suspension</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule Rrule" valign="top"><span class="Bold">n=557(%)</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">n=262(%)</span></th><th align="center" class="Botrule Rrule" valign="top"><span class="Bold">n=239(%)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">ALT &gt; 3.0 × ULN</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">16/537 (3)</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">13/254 (5)</p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First">25/226 (11)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">AST &gt; 3.0 × ULN</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">33/537 (6)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">26/254 (10)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">39/223 (17)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Total Bilirubin &gt; 1.5 × ULN</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15/536 (3)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5/254 (2)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9/197 (5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Alkaline Phosphatase &gt; 3.0 × ULN</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">17/535 (3)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15/253 (6)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">24/190 (13)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="4" valign="bottom"> <p class="First">ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.</p> </td> </tr> </tbody> </table></div>

The number of patients treated for invasive aspergillosis with clinically significant liver test abnormalities at any time during the Aspergillosis Treatment Study is provided in Table 14. Liver test abnormalities present prior to the initiation of study drug included ALT (22%), AST (13%), and bilirubin (13%).

Table 14: Aspergillosis Treatment Study: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="28%"/> <col width="38%"/> <col width="33%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Number (%) of Patients with Change*</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First"> <span class="Bold">Laboratory Parameter</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Posaconazole n/N <br/>(%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Voriconazole <br/>n/N (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First">AST</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">22/281 (8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">21/285 (7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First">ALT</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">29/281(10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">23/282 (8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First">Bilirubin</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">26/280 (9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">25/284 (9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First">Alkaline Phosphatase</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">12/282 (4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">20/284 (7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First">*Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form n/N, where n represents the number of patients who met the criterion as indicated, and N represents the number of patients who had a baseline observation and at least one post-baseline observation. <br/>N=Number of subjects for a given laboratory test with a baseline value of CTC Grade 0, 1, or 2 and at least one post-baseline value. <br/>CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase.</p> </td> </tr> </tbody> </table></div>

The following adverse reaction has been identified during the post-approval use of posaconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Endocrine Disorders: Pseudoaldosteronism

Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3)].

Tacrolimus: Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications (4.3) and Warnings and Precautions (5.2)].

Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 [see Contraindications (4.4) and Clinical Pharmacology (12.3)].

Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids [see Contraindications (4.5)].

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].

Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.

Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see Clinical Pharmacology (12.3)]. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.

Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see Clinical Pharmacology (12.3)].

Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.

Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.

Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with posaconazole oral suspension results in decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. It is recommended to avoid concomitant use of cimetidine and esomeprazole with posaconazole oral suspension unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.

No clinically relevant effects were observed when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. No dosage adjustment of posaconazole oral suspension is required when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine.

Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions [see Warnings and Precautions (5.8)]. Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.

Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.

Metoclopramide, when given with posaconazole oral suspension, decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. If metoclopramide is concomitantly administered with posaconazole oral suspension, it is recommended to closely monitor for breakthrough fungal infections.

Loperamide does not affect posaconazole plasma concentrations after posaconazole oral suspension administration [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole oral suspension is required when loperamide and posaconazole oral suspension are used concomitantly.

Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.

Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities [see Contraindications (4.6), Warnings and Precautions (5.11)]. Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

Risk Summary:

Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses 5 times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of ≥ 3 times the clinical exposure caused an increase in resorptions in these rabbits (see Data). Based on animal 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. 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:

Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.

Risk Summary:

There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition.

The safety and effectiveness of posaconazole oral suspension for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 13 and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy.

The safety and effectiveness of posaconazole oral suspension have been established for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients aged 13 years and older.

Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

The safety and effectiveness of posaconazole oral suspension have not been established in pediatric patients younger than 13 years of age.

No overall differences in the safety of posaconazole oral suspension were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for posaconazole oral suspension in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].

Of the 605 patients randomized to posaconazole oral suspension in the Posaconazole Oral Suspension Study 1 and Study 2, 63 (10%) were ≥65 years of age. In addition, 48 patients treated with greater than or equal to 800-mg/day posaconazole oral suspension in another indication were ≥65 years of age.

No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

Following single-dose administration of 400 mg of the posaconazole oral suspension, there was no significant effect of mild (eGFR: 50 to 80 mL/min/1.73 m2, n=6) or moderate (eGFR: 20 to 49 mL/min/1.73 m2, n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2)].

After a single oral dose of posaconazole oral suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.

It is recommended that no dose adjustment of posaconazole oral suspension is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2) and Warnings and Precautions (5.5)].

The pharmacokinetics of posaconazole are comparable in males and females. No adjustment in the dosage of posaconazole is necessary based on gender.

The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of posaconazole is necessary based on race.

Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections [see Clinical Pharmacology (12.3)].

During the clinical trials, some patients received posaconazole oral suspension up to 1,600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1,200 mg twice daily posaconazole oral suspension for 3 days. No related adverse reactions were noted by the investigator.

{ "type": "p", "children": [], "text": "During the clinical trials, some patients received posaconazole oral suspension up to 1,600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1,200 mg twice daily posaconazole oral suspension for 3 days. No related adverse reactions were noted by the investigator." }

Posaconazole is not removed by hemodialysis.

{ "type": "p", "children": [], "text": "Posaconazole is not removed by hemodialysis." }

Posaconazole is an azole antifungal agent available as an injection solution to be diluted before intravenous administration, delayed-release tablet, oral suspension, and powder for delayed-release oral suspension intended for oral administration.

{ "type": "p", "children": [], "text": "Posaconazole is an azole antifungal agent available as an injection solution to be diluted before intravenous administration, delayed-release tablet, oral suspension, and powder for delayed-release oral suspension intended for oral administration. " }

Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:

{ "type": "p", "children": [], "text": "Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:" }

Posaconazole is a white to off-white powder that is practically insoluble in water.

{ "type": "p", "children": [], "text": "Posaconazole is a white to off-white powder that is practically insoluble in water." }

Posaconazole oral suspension is a white to off-white, cherry-brandy flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: cherry-brandy flavor, citric acid monohydrate, hydroxyethyl cellulose, glycerin, polyoxyl 35 castor oil, simethicone emulsion, sodium benzoate, sodium citrate, sorbitol solution, titanium dioxide, and water.

{ "type": "p", "children": [], "text": "Posaconazole oral suspension is a white to off-white, cherry-brandy flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: cherry-brandy flavor, citric acid monohydrate, hydroxyethyl cellulose, glycerin, polyoxyl 35 castor oil, simethicone emulsion, sodium benzoate, sodium citrate, sorbitol solution, titanium dioxide, and water." }

Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].

Exposure Response Relationship Prophylaxis: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), a wide range of plasma exposures to posaconazole was noted following administration of posaconazole oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 17). A lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.

Table 17: Posaconazole Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials

<div class="scrollingtable"><table width="100%"> <col width="14%"/> <col width="20%"/> <col width="20%"/> <col width="22%"/> <col width="24%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Prophylaxis in AML/MDS</span><a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Prophylaxis in GVHD</span><a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Cavg Range (ng/mL)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Treatment Failure</span><a class="Sup" href="#footnote-5" name="footnote-reference-5">‡</a><span class="Bold"> (%)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Cavg Range (ng/mL)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Treatment Failure</span><a class="Sup" href="#footnote-5">‡</a><span class="Bold"> (%)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>HSCT recipients with GVHD</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">‡</a> </dt> <dd>Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections<br/> </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Quartile 1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">90 to 322</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">54.7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22 to 557</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Quartile 2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">322 to 490</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">37.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">557 to 915</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Quartile 3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">490 to 734</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">46.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">915 to 1,563</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Quartile 4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">734 to 2,200</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1,563 to 3,650</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17.5</p> </td> </tr> <tr class="Last"> <td colspan="5" valign="bottom"> <p class="First">     Cavg = the average posaconazole concentration when measured at steady state</p> </td> </tr> </tbody> </table></div>

General Pharmacokinetic Characteristics:

Dose-proportional increases in plasma exposure (AUC) to posaconazole oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections.

The mean (%CV) [min-max] posaconazole oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times a day and 400 mg twice daily of the oral suspension are provided in Table 21.

Table 21: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole Oral Suspension 200 mg Three Times a Day and 400 mg Twice Daily

<div class="scrollingtable"><table width="100%"> <col width="18%"/> <col width="16%"/> <col width="17%"/> <col width="16%"/> <col width="16%"/> <col width="17%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Dose</span><a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Cavg (ng/mL)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">AUC</span><a class="Sup" href="#footnote-7" name="footnote-reference-7">†</a><span class="Bold"> (ng∙hr/mL)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">CL/F (L/hr)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">V/F (L)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">t<span class="Sub">½</span> (hr)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Oral suspension administration</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">†</a> </dt> <dd>AUC (0 to 24 hr) for 200 mg three times a day and AUC (0 to 12 hr) for 400 mg twice daily</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">‡</a> </dt> <dd>HSCT recipients with GVHD</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">§</a> </dt> <dd>Not done</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">¶</a> </dt> <dd>Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">#</a> </dt> <dd>Febrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24 <br/>The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">200 mg three times a day<a class="Sup" href="#footnote-8" name="footnote-reference-8">‡</a> (n=252)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1,103 (67)<br/>[21.5 to 3650]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">ND<a class="Sup" href="#footnote-9" name="footnote-reference-9">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">ND<a class="Sup" href="#footnote-9">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">ND<a class="Sup" href="#footnote-9">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">ND<a class="Sup" href="#footnote-9">§</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">200 mg three times a day<a class="Sup" href="#footnote-10" name="footnote-reference-10">¶</a> (n=215)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">583 (65)<br/>[89.7 to 2,200]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15,900 (62)<br/>[4100 to 56,100]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">51.2 (54)<br/>[10.7 to 146]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2425 (39)<br/>[828 to 5,702]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">37.2 (39)<br/>[19.1 to 148]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">400 mg twice daily<a class="Sup" href="#footnote-11" name="footnote-reference-11">#</a> (n=23)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">723 (86)<br/>[6.70 to 2,256]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9093 (80)<br/>[1,564 to 26,794]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">76.1 (78)<br/>[14.9 to 256]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3088 (84)<br/>[407 to 13,140]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">31.7 (42)<br/>[12.4 to 67.3]</p> </td> </tr> <tr class="Last"> <td colspan="6" valign="top"> <p class="First">     Cavg = the average posaconazole concentration when measured at steady state</p> </td> </tr> </tbody> </table></div>

Absorption:

Posaconazole oral suspension is absorbed with a median Tmax of ~3 to 5 hours. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration.

Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when the oral suspension is administered with a nonfat meal and approximately 4-times higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of posaconazole oral suspension 400 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 24). In addition, the effects of varying gastric administration conditions on the Cmax and AUC of posaconazole oral suspension in healthy volunteers have been investigated and are shown in Table 25.

In order to assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole oral suspension during or immediately following a full meal. In patients who cannot eat a full meal, posaconazole oral suspension should be taken with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).

Table 24: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="22%"/> <col width="17%"/> <col width="13%"/> <col width="18%"/> <col width="15%"/> <col width="16%"/> <thead> <tr> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Dose (mg)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">C<span class="Sub">max</span></span> <br/> <span class="Bold">(ng/mL)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">T<span class="Sub">max</span></span><a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a> <br/> <span class="Bold">(hr)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">AUC (I)</span> <br/> <span class="Bold">(ng∙hr/mL)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">CL/F</span> <br/> <span class="Bold">(L/hr)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">t<span class="Sub">½</span></span> <br/> <span class="Bold">(hr)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>Median [min-max].</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>n=15 for AUC (I), CL/F, and t<span class="Sub">½</span> </dd> <dt> <a href="#footnote-reference-14" name="footnote-14">‡</a> </dt> <dd>The subject with T<span class="Sub">max</span> of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs).</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">§</a> </dt> <dd>n=10 for AUC (I), CL/F, and t<span class="Sub">½</span> </dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">200 mg fasted<br/>(n=20)<a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">132 (50)<br/>[45 to 267]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.50<br/>[1.5 to 36<a class="Sup" href="#footnote-14" name="footnote-reference-14">‡</a>]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4179 (31)<br/>[2,705 to 7,269]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">51 (25)<br/>[28 to 74]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23.5 (25)<br/>[15.3 to 33.7]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">200 mg nonfat<br/>(n=20)<a class="Sup" href="#footnote-13">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">378 (43)<br/>[131 to 834]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 [3 to 5]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10,753 (35)<br/>[4,579 to 17,092]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21 (39)<br/>[12 to 44]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22.2 (18)<br/>[17.4 to 28.7]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">200 mg high fat<br/>(54 gm fat)<br/>(n=20)<a class="Sup" href="#footnote-13">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">512 (34)<br/>[241 to 1,016]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 [4 to 5]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">15,059 (26)<br/>[10,341 to 24,476]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14 (24)<br/>[8.2 to 19]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">23.0 (19)<br/>[17.2 to 33.4]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">400 mg fasted<br/>(n=23)<a class="Sup" href="#footnote-15" name="footnote-reference-15">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">121 (75)<br/>[27 to 366]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 [2 to 12]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5258 (48)<br/>[2,834 to 9,567]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">91 (40)<br/>[42 to 141]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27.3 (26)<br/>[16.8 to 38.9]</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg with liquid nutritional supplement<br/>(14 gm fat)<br/>(n=23)<a class="Sup" href="#footnote-15">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">355 (43)<br/>[145 to 720]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 [4 to 8]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">11,295 (40)<br/>[3,865 to 20,592]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">43 (56)<br/>[19 to 103]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">26.0 (19)<br/>[18.2 to 35.0]</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 25: The Effect of Varying Gastric Administration Conditions on the C<span class="Sub">max</span> and AUC of Posaconazole Oral Suspension in Healthy Volunteers<a class="Sup" href="#footnote-16" name="footnote-reference-16">*</a></span> </caption> <col width="27%"/> <col width="27%"/> <col width="27%"/> <col width="20%"/> <thead> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Study Description</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Administration Arms</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Change in C<span class="Sub">max</span></span> <br/> <span class="Bold">(ratio estimate</span><a class="Sup" href="#footnote-17" name="footnote-reference-17">†</a><span class="Bold">;</span> <br/> <span class="Bold">90% CI of the ratio estimate)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Change in AUC</span> <br/> <span class="Bold">(ratio estimate</span><a class="Sup" href="#footnote-17">†</a><span class="Bold">;</span> <br/> <span class="Bold">90% CI of the ratio estimate)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-16" name="footnote-16">*</a> </dt> <dd>In 5 subjects, the C<span class="Sub">max</span> and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when posaconazole was administered via an NG tube compared to when posaconazole was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when posaconazole is administered via an NG tube because a lower plasma exposure may be associated with an increased risk of treatment failure.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">†</a> </dt> <dd>Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C<span class="Sub">max </span>or AUC.</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">‡</a> </dt> <dd>NG = nasogastric</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td class="Botrule Lrule Rrule" rowspan="3" valign="middle"> <p class="First">400 mg single dose with a high-fat meal relative to fasted state (n=12)<br/> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5 minutes before high-fat meal</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑96%<br/>(1.96; 1.48 to 2.59)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑111%<br/>(2.11; 1.60 to 2.78)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">During high-fat meal</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑339%<br/>(4.39; 3.32 to 5.80)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑382%<br/>(4.82; 3.66 to 6.35)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20 minutes after high-fat meal</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑333%<br/>(4.33; 3.28 to 5.73)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑387%<br/>(4.87; 3.70 to 6.42)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First">400 mg twice daily and 200 mg four times daily for 7 days in fasted state and with liquid nutritional supplement (BOOST<span class="Sup">®</span>) (n=12)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400 mg twice daily with BOOST</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑65%<br/>(1.65; 1.29 to 2.11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑66%<br/>(1.66; 1.30 to 2.13)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 mg four times daily with BOOST</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">No Effect</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">No Effect</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First">Divided daily dose from 400 mg twice daily to 200 mg four times daily for 7 days regardless of fasted conditions or with BOOST (n=12)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Fasted state</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑136%<br/>(2.36; 1.84 to 3.02)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑161%<br/>(2.61; 2.04 to 3.35)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">With BOOST</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑137%<br/>(2.37; 1.86 to 3.04)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑157%<br/>(2.57; 2.00 to 3.30)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First">400-mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Ginger ale</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑92%<br/>(1.92; 1.51 to 2.44)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑70%<br/>(1.70; 1.43 to 2.03)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Esomeprazole</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓32%<br/>(0.68; 0.53 to 0.86)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓30%<br/>(0.70; 0.59 to 0.83)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First">400-mg single dose with a prokinetic agent (metoclopramide 10 mg three times a day for 2 days) + BOOST or an antikinetic agent (loperamide 4-mg single dose) + BOOST (n=12)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">With metoclopramide + BOOST</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓21%<br/>(0.79; 0.72 to 0.87)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓19%<br/>(0.81; 0.72 to 0.91)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">With loperamide + BOOST</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓3%<br/>(0.97; 0.88 to 1.07)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑11%<br/>(1.11; 0.99 to 1.25)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400-mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Via NG tube<a class="Sup" href="#footnote-18" name="footnote-reference-18">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓19%<br/>(0.81; 0.71 to 0.91)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓23%<br/>(0.77; 0.69 to 0.86)</p> </td> </tr> </tbody> </table></div>

Concomitant administration of posaconazole oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (See Table 26).

Table 26: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Oral Suspension in Healthy Volunteers

<div class="scrollingtable"><table class="Noautorules" width="90%"> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <thead> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="bottom"><span class="Bold">Coadministered Drug (Postulated Mechanism of Interaction)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="bottom"><span class="Bold">Coadministered Drug Dose/Schedule</span></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="bottom"><span class="Bold">Posaconazole Dose/Schedule</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"><span class="Bold">Effect on Bioavailability of Posaconazole</span></th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Change in Mean</span> <br/> <span class="Bold">C<span class="Sub">max</span></span> <br/> <span class="Bold">(ratio estimate</span><a class="Sup" href="#footnote-19" name="footnote-reference-19">*</a><span class="Bold">; 90% CI of the ratio estimate)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Change in Mean AUC</span> <br/> <span class="Bold">(ratio estimate</span><a class="Sup" href="#footnote-19">*</a><span class="Bold">; 90% CI of the ratio estimate)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-19" name="footnote-19">*</a> </dt> <dd>Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C<span class="Sub">max</span> or AUC.</dd> <dt> <a href="#footnote-reference-20" name="footnote-20">†</a> </dt> <dd>The tablet refers to a non-commercial tablet formulation without polymer.</dd> <dt> <a href="#footnote-reference-21" name="footnote-21">‡</a> </dt> <dd>The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cimetidine<br/>(Alteration of gastric pH)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400 mg twice daily × 10 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 mg (tablets) once daily × 10 days<a class="Sup" href="#footnote-20" name="footnote-reference-20">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓ 39%<br/>(0.61; 0.53 to 0.70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓ 39%<br/>(0.61; 0.54 to 0.69)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Esomeprazole (Increase in gastric pH)<a class="Sup" href="#footnote-21" name="footnote-reference-21">‡</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">40 mg every morning × 3 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400 mg (oral suspension) single dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓ 46%<br/>(0.54; 0.43 to 0.69)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓ 32%<br/>(0.68; 0.57 to 0.81)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Metoclopramide (Increase in gastric motility)<a class="Sup" href="#footnote-21">‡</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 mg three times a day × 2 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400 mg (oral suspension) single dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓ 21%<br/>(0.79; 0.72 to 0.87)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓ 19%<br/>(0.81; 0.72 to 0.91)</p> </td> </tr> </tbody> </table></div>

Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226 to 295 L between studies and dose levels.

Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.

Metabolism: Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.

Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27.

Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers

<div class="scrollingtable"><table class="Noautorules" width="90%"> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <thead> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Coadministered Drug (Postulated Mechanism of Interaction)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Coadministered Drug Dose/Schedule</span></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Posaconazole Dose/Schedule</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"><span class="Bold">Effect on Bioavailability of Posaconazole</span></th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Change in Mean</span> <br/> <span class="Bold">C<span class="Sub">max</span></span> <br/> <span class="Bold">(ratio estimate</span><a class="Sup" href="#footnote-22" name="footnote-reference-22">*</a><span class="Bold">; 90% CI of the ratio estimate)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Change in Mean AUC</span> <br/> <span class="Bold">(ratio estimate</span><a class="Sup" href="#footnote-22">*</a><span class="Bold">; 90% CI of the ratio estimate)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-22" name="footnote-22">*</a> </dt> <dd>Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for C<span class="Sub">max</span> or AUC.</dd> <dt> <a href="#footnote-reference-23" name="footnote-23">†</a> </dt> <dd>The tablet refers to a non-commercial tablet formulation without polymer.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Efavirenz<br/>(UDP-G Induction)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg once daily × 10 and 20 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg (oral suspension) twice daily × 10 and 20 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓45%<br/>(0.55; 0.47 to 0.66)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 50%<br/>(0.50; 0.43 to 0.60)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fosamprenavir (unknown mechanism)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">700 mg twice daily × 10 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg once daily on the 1<span class="Sup">st</span> day, 200 mg twice daily on the 2<span class="Sup">nd</span> day, then 400 mg twice daily × 8 Days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓21%<br/>0.79 (0.71 to 0.89)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓23%<br/>0.77 (0.68 to 0.87)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rifabutin<br/>(UDP-G Induction)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">300 mg once daily × 17 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg (tablets) once daily × 10 days<a class="Sup" href="#footnote-23" name="footnote-reference-23">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 43%<br/>(0.57; 0.43 to 0.75)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 49%<br/>(0.51; 0.37 to 0.71)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Phenytoin<br/>(UDP-G Induction)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg once daily × 10 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg (tablets) once daily × 10 days<a class="Sup" href="#footnote-23">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 41%<br/>(0.59; 0.44 to 0.79)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 50%<br/>(0.50; 0.36 to 0.71)</p> </td> </tr> </tbody> </table></div>

In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 28[see Contraindications (4) and Drug Interactions (7.1) including recommendations].

Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and Patients

<div class="scrollingtable"><table class="Noautorules" width="90%"> <col width="18%"/> <col width="22%"/> <col width="20%"/> <col width="19%"/> <col width="21%"/> <thead> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="bottom"><span class="Bold">Coadministered Drug</span> <br/> <span class="Bold">(Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="bottom"><span class="Bold">Coadministered Drug Dose/Schedule</span></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="bottom"><span class="Bold">Posaconazole Dose/Schedule</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"><span class="Bold">Effect on Bioavailability of Coadministered Drugs</span></th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Change in Mean C<span class="Sub">max</span></span> <br/> <span class="Bold">(ratio estimate</span><a class="Sup" href="#footnote-24" name="footnote-reference-24">*</a><span class="Bold">; 90% CI of the ratio estimate)</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Change in Mean AUC</span> <br/> <span class="Bold">(ratio estimate</span><a class="Sup" href="#footnote-24">*</a><span class="Bold">; 90% CI of the ratio estimate)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-24" name="footnote-24">*</a> </dt> <dd>The Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C<span class="Sub">max</span> or AUC.</dd> <dt> <a href="#footnote-reference-25" name="footnote-25">†</a> </dt> <dd>The tablet refers to a non-commercial tablet formulation without polymer.</dd> <dt> <a href="#footnote-reference-26" name="footnote-26">‡</a> </dt> <dd>The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Sirolimus</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 mg single oral dose</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg (oral suspension) twice daily × 16 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 572%<br/>(6.72; 5.62 to 8.03)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 788%<br/>(8.88; 7.26 to 10.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cyclosporine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Stable maintenance dose in heart transplant recipients</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg (tablets) once daily × 10 days<a class="Sup" href="#footnote-25" name="footnote-reference-25">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">↑ cyclosporine whole blood trough concentrations<br/>Cyclosporine dose reductions of up to 29% were required</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tacrolimus</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.05 mg/kg single oral dose</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg (oral suspension) twice daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 121%<br/>(2.21; 2.01 to 2.42)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 358%<br/>(4.58; 4.03 to 5.19)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Simvastatin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40 mg single oral dose</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100 mg (oral suspension) once daily × 13 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Simvastatin<br/>↑ 841%<br/>(9.41, 7.13 to 12.44)<br/>Simvastatin Acid<br/>↑ 817%<br/>(9.17, 7.36 to 11.43)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Simvastatin<br/>↑ 931%<br/>(10.31, 8.40 to 12.67)<br/>Simvastatin Acid<br/>↑634%<br/>(7.34, 5.82 to 9.25)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg (oral suspension) once daily × 13 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Simvastatin<br/>↑ 1041%<br/>(11.41, 7.99 to 16.29)<br/>Simvastatin Acid<br/>↑851%<br/>(9.51, 8.15 to 11.10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Simvastatin<br/>↑ 960%<br/>(10.60, 8.63 to 13.02)<br/>Simvastatin Acid<br/>↑748%<br/>(8.48, 7.04 to 10.23)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Midazolam</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4 mg single intravenous dose<a class="Sup" href="#footnote-26" name="footnote-reference-26">‡</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg (oral suspension) twice daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 30%<br/>(1.3; 1.13 to 1.48)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 362%<br/>(4.62; 4.02 to 5.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4 mg single intravenous dose<a class="Sup" href="#footnote-26">‡</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg (oral suspension) twice daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑62%<br/>(1.62; 1.41 to 1.86)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑524%<br/>(6.24; 5.43 to 7.16)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 mg single oral dose<a class="Sup" href="#footnote-26">‡</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg (oral suspension) once daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 169%<br/>(2.69; 2.46 to 2.93)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 470%<br/>(5.70; 4.82 to 6.74)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 mg single oral dose<a class="Sup" href="#footnote-26">‡</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg (oral suspension) twice daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 138%<br/>(2.38; 2.13 to 2.66)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 397%<br/>(4.97; 4.46 to 5.54)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rifabutin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">300 mg once daily × 17 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg (tablets) once daily × 10 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 31%<br/>(1.31; 1.10 to 1.57)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 72%<br/>(1.72;1.51 to 1.95)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Phenytoin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg once daily PO × 10 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg (tablets) once daily × 10 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 16%<br/>(1.16; 0.85 to 1.57)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 16%<br/>(1.16; 0.84 to 1.59)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Ritonavir</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100 mg once daily × 14 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg (oral suspension)<br/>twice daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 49%<br/>(1.49; 1.04 to 2.15)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 80%<br/>(1.8;1.39 to 2.31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Atazanavir</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">300 mg once daily × 14 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg (oral suspension) twice daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 155%<br/>(2.55; 1.89 to 3.45)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 268%<br/>(3.68; 2.89 to 4.70)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Atazanavir/ ritonavir boosted regimen</p> </td><td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">300 mg/100 mg once daily × 14 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">400 mg (oral suspension) twice daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 53%<br/>(1.53; 1.13 to 2.07)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 146%<br/>(2.46; 1.93 to 3.13)</p> </td> </tr> </tbody> </table></div>

Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg once daily.

Excretion: Following administration of posaconazole oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).

Posaconazole oral suspension is eliminated with a mean half-life (t½) of 35 hours (range: 20 to 66 hours).

Specific Populations:

No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment).

Race/Ethnicity: In a population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure.

Patients Weighing More Than 120 kg: Weight has a clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)].

Pediatric Patients:

The population pharmacokinetic analysis of posaconazole in pediatric patients suggests that age, sex, renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics of posaconazole.

A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of posaconazole oral suspension for prophylaxis of invasive fungal infections. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (≥18 years of age). In a study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with posaconazole oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.

Mechanism of Action: Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.

Resistance: Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.

Antimicrobial Activity: Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].

Microorganisms:Aspergillus spp. and Candida spp.

Susceptibility Testing: For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Carcinogenesis: No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times the exposure achieved with a 400-mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400-mg twice daily oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with a 400-mg twice daily oral suspension regimen.

Mutagenesis: Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study.

Impairment of Fertility: Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400-mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400-mg twice daily oral suspension regimen).

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in a separate study of 10-week-old dogs dosed with intravenous posaconazole for 13 weeks with a 9-week recovery period or a follow-up study of 31-week-old dogs dosed for 3 months.

Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems.

The first study (Posaconazole Oral Suspension Study 1) was a randomized, double-blind trial that compared posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may have met more than one of these criteria). This assessed all patients while on study therapy plus 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (80 days, posaconazole oral suspension; 77 days, fluconazole). Table 32 contains the results from Posaconazole Oral Suspension Study 1.

Table 32: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Posaconazole Oral Suspension Study 1

<div class="scrollingtable"><table class="Noautorules" width="75%"> <col width="38%"/> <col width="24%"/> <col width="23%"/> <thead> <tr> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Posaconazole</span> <br/> <span class="Bold">n=301</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Fluconazole</span> <br/> <span class="Bold">n=299</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-27" name="footnote-27">*</a> </dt> <dd>Patients may have met more than one criterion defining failure.</dd> <dt> <a href="#footnote-reference-28" name="footnote-28">†</a> </dt> <dd>Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage &gt;4 consecutive days).</dd> <dt> <a href="#footnote-reference-29" name="footnote-29">‡</a> </dt> <dd>95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%).</dd> <dt> <a href="#footnote-reference-30" name="footnote-30">§</a> </dt> <dd>Patients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. These patients were considered failures.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">On therapy plus 7 days</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Clinical Failure</span><a class="Sup" href="#footnote-27" name="footnote-reference-27">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">50 (17%)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">55 (18%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">  Failure due to:</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Proven/Probable IFI</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7 (2%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22 (7%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(<span class="Italics">Aspergillus</span>)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17 (6%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(<span class="Italics">Candida</span>)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (&lt;1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(Other)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    All Deaths</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22 (7%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24 (8%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">Proven/probable fungal <br/>infection prior to death</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (&lt;1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 (2%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    SAF<a class="Sup" href="#footnote-28" name="footnote-reference-28">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27 (9%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25 (8%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Through 16 weeks</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Clinical Failure</span><a class="Sup" href="#footnote-27">*</a><span class="Bold"><span class="Sup">,</span></span><a class="Sup" href="#footnote-29" name="footnote-reference-29">‡</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">99 (33%)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">110 (37%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">  Failure due to:</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Proven/Probable IFI</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16 (5%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27 (9%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(<span class="Italics">Aspergillus</span>)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7 (2%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">21 (7%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(<span class="Italics">Candida</span>)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (1%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(Other)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5 (2%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2 (1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    All Deaths</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">58 (19%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">59 (20%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">Proven/probable fungal <br/>infection prior to death</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 (3%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16 (5%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    SAF<a class="Sup" href="#footnote-28">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">26 (9%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30 (10%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">    Event free lost to follow-up<a class="Sup" href="#footnote-30" name="footnote-reference-30">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24 (8%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30 (10%)</p> </td> </tr> </tbody> </table></div>

The second study (Posaconazole Oral Suspension Study 2) was a randomized, open-label study that compared posaconazole oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Posaconazole Oral Suspension Study 1, efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). This study assessed patients while on treatment plus 7 days and 100 days postrandomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 33 contains the results from Posaconazole Oral Suspension Study 2.

Table 33: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Posaconazole Oral Suspension Study 2

<div class="scrollingtable"><table class="Noautorules" width="75.86%"> <col width="30%"/> <col width="26%"/> <col width="29%"/> <thead> <tr> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Posaconazole</span> <br/> <span class="Bold">n=304</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Fluconazole/Itraconazole</span> <br/> <span class="Bold">n=298</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>95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%).</dd> <dt> <a href="#footnote-reference-32" name="footnote-32">†</a> </dt> <dd>Patients may have met more than one criterion defining failure.</dd> <dt> <a href="#footnote-reference-33" name="footnote-33">‡</a> </dt> <dd>Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage &gt;3 consecutive days).</dd> <dt> <a href="#footnote-reference-34" name="footnote-34">§</a> </dt> <dd>Patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">On therapy plus 7 days</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Clinical Failure</span><a class="Sup" href="#footnote-31" name="footnote-reference-31">*</a><span class="Bold"><span class="Sup">,</span></span><a class="Sup" href="#footnote-32" name="footnote-reference-32">†</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">82 (27%)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">126 (42%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">  Failure due to:</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Proven/Probable IFI</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7 (2%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25 (8%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(<span class="Italics">Aspergillus</span>)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20 (7%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(<span class="Italics">Candida</span>)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (1%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(Other)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    All Deaths</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17 (6%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25 (8%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">Proven/probable fungal infection prior to death</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (&lt;1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    SAF<a class="Sup" href="#footnote-33" name="footnote-reference-33">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">67 (22%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">98 (33%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Through 100 days postrandomization</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Clinical Failure</span><a class="Sup" href="#footnote-32">†</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">158 (52%)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">191 (64%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">  Failure due to:</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Proven/Probable IFI</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14 (5%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">33 (11%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(<span class="Italics">Aspergillus</span>)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">26 (9%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(<span class="Italics">Candida</span>)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 (3%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (1%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">(Other)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    All Deaths</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44 (14%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">64 (21%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First">Proven/probable fungal infection prior to death</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (1%)</p> </td><td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16 (5%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">    SAF<a class="Sup" href="#footnote-33">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">98 (32%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">125 (42%)</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">    Event free lost <br/>to follow-up<a class="Sup" href="#footnote-34" name="footnote-reference-34">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">34 (11%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24 (8%)</p> </td> </tr> </tbody> </table></div>

In summary, 2 clinical studies of prophylaxis were conducted with the posaconazole oral suspension. As seen in the accompanying tables (Tables 32 and 33), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Posaconazole Oral Suspension Study 1 (Table 32), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole–comparator -11.5% to 3.7%) while in Posaconazole Oral Suspension Study 2 (Table 33) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole–comparator -22.9% to -7.8%).

All-cause mortality was similar at 16 weeks for both treatment arms in Posaconazole Oral Suspension Study 1 [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in Posaconazole Oral Suspension Study 2 [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated substantially fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.

Posaconazole Oral Suspension Study 3 was a randomized, controlled, evaluator-blinded study in HIV-infected patients with oropharyngeal candidiasis. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).

Clinical and mycological outcomes were assessed after 14 days of treatment and at 4 weeks after the end of treatment. Patients who received at least 1 dose of study medication and had a positive oral swish culture of Candida species at baseline were included in the analyses (see Table 34). The majority of the subjects had C. albicans as the baseline pathogen.

Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms) and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) 4 weeks after the end of treatment were similar between the treatment arms (see Table 34).

Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also similar between the treatment arms (see Table 34).

Table 34: Posaconazole Oral Suspension Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal Candidiasis

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="70%"/> <col width="15%"/> <col width="15%"/> <thead> <tr> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Posaconazole</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Fluconazole</span></th> </tr> </thead> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Clinical Success at End of Therapy (Day 14)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">155/169 (91.7%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">148/160 (92.5%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Clinical Relapse (4 Weeks after End of Therapy)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">45/155 (29.0%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">52/148 (35.1%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Mycological Eradication (Absence of CFU) at End of Therapy (Day 14)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">88/169 (52.1%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">80/160 (50.0%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Mycological Relapse (4 Weeks after End of Treatment)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">49/88 (55.6%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">51/80 (63.7%)</p> </td> </tr> </tbody> </table></div>

Mycologic response rates, using a criterion for success as a posttreatment quantitative culture with ≤20 colony forming units (CFU/mL) were also similar between the two groups (posaconazole 68.0%, fluconazole 68.1%). The clinical significance of this finding is unknown.

Posaconazole Oral Suspension Study 4 was a noncomparative study of posaconazole oral suspension in HIV-infected subjects with OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was considered refractory if there was failure to improve or worsening of OPC after a standard course of therapy with fluconazole greater than or equal to 100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with posaconazole. Of the 199 subjects enrolled in this study, 89 subjects met these strict criteria for refractory infection.

Forty-five subjects with refractory OPC were treated with posaconazole oral suspension 400 mg twice daily for 3 days, followed by 400 mg once daily for 25 days with an option for further treatment during a 3-month maintenance period. Following a dosing amendment, a further 44 subjects were treated with posaconazole 400 mg twice daily for 28 days. The efficacy of posaconazole was assessed by the clinical success (cure or improvement) rate after 4 weeks of treatment. The clinical success rate was 74.2% (66/89). The clinical success rates for both the original and the amended dosing regimens were similar (73.3% and 75.0%, respectively).

Posaconazole Oral Suspension

Posaconazole oral suspension is available as a white to off-white, cherry brandy flavored suspension in 4-ounce (120 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL).

NDC 0054-0449-49: Bottle of 105 mL

Supplied with each oral suspension bottle is a plastic dosing spoon calibrated for measuring 2.5-mL and 5-mL doses.

Store at 20° to 25°C (68° to 77°F); [See USP Controlled Room Temperature.]

DO NOT FREEZE.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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Important Administration Instructions

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Advise patients to take each dose of posaconazole oral suspension during or immediately (i.e., within 20 minutes) following a full meal. In patients who cannot eat a full meal, each dose of posaconazole oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in order to enhance absorption.

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Instruct patients that if they miss a dose, they should take it as soon as they remember. However, if it is almost time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

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Drug Interactions

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Advise patients to inform their physician immediately if they:

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Serious and Potentially Serious Adverse Reactions

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Advise patients to inform their physician immediately if they:

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The trademarks referenced herein are owned by their respective companies.

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Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50000256/06 Revised December 2024

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Posaconazole Oral Suspension

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(poe’ sa kon’ a zole)

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Rx only

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What is posaconazole oral suspension?

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Posaconazole oral suspension is a prescription medicine used in adults and children to help prevent or treat fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Posaconazole is used in people who have an increased chance of getting these infections due to a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a low white blood cell count due to chemotherapy for blood cancers (hematologic malignancies).

{ "type": "p", "children": [], "text": "Posaconazole oral suspension is a prescription medicine used in adults and children to help prevent or treat fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Posaconazole is used in people who have an increased chance of getting these infections due to a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a low white blood cell count due to chemotherapy for blood cancers (hematologic malignancies)." }

Posaconazole oral suspension is used for:

{ "type": "p", "children": [], "text": "\nPosaconazole oral suspension is used for: " }

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Posaconazole oral suspension is also used to treat a fungal infection called "thrush" caused by Candida in your mouth or throat area. Posaconazole oral suspension can be used as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked.

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Posaconazole oral suspension is for adults and children over 13 years of age and older.

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Who should not take posaconazole oral suspension?

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Do not take posaconazole if you:

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Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. Do not start taking a new medicine without talking to your healthcare provider or pharmacist.

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What should I tell my healthcare provider before taking posaconazole oral suspension?

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Before you take posaconazole, tell your healthcare provider if you:

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Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Posaconazole can affect the way other medicines work, and other medicines can affect the way posaconazole works, and can cause serious side effects.

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Especially tell your healthcare provider if you take:

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Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.

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

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How will I take posaconazole oral suspension?

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Figure A

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Figure B

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

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

Follow the instructions from your healthcare provider on how much posaconazole you should take and when to take it.

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What are the possible side effects of posaconazole oral suspension?

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Posaconazole may cause serious side effects, including:

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

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The most common side effects of posaconazole include:

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If you take posaconazole oral suspension, tell your healthcare provider right away if you have diarrhea or vomiting.

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

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

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

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store posaconazole oral suspension?

{ "type": "p", "children": [], "text": "\nHow should I store posaconazole oral suspension?\n" }

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

Safely throw away medicine that is out of date or no longer needed.

{ "type": "p", "children": [], "text": "Safely throw away medicine that is out of date or no longer needed." }

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

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

General information about the safe and effective use of posaconazole.

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

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

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

What are the ingredients in posaconazole oral suspension?

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Active ingredient: posaconazole Inactive ingredients: cherry-brandy flavor, citric acid monohydrate, hydroxyethyl cellulose, glycerin, polyoxyl 35 castor oil, simethicone emulsion, sodium benzoate, sodium citrate, sorbitol solution, titanium dioxide, and water.

{ "type": "p", "children": [], "text": "\nActive ingredient: posaconazole\nInactive ingredients: cherry-brandy flavor, citric acid monohydrate, hydroxyethyl cellulose, glycerin, polyoxyl 35 castor oil, simethicone emulsion, sodium benzoate, sodium citrate, sorbitol solution, titanium dioxide, and water." }

The trademarks depicted in this piece are owned by their respective companies.

{ "type": "p", "children": [], "text": "The trademarks depicted in this piece are owned by their respective companies." }

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

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

Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50000256/06 Revised December 2024

{ "type": "p", "children": [], "text": "Distributed by: \nHikma Pharmaceuticals USA Inc.\nBerkeley Heights, NJ 07922\n\nC50000256/06 Revised December 2024\n" }

NDC 0054-0449-49105 mL Posaconazole Oral Suspension 200 mg/5 mL Each mL contains 40 mg posaconazole. Rx Only

{ "type": "p", "children": [], "text": "\nNDC 0054-0449-49105 mL\n\nPosaconazole Oral Suspension\n\n\n200 mg/5 mL \nEach mL contains 40 mg posaconazole. \n\nRx Only\n" }

NDC 0054-0449-49105 mL Posaconazole Oral Suspension 200 mg/5 mL Each mL contains 40 mg posaconazole. Rx Only

{ "type": "p", "children": [], "text": "\nNDC 0054-0449-49105 mL\n\nPosaconazole Oral Suspension\n\n\n200 mg/5 mL \nEach mL contains 40 mg posaconazole. \n\nRx Only\n" }

Posaconazole is indicated for the prophylaxis of invasive Aspergillusand Candidainfections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies ( 14.1)] as follows: • Posaconazole injection:adults and pediatric patients 2 years of age and older.

Posaconazole Injection • Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes [see Dosage and Administration (2.4)] . • If a central venous catheter is not available, posaconazole injection may be administered through a peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other intravenous treatment. • When multiple dosing is required, the infusion should be done via a central venous line. • Do NOTadminister posaconazole injection as an intravenous bolus injection.

Table 1: Dosing Regimens in Adult Patients

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Indication</span> <br/> </td><td align="justify" class="Rrule" valign="top"><span class="Bold">Dose and Frequency</span> <br/> </td><td align="justify" class="Rrule" valign="top"><span class="Bold">Duration of Therapy</span> <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">  <br/>   <br/>   <br/> Prophylaxis of invasive <br/> <span class="Italics">Aspergillus</span>and <span class="Italics">Candida</span> <br/> infections <br/> </td><td align="justify" class="Rrule" valign="top"><span class="Bold">Posaconazole Injection:</span> <br/> <span class="Underline">Loading dose:</span> <br/> 300 mg Posaconazole injection intravenously <br/> twice a day on the first <br/> day. <br/> <span class="Underline">Maintenance dose:</span> <br/> 300 mg posaconazole <br/> injection intravenously <br/> once a day, thereafter. <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> <span class="Underline">Loading dose:</span> <br/> 1 day <br/> <span class="Underline">Maintenance dose:</span> <br/> Duration of therapy is <br/> based on recovery from <br/> neutropenia or <br/> immunosuppression. <br/> </td> </tr> </tbody> </table></div>

The recommended dosing regimen of posaconazole injection for pediatric patients 2 to less than 18 years of age is shown in Table 2[see Clinical Pharmacology (12.3)]. Table 2: Posaconazole Injection Dosing Regimens for Pediatric Patients (ages 2 to less than 18 years of age)

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="817.95"> <col width="20.4878048780488%"/> <col width="20.3252032520325%"/> <col width="37.7235772357724%"/> <col width="21.4634146341463%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"> <br/>   </td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold"><span class="Underline">Recommended Pediatric Dosage and Formulation</span></span></td><td align="justify" class="Rrule" valign="top"> <br/>   </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold"><span class="Underline">Indication</span></span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold"><span class="Underline">Weight/Age</span></span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold"><span class="Underline">Injection</span></span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold"><span class="Underline">Duration of therapy</span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> Prophylaxis of <br/> invasive <span class="Italics">Aspergillus</span> <br/> and <span class="Italics">Candida</span> <br/> infections </td><td align="justify" class="Rrule" valign="top"> <br/> Less than or equal <br/> to 40 kg (2 to less <br/> than 18 years of <br/> age) </td><td align="justify" class="Rrule" rowspan="2" valign="top"> <br/> <span class="Underline">Loading dose:</span> <br/> 6 mg/kg up to a maximum of 300 mg twice daily on the first day <br/> <span class="Underline">Maintenance dose:</span> <br/> 6 mg/kg up to a maximum of 300 mg once daily </td><td align="justify" class="Rrule" rowspan="2" valign="top"> <br/> Duration of therapy is based on recovery from neutropenia or <br/> immunosuppression. </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Greater than 40 kg <br/> (2 to less than 18 <br/> years of age) </td> </tr> </tbody> </table></div>

Preparation: • Equilibrate the refrigerated vial of posaconazole injection to room temperature.  • To prepare the required dose, aseptically transfer one vial (16.7 mL) of posaconazole injection (containing 300 mg of posaconazole in solution) to an intravenous bag (or bottle) of a compatible admixture diluent (as described in Table 5), to achieve a final concentration of posaconazole that is between 1 mg/mL and 2 mg/mL. Use of other diluents is not recommended because they may result in particulate formation. • Posaconazole injection is a single-dose sterile solution without preservatives. Discard any unused portion from the vial. • Once admixed, the diluted solution of posaconazole in the intravenous bag (or bottle) should be used immediately. If not used immediately, the solution can be stored up to 24 hours refrigerated 2 to 8°C (36 to 46°F). Discard any unused portion. • Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Once admixed, the solution of posaconazole ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product. Intravenous Line Compatibility: A study was conducted to evaluate physical compatibility of posaconazole injection with injectable drug products and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined through visual observations, measurement of particulate matter and turbidity. Compatible diluents and drug products are listed in Tables 5 and 6below. Any diluents or drug products not listed in the tables below should not be co-administered through the same intravenous line (or cannula). • Posaconazole injection can be infused at the same time through the same intravenous line (or cannula) with the following compatible diluents: Table 5: Compatible Diluents

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="426.93"> <col width="100%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 0.45% sodium chloride </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 0.9% sodium chloride </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 5% dextrose in water </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 5% dextrose and 0.45% sodium chloride </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 5% dextrose and 0.9% sodium chloride </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 5% dextrose and 20 mEq potassium chloride </td> </tr> </tbody> </table></div>

• Posaconazole injection can be infused at the same time through the same intravenous line (or cannula) with the following drug products prepared in 5% dextrose in water or sodium chloride 0.9%. Coadministration of drug products prepared in other diluents may result in particulate formation. Table 6: Compatible Drugs

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="422.94"> <col width="100%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Amikacin sulfate </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Caspofungin </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Ciprofloxacin </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Daptomycin </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Dobutamine hydrochloride </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Famotidine </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Filgrastim </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Gentamicin sulfate </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Hydromorphone hydrochloride </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Levofloxacin </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Lorazepam </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Meropenem </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Micafungin </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Morphine sulfate </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Norepinephrine bitartrate </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Potassium chloride </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Vancomycin hydrochloride </td> </tr> </tbody> </table></div>

Incompatible Diluents: Posaconazole injection must not be diluted with the following diluents: Lactated Ringer’s solution 5% dextrose with Lactated Ringer’s solution 4.2% sodium bicarbonate Administration: • Posaconazole injection must be administered through a 0.22-micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter. • Administer via a central venous line, including a central venous catheter or PICC by slow infusion over approximately 90 minutes. Posaconazole injection is not for bolus administration. • If a central venous catheter is not available, posaconazole injection may be administered through a peripheral venous catheter only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other treatment. • When multiple dosing is required, the infusion should be done via a central venous line. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes. Note: In clinical trials, multiple peripheral infusions given through the same vein resulted in infusion site reactions [see Adverse Reactions (6.1)].

• Posaconazole injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole injection. • In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), receiving the posaconazole injection, accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral posaconazole therapy.

Posaconazole injection Posaconazole injection (300 mg per vial) is available as a clear, colorless to yellow sterile liquid in a single-dose vial.

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Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.

Posaconazole is contraindicated with sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)] .

Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see Warnings and Precautions (5.2)and Drug Interactions (7.2)] .

Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)] .

Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see  Drug Interactions (7.4)] .

Coadministration of posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Warnings and Precautions (5.11) and Drug Interactions (7.16)] .

Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)] . Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole.  Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18 to 85 years of age) administered Noxafil oral suspension 400 mg twice daily with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.  Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see  Contraindications (4.3)and Drug Interactions (7.2)] .

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.

Pseudoaldosteronism,manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11-deoxycortisol), has beenreported with posaconazole use in the postmarket setting. Monitor blood pressure and potassium levels and manage as necessary. Managementof pseudoaldosteronism may include discontinuation of Noxafil, substitution with an appropriate antifungal drug that is not associatedwith pseudoaldosteronism, or use of aldosterone receptor antagonists.

Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the Noxafil oral suspension 800 mg daily (400 mg twice daily or 200 mg four times a day) in clinical trials. Liver tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.

Posaconazole injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the posaconazole injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral posaconazole therapy [see Dosage and Administration (2.9) and Use in Specific Populations (8.6)] .

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)] .

Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.10)] .

Concomitant administration of posaconazole, a strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of posaconazole during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications (4.6)] . Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax [see Drug Interactions (7.16)] . Refer to the venetoclax prescribing information for dosing instructions.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trial Experience in Adults Clinical Trial Experience with Posaconazole Injection for Prophylaxis Multiple doses of posaconazole injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, posaconazole injection was administered via central venous catheter. The safety of posaconazole injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole injection when given as antifungal prophylaxis (Posaconazole Injection Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18 to 82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single dose of 200 mg posaconazole injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days. Table 8presents adverse reactions observed in patients treated with posaconazole injection 300 mg daily dose in the posaconazole Injection Study. Each patient received a loading dose, 300 mg twice on Day 1. Following posaconazole intravenous therapy, patients received Noxafil oral suspension to complete 28 days of total posaconazole therapy. Table 8: Posaconazole Injection Study: Adverse Reactions in at Least 10% of Subjects Treated with Posaconazole Injection 300 mg Daily Dose

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="798"> <colgroup> <col width="40.8333333333333%"/> <col width="15.3333333333333%"/> <col width="14.5%"/> <col width="14.6666666666667%"/> <col width="14.6666666666667%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold"><span class="Italics">Body System</span></span></td><td align="justify" class="Rrule" colspan="3" valign="top"><span class="Bold">Posaconazole</span> <br/> <span class="Bold">Injection</span> <br/> <span class="Bold">Treatment Phase</span> <br/> <span class="Bold">n=237 (%) <span class="Sup">*</span></span></td><td align="justify" class="Rrule" colspan="3" valign="top"><span class="Bold">Posaconazole</span> <br/> <span class="Bold">Injection</span> <br/> <span class="Bold">Treatment Phase</span> <br/> <span class="Bold">or</span> <br/> <span class="Bold">Subsequent</span> <br/> <span class="Bold">Noxafil Oral</span> <br/> <span class="Bold">Suspension</span> <br/> <span class="Bold">Treatment Phase</span> <br/> <span class="Bold">n=237 (%) <span class="Sup">†</span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Subjects Reporting any Adverse <br/> Reaction </td><td align="justify" class="Rrule" colspan="2" valign="top">220</td><td align="justify" class="Rrule" valign="top">(93)</td><td align="justify" class="Rrule" valign="top">235</td><td align="justify" class="Rrule" colspan="2" valign="top">(99)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top"><span class="Italics">Blood and Lymphatic System Disorder</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Anemia</td><td align="justify" class="Rrule" valign="top">16</td><td align="justify" class="Rrule" colspan="2" valign="top">(7)</td><td align="justify" class="Rrule" colspan="2" valign="top">23</td><td align="justify" class="Rrule" valign="top">(10)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Thrombocytopenia</td><td align="justify" class="Rrule" valign="top">17</td><td align="justify" class="Rrule" colspan="2" valign="top">(7)</td><td align="justify" class="Rrule" colspan="2" valign="top">25</td><td align="justify" class="Rrule" valign="top">(11)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top"><span class="Italics">Gastrointestinal Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Abdominal Pain Upper</td><td align="justify" class="Rrule" colspan="2" valign="top">15</td><td align="justify" class="Rrule" valign="top">(6)</td><td align="justify" class="Rrule" colspan="2" valign="top">25</td><td align="justify" class="Rrule" valign="top">(11)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Abdominal Pain</td><td align="justify" class="Rrule" colspan="2" valign="top">30</td><td align="justify" class="Rrule" valign="top">(13)</td><td align="justify" class="Rrule" colspan="2" valign="top">41</td><td align="justify" class="Rrule" valign="top">(17)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Constipation</td><td align="justify" class="Rrule" colspan="2" valign="top">18</td><td align="justify" class="Rrule" valign="top">(8)</td><td align="justify" class="Rrule" colspan="2" valign="top">31</td><td align="justify" class="Rrule" valign="top">(13)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Diarrhea</td><td align="justify" class="Rrule" colspan="2" valign="top">75</td><td align="justify" class="Rrule" valign="top">(32)</td><td align="justify" class="Rrule" colspan="2" valign="top">93</td><td align="justify" class="Rrule" valign="top">(39)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Nausea</td><td align="justify" class="Rrule" colspan="2" valign="top">46</td><td align="justify" class="Rrule" valign="top">(19)</td><td align="justify" class="Rrule" colspan="2" valign="top">70</td><td align="justify" class="Rrule" valign="top">(30)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Vomiting</td><td align="justify" class="Rrule" colspan="2" valign="top">29</td><td align="justify" class="Rrule" valign="top">(12)</td><td align="justify" class="Rrule" colspan="2" valign="top">45</td><td align="justify" class="Rrule" valign="top">(19)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top"><span class="Italics">General Disorders and Administration Site Conditions</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Fatigue</td><td align="justify" class="Rrule" colspan="2" valign="top">19</td><td align="justify" class="Rrule" valign="top">(8)</td><td align="justify" class="Rrule" colspan="2" valign="top">24</td><td align="justify" class="Rrule" valign="top">(10)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Chills</td><td align="justify" class="Rrule" colspan="2" valign="top">28</td><td align="justify" class="Rrule" valign="top">(12)</td><td align="justify" class="Rrule" colspan="2" valign="top">38</td><td align="justify" class="Rrule" valign="top">(16)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Edema Peripheral</td><td align="justify" class="Rrule" colspan="2" valign="top">28</td><td align="justify" class="Rrule" valign="top">(12)</td><td align="justify" class="Rrule" colspan="2" valign="top">35</td><td align="justify" class="Rrule" valign="top">(15)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Pyrexia</td><td align="justify" class="Rrule" colspan="2" valign="top">49</td><td align="justify" class="Rrule" valign="top">(21)</td><td align="justify" class="Rrule" colspan="2" valign="top">73</td><td align="justify" class="Rrule" valign="top">(31)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top"><span class="Italics">Metabolism and Nutrition Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Decreased appetite</td><td align="justify" class="Rrule" colspan="2" valign="top">23</td><td align="justify" class="Rrule" valign="top">(10)</td><td align="justify" class="Rrule" colspan="2" valign="top">29</td><td align="justify" class="Rrule" valign="top">(12)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Hypokalemia</td><td align="justify" class="Rrule" colspan="2" valign="top">51</td><td align="justify" class="Rrule" valign="top">(22)</td><td align="justify" class="Rrule" colspan="2" valign="top">67</td><td align="justify" class="Rrule" valign="top">(28)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Hypomagnesemia</td><td align="justify" class="Rrule" colspan="2" valign="top">25</td><td align="justify" class="Rrule" valign="top">(11)</td><td align="justify" class="Rrule" colspan="2" valign="top">30</td><td align="justify" class="Rrule" valign="top">(13)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top"><span class="Italics">Nervous System Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Headache</td><td align="justify" class="Rrule" colspan="2" valign="top">33</td><td align="justify" class="Rrule" valign="top">(14)</td><td align="justify" class="Rrule" colspan="2" valign="top">49</td><td align="justify" class="Rrule" valign="top">(21)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top"><span class="Italics">Respiratory, Thoracic and Mediastinal Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Cough</td><td align="justify" class="Rrule" colspan="2" valign="top">21</td><td align="justify" class="Rrule" valign="top">(9)</td><td align="justify" class="Rrule" colspan="2" valign="top">31</td><td align="justify" class="Rrule" valign="top">(13)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Dyspnea</td><td align="justify" class="Rrule" colspan="2" valign="top">16</td><td align="justify" class="Rrule" valign="top">(7)</td><td align="justify" class="Rrule" colspan="2" valign="top">24</td><td align="justify" class="Rrule" valign="top">(10)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Epistaxis</td><td align="justify" class="Rrule" colspan="2" valign="top">34</td><td align="justify" class="Rrule" valign="top">(14)</td><td align="justify" class="Rrule" colspan="2" valign="top">40</td><td align="justify" class="Rrule" valign="top">(17)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top"><span class="Italics">Skin and Subcutaneous Tissue Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Petechiae</td><td align="justify" class="Rrule" colspan="2" valign="top">20</td><td align="justify" class="Rrule" valign="top">(8)</td><td align="justify" class="Rrule" colspan="2" valign="top">24</td><td align="justify" class="Rrule" valign="top">(10)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Rash</td><td align="justify" class="Rrule" colspan="2" valign="top">35</td><td align="justify" class="Rrule" valign="top">(15)</td><td align="justify" class="Rrule" colspan="2" valign="top">56</td><td align="justify" class="Rrule" valign="top">(24)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top"><span class="Italics">Vascular Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Hypertension</td><td align="justify" class="Rrule" colspan="2" valign="top">20</td><td align="justify" class="Rrule" valign="top">(8)</td><td align="justify" class="Rrule" colspan="2" valign="top"> <br/> 26 </td><td align="justify" class="Rrule" valign="top">(11)</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top"> <br/> *Adverse reactions reported in patients with an onset during the posaconazole intravenous dosing phase of the study. <br/> <span class="Sup">†</span>Adverse reactions reported with an onset at any time during the study in patients who were treated for up to 28 days of posaconazole therapy. </td> </tr> </tbody> </table></div>

The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil oral suspension.

Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of posaconazole are listed below: • Blood and lymphatic system disorders:hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated • Endocrine disorders:adrenal insufficiency • Nervous system disorders:paresthesia • Immune system disorders:allergic reaction [see Contraindications (4.1)] • Cardiac disorders:torsades de pointes [see Warnings and Precautions (5.2)] • Vascular disorders:pulmonary embolism • Gastrointestinal disorders:pancreatitis • Liver and Biliary System Disorders:hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice • Renal & Urinary System Disorders:renal failure acute Clinical Trial Experience in Pediatrics Clinical Trial Experience in Pediatric Patients (2 to less than 18 Years of Age) The safety of posaconazole injection and Noxafil PowderMix for delayed-release oral suspension for prophylaxis of invasive fungal infections has been assessed in an open label uncontrolled dose-ranging PK and safety study (Posaconazole injection/ Noxafil PowderMix for delayed-release oral suspension Pediatric Study 1, NCT02452034); hereinafter referred to as Posaconazole Pediatric Study) in 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia. Posaconazole injection and Noxafil PowderMix for delayed-release oral suspension was administered at daily doses of up to 6 mg/kg (twice daily on day 1) in three dose cohorts. All 115 subjects initially received posaconazole injection for at least 7 days, and 63 subjects were transitioned to Noxafil PowderMix for delayed-release oral suspension. The mean overall treatment duration for all treated subjects was 20.6 days with 14.3 days (range: 1 to 28 days) on posaconazole injection and 11.6 days (range: 2 to 18 days) on Noxafil PowderMix for delayed-release oral suspension [see Clinical Pharmacology (12.3)]. Table 15presents adverse reactions observed in greater than or equal to 10% of pediatric patients treated with posaconazole in the Posaconazole Pediatric Study. Reported adverse reaction profile of posaconazole in pediatric patients was consistent with the safety profile of posaconazole in adults. The most common adverse reactions (occurring in greater than 20% of pediatric patients receiving 6 mg/kg posaconazole injection and Noxafil PowderMix for delayed-release oral suspension daily dose) were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis. Table 15: Adverse Reactions in at Least 10% of Pediatric Patients Treated with Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="798"> <colgroup> <col width="33.3333333333333%"/> <col width="33.3333333333333%"/> <col width="33.3333333333333%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Adverse Reaction</span></td><td align="justify" class="Rrule" valign="top"><span class="Bold">Posaconazole Injection</span> <br/> <span class="Bold">and</span> <br/> <span class="Bold">Noxafil PowderMix for</span> <br/> <span class="Bold">Delayed-Release Oral</span> <br/> <span class="Bold">Suspension</span> <br/> <span class="Bold">6 mg/kg Dose Cohort</span> <br/> <span class="Bold">n=49 (%)</span></td><td align="justify" class="Rrule" valign="top"><span class="Bold">Posaconazole Injection</span> <br/> <span class="Bold">and</span> <br/> <span class="Bold">Noxafil PowderMix for</span> <br/> <span class="Bold">Delayed-Release Oral</span> <br/> <span class="Bold">Suspension</span> <br/> <span class="Bold">All Dose Cohorts</span> <br/> <span class="Bold">n=115 (%)</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Pyrexia</td><td align="justify" class="Rrule" valign="top">16 (33)</td><td align="justify" class="Rrule" valign="top">50 (43)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Febrile neutropenia</td><td align="justify" class="Rrule" valign="top">15 (31)</td><td align="justify" class="Rrule" valign="top">25 (22)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Vomiting</td><td align="justify" class="Rrule" valign="top">12 (24)</td><td align="justify" class="Rrule" valign="top">30 (26)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Mucosal inflammation</td><td align="justify" class="Rrule" valign="top">11 (22)</td><td align="justify" class="Rrule" valign="top">32 (28)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Pruritus</td><td align="justify" class="Rrule" valign="top">11 (22)</td><td align="justify" class="Rrule" valign="top">18 (16)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Hypertension</td><td align="justify" class="Rrule" valign="top">10 (20)</td><td align="justify" class="Rrule" valign="top">20 (17)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Hypokalemia</td><td align="justify" class="Rrule" valign="top">10 (20)</td><td align="justify" class="Rrule" valign="top">16 (14)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Stomatitis</td><td align="justify" class="Rrule" valign="top">10 (20)</td><td align="justify" class="Rrule" valign="top">13 (11)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Diarrhea</td><td align="justify" class="Rrule" valign="top">9 (18)</td><td align="justify" class="Rrule" valign="top">25 (22)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Nausea</td><td align="justify" class="Rrule" valign="top">9 (18)</td><td align="justify" class="Rrule" valign="top">18 (16)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Abdominal pain</td><td align="justify" class="Rrule" valign="top">8 (16)</td><td align="justify" class="Rrule" valign="top">20 (17)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Decreased appetite</td><td align="justify" class="Rrule" valign="top">7 (14)</td><td align="justify" class="Rrule" valign="top">17 (15)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Rash</td><td align="justify" class="Rrule" valign="top">7 (14)</td><td align="justify" class="Rrule" valign="top">18 (16)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Alanine aminotransferase increased</td><td align="justify" class="Rrule" valign="top">6 (12)</td><td align="justify" class="Rrule" valign="top">8 (7)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Headache</td><td align="justify" class="Rrule" valign="top">6 (12)</td><td align="justify" class="Rrule" valign="top">16 (14)</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Aspartate aminotransferase increased</td><td align="justify" class="Rrule" valign="top">5 (10)</td><td align="justify" class="Rrule" valign="top">8 (7)</td> </tr> </tbody> </table></div>

The number of patients receiving posaconazole in the Posaconazole Pediatric Study who had changes in liver tests from Grade 0, 1, or 2 at baseline to Grade 3 or 4 is presented in Table 16.

Table 16: Posaconazole Pediatric Study: Changes in Liver Tests from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="799.33"> <colgroup> <col width="48.7520798668885%"/> <col width="51.2479201331115%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Number (%) of Patients with Change*</span> <br/> <span class="Bold">Pediatric Study 1</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Laboratory Parameter</td><td align="justify" class="Rrule" valign="top"><span class="Bold">Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension (6 mg/kg daily)</span> <br/> <span class="Bold">n=49 (%)</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">AST</td><td align="justify" class="Rrule" valign="top">2/49 (4)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">ALT</td><td align="justify" class="Rrule" valign="top">3/49 (6)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Bilirubin</td><td align="justify" class="Rrule" valign="top">0/48 (0)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Alkaline Phosphatase</td><td align="justify" class="Rrule" valign="top">0/48 (0)</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Sup">*</span>Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation. <br/> CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; <br/> ALT= Alanine Aminotransferase </td> </tr> </tbody> </table></div>

The following adverse reaction has been identified during the post-approval use of posaconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. Endocrine Disorders:Pseudoaldosteronism

Sirolimus:Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3)] .

Tacrolimus:Posaconazole has been shown to significantly increase the C maxand AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] .

Cyclosporine:Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and  Clinical Pharmacology (12.3)] .

Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications (4.3) and Warnings and Precautions (5.2)] .

Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 [see Contraindications (4.4) and Clinical Pharmacology (12.3)] .

Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids [see Contraindications (4.5)] .

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)] . 

Efavirenz:Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3)] . It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks. Ritonavir and Atazanavir:Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see Clinical Pharmacology (12.3)] . Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.      Fosamprenavir:Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see Clinical Pharmacology (12.3)] .

Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations [see Clinical Pharmacology (12.3)] . Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.

Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see Clinical Pharmacology (12.3)] . Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.

Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole injection, with vincristine has been associated with serious adverse reactions [see Warnings and Precautions (5.8)] . Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole injection, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.

Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.

Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.

Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax C maxand AUC 0-INF, which may increase venetoclax toxicities [see Contraindications (4.6), Warnings and Precautions (5.11)] . Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

Risk Summary Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses 5 times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of ≥ 3 times the clinical exposure caused an increase in resorptions in these rabbits (see Data). Based on animal 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. 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 Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.

Risk Summary There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition.

The safety and effectiveness of posaconazole injectionfor the prophylaxis of invasive Aspergillusand Candidainfections have been established in pediatric patients aged 2 and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 2 years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)]. The safety and effectiveness of posaconazole have not been established in pediatric patients younger than 2 years of age.

No overall differences in the safety of posaconazole injectionwas observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of posaconazole in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)] . Of the 279 patients treated with posaconazole injectionin the

posaconazole Injection Study, 52 (19%) were greater than 65 years of age.

No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

Posaconazole injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the posaconazole injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral posaconazole therapy [see Dosage and Administration (2.9) and Warnings and Precautions (5.6)] .

It is recommended that no dose adjustment of posaconazole injection is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2)  and Warnings and Precautions (5.5)] . However, a specific study has not been conducted with posaconazole injection.

The pharmacokinetics of posaconazole are comparable in males and females. No adjustment in the dosage of posaconazole is necessary based on gender.

The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of posaconazole is necessary based on race.

Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections [see Clinical Pharmacology (12.3)] .

There is no experience with overdosage of posaconazole injection.  During the clinical trials, some patients received Noxafil oral suspension up to 1,600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1,200 mg twice daily Noxafil oral suspension for 3 days. No related adverse reactions were noted by the investigator. Posaconazole is not removed by hemodialysis.

{ "type": "p", "children": [], "text": "There is no experience with overdosage of posaconazole injection.  \n During the clinical trials, some patients received Noxafil oral suspension up to 1,600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1,200 mg twice daily Noxafil oral suspension for 3 days. No related adverse reactions were noted by the investigator. \n Posaconazole is not removed by hemodialysis.\n " }

Posaconazole is an azole antifungal agent. Posaconazole is available as an injection solution to be diluted before intravenous administration. Posaconazole is designated chemically as 4-[4-[4-[4-[[(3 R, 5 R)-5-(2,4-difluoro phenyl) tetrahydro-5-(1 H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl] -2-[(1 S,2 S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3 H-1,2,4-triazol-3-one with an molecular formula of C 37H 42 F 2N 8O 4and a molecular weight of 700.79. The chemical structure is:

{ "type": "p", "children": [], "text": "Posaconazole is an azole antifungal agent. Posaconazole is available as an injection solution to be diluted before intravenous administration. \n Posaconazole is designated chemically as 4-[4-[4-[4-[[(3\n \n R, 5\n \n R)-5-(2,4-difluoro phenyl) tetrahydro-5-(1\n \n H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl] -2-[(1\n \n S,2\n \n S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3\n \n H-1,2,4-triazol-3-one with an molecular formula of C\n \n 37H\n \n 42 F\n \n 2N\n \n 8O\n \n 4and a molecular weight of 700.79. The chemical structure is:\n\n " }

Posaconazole is an off-white to white powder, slightly soluble in methanol and sparingly soluble in dimethyl sulfoxide. Posaconazole injection is available as a clear colorless to yellow, sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g betadex sulfobutyl ether sodium (SBECD), 0.0033 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection.

{ "type": "p", "children": [], "text": "Posaconazole is an off-white to white powder, slightly soluble in methanol and sparingly soluble in dimethyl sulfoxide. \n Posaconazole injection is available as a clear colorless to yellow, sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g betadex sulfobutyl ether sodium (SBECD), 0.0033 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection.\n " }

Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)] .

Exposure Response Relationship Prophylaxis:In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), a wide range of plasma exposures to posaconazole was noted following administration of Noxafil oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 17).A lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections. Table 17: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="798"> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> </td><td align="justify" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Prophylaxis in AML/MDS <span class="Sup">*</span></span></td><td align="justify" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Prophylaxis in GVHD <span class="Sup">†</span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Cavg Range (ng/mL) </td><td align="justify" class="Rrule" valign="top"> <br/> Treatment Failure <span class="Sup">‡</span>(%) </td><td align="justify" class="Rrule" valign="top"> <br/> Cavg Range (ng/mL) </td><td align="justify" class="Rrule" valign="top"> <br/> Treatment Failure <span class="Sup">‡</span> <br/> (%) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Quartile 1 </td><td align="justify" class="Rrule" valign="top"> <br/> 90 to 322 </td><td align="justify" class="Rrule" valign="top"> <br/> 54.7 </td><td align="justify" class="Rrule" valign="top"> <br/> 22 to 557 </td><td align="justify" class="Rrule" valign="top"> <br/> 44.4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Quartile 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 322 to 490 </td><td align="justify" class="Rrule" valign="top"> <br/> 37 </td><td align="justify" class="Rrule" valign="top"> <br/> 557 to 915 </td><td align="justify" class="Rrule" valign="top"> <br/> 20.6 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Quartile 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 490 to 734 </td><td align="justify" class="Rrule" valign="top"> <br/> 46.8 </td><td align="justify" class="Rrule" valign="top"> <br/> 915 to 1,563 </td><td align="justify" class="Rrule" valign="top"> <br/> 17.5 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Quartile 4 </td><td align="justify" class="Rrule" valign="top"> <br/> 734 to 2,200 </td><td align="justify" class="Rrule" valign="top"> <br/> 27.8 </td><td align="justify" class="Rrule" valign="top"> <br/> 1,563 to 3,650 </td><td align="justify" class="Rrule" valign="top"> <br/> 17.5 </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"> <br/> Cavg = the average posaconazole concentration when measured at steady state <br/> <span class="Sup">*</span>Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS <br/> <span class="Sup">†</span>HSCT recipients with GVHD <br/> <span class="Sup">‡</span>Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of <br/> breakthrough invasive fungal infections </td> </tr> </tbody> </table></div>

General Pharmacokinetic Characteristics Posaconazole Injection Posaconazole injection exhibits dose proportional pharmacokinetics after single doses between 200 and 300 mg in healthy volunteers and patients. The mean pharmacokinetic parameters after single doses with posaconazole injection in healthy volunteers and patients are shown in Table 18. Table 18: Summary of Mean Pharmacokinetic Parameters (%CV) in Healthy Volunteers (30-minute infusion via peripheral venous line) and Patients (90 minute infusion via central venous line) after Dosing with Posaconazole Injection on Day 1

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="800.66"> <col width="12.1262458471761%"/> <col width="12.2923588039867%"/> <col width="12.2923588039867%"/> <col width="13.1229235880399%"/> <col width="13.1229235880399%"/> <col width="12.4584717607973%"/> <col width="12.2923588039867%"/> <col width="12.2923588039867%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/>   </td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">Dose (mg)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">n</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">AUC <span class="Sub">0-</span></span><span class="Bold"><span class="Sub">∞</span></span> <br/> <span class="Bold">(ng·hr/mL)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">AUC <span class="Sub">0-12</span></span> <br/> <span class="Bold">(ng·hr/mL)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">C <span class="Sub">max</span></span> <br/> <span class="Bold">(ng/mL)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">t <span class="Sub">1/2</span></span> <br/> <span class="Bold">(hr)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">CL</span> <br/> <span class="Bold">(L/hr)</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> Healthy <br/> Volunteers </td><td align="justify" class="Rrule" valign="top"> <br/> 200 </td><td align="justify" class="Rrule" valign="top"> <br/> 9 </td><td align="justify" class="Rrule" valign="top"> <br/> 35,400 (50) </td><td align="justify" class="Rrule" valign="top"> <br/> 8,840 (20) </td><td align="justify" class="Rrule" valign="top"> <br/> 2,250 (29) </td><td align="justify" class="Rrule" valign="top"> <br/> 23.6 (23) </td><td align="justify" class="Rrule" valign="top"> <br/> 6.5 (32) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 300 </td><td align="justify" class="Rrule" valign="top"> <br/> 9 </td><td align="justify" class="Rrule" valign="top"> <br/> 46,400 (26) </td><td align="justify" class="Rrule" valign="top"> <br/> 13,000 (13) </td><td align="justify" class="Rrule" valign="top"> <br/> 2,840 (30) </td><td align="justify" class="Rrule" valign="top"> <br/> 24.6 (20) </td><td align="justify" class="Rrule" valign="top"> <br/> 6.9 (27) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> Patients </td><td align="justify" class="Rrule" valign="top"> <br/> 200 </td><td align="justify" class="Rrule" valign="top"> <br/> 30 </td><td align="justify" class="Rrule" valign="top"> <br/> N/D </td><td align="justify" class="Rrule" valign="top"> <br/> 5,570 (32) </td><td align="justify" class="Rrule" valign="top"> <br/> 954 (44) </td><td align="justify" class="Rrule" valign="top"> <br/> N/D </td><td align="justify" class="Rrule" valign="top"> <br/> N/D </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 300 </td><td align="justify" class="Rrule" valign="top"> <br/> 22 </td><td align="justify" class="Rrule" valign="top"> <br/> N/D </td><td align="justify" class="Rrule" valign="top"> <br/> 8,240 (26) </td><td align="justify" class="Rrule" valign="top"> <br/> 1,590 (62) </td><td align="justify" class="Rrule" valign="top"> <br/> N/D </td><td align="justify" class="Rrule" valign="top"> <br/> N/D </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="8" valign="top"> <br/> AUC <span class="Sub">0-</span><span class="Sub">∞</span>= Area under the plasma concentration-time curve from time zero to infinity; AUC <span class="Sub">0 to 12</span>= Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; C <span class="Sub">max</span>= maximum observed concentration; t <span class="Sub">½</span>= terminal phase half-life; CL = total body clearance; N/D = Not Determined </td> </tr> </tbody> </table></div>

Table 19displays the pharmacokinetic parameters of posaconazole in patients following administration of posaconazole injection 300 mg taken once a day for 10 or 14 days following twice daily dosing on Day 1. Table 19: Arithmetic Mean (%CV) of PK Parameters in Serial PK-Evaluable Patients Following Dosing of Posaconazole Injection (300 mg)*

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="798"> <col width="9.33333333333333%"/> <col width="4.66666666666667%"/> <col width="18.8333333333333%"/> <col width="17.3333333333333%"/> <col width="17.3333333333333%"/> <col width="18.1666666666667%"/> <col width="14.3333333333333%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Day</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">N</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">C <span class="Sub">max</span></span> <br/> <span class="Bold"><span class="Sub">(ng/mL)</span></span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">T <span class="Sub">max</span><span class="Sup">†</span></span> <br/> <span class="Bold">(hr)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">AUC <span class="Sub">0-24</span></span> <br/> <span class="Bold">(ng*hr/mL)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">Cav</span> <br/> <span class="Bold">(ng/mL)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">C <span class="Sub">min</span></span> <br/> <span class="Bold">(ng/mL)</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 10/14 </td><td align="justify" class="Rrule" valign="top"> <br/> 49 </td><td align="justify" class="Rrule" valign="top"> <br/> 3,280 (74) </td><td align="justify" class="Rrule" valign="top"> <br/> 1.5 (0.98 to 4.0) </td><td align="justify" class="Rrule" valign="top"> <br/> 36,100 (35) </td><td align="justify" class="Rrule" valign="top"> <br/> 1,500 (35) </td><td align="justify" class="Rrule" valign="top"> <br/> 1,090 (44) </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top"> <br/> AUC <span class="Sub">0-24</span>= area under the concentration-time curve over the dosing interval (i.e. 24 hours); Cav= time-averaged concentrations (i.e., AUC <span class="Sub">0-24h</span>/24hr); <br/> C <span class="Sub">min</span>= POS trough level immediately before a subject received the dose of POS on the day specified in the protocol; C <span class="Sub">max</span>= observed maximum plasma concentration; CV = coefficient of variation, expressed as a percent (%); Day = study day on treatment; T <span class="Sub">max</span>= time of observed maximum plasma concentration. <br/> <span class="Sup">*</span>300 mg dose administered over 90 minutes once a day following twice daily dosing on Day 1 <br/> <span class="Sup">†</span>Median (minimum-maximum) </td> </tr> </tbody> </table></div>

Distribution:  The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226 to 295 L between studies and dose levels. Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin. Metabolism: Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27. Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="798"> <col width="20.6666666666667%"/> <col width="20.6666666666667%"/> <col width="21.5%"/> <col width="17.8333333333333%"/> <col width="19.3333333333333%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Coadministered</span> <br/> <span class="Bold">Drug</span> <br/> <span class="Bold">(Postulated</span> <br/> <span class="Bold">Mechanism of</span> <br/> <span class="Bold">Interaction)</span></td><td align="justify" class="Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Coadministered</span> <br/> <span class="Bold">Drug</span> <br/> <span class="Bold">Dose/Schedule</span></td><td align="justify" class="Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Posaconazole</span> <br/> <span class="Bold">Dose/Schedule</span></td><td align="justify" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Effect on Bioavailability</span> <br/> <span class="Bold">of Posaconazole</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Change in</span> <br/> <span class="Bold">Mean</span> <br/> <span class="Bold">C <span class="Sub">max</span></span>(ratio <br/> estimate*; <br/> 90% CI of the <br/> ratio <br/> estimate) </td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">Change in</span> <br/> <span class="Bold">Mean AUC</span> <br/> (ratio <br/> estimate*; <br/> 90% CI of the <br/> ratio <br/> estimate) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Efavirenz <br/> (UDP-G Induction) </td><td align="justify" class="Rrule" valign="top"> <br/> 400 mg once daily <br/> x 10 and 20 days </td><td align="justify" class="Rrule" valign="top"> <br/> 400 mg (oral <br/> suspension) twice <br/> daily x 10 and 20 <br/> days </td><td align="justify" class="Rrule" valign="top"> <br/> ↓ 45% <br/> (0.55; 0.47 to 0.66) </td><td align="justify" class="Rrule" valign="top"> <br/> ↓ 50% <br/> (0.50; 0.43 to 0.60) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Fosamprenavir <br/> (unknown <br/> mechanism) </td><td align="justify" class="Rrule" valign="top"> <br/> 700 mg twice <br/> daily x 10 days </td><td align="justify" class="Rrule" valign="top"> <br/> 200 mg once daily <br/> on the 1 <span class="Sup">st</span>day, 200 <br/> mg twice daily on <br/> the 2 <span class="Sup">nd</span>day, then <br/> 400 mg twice daily x <br/> 8 Days </td><td align="justify" class="Rrule" valign="top"> <br/> ↓ 21% <br/> 0.79 (0.71 to <br/> 0.89) </td><td align="justify" class="Rrule" valign="top"> <br/> ↓ 23% <br/> 0.77 (0.68 to <br/> 0.87) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Rifabutin <br/> (UDP-G Induction) </td><td align="justify" class="Rrule" valign="top"> <br/> 300 mg once daily <br/> x 17 days </td><td align="justify" class="Rrule" valign="top"> <br/> 200 mg (tablets) once <br/> daily × 10 days <span class="Sup">†</span></td><td align="justify" class="Rrule" valign="top"> <br/> ↓ 43% <br/> (0.57; 0.43 to 0.75) </td><td align="justify" class="Rrule" valign="top"> <br/> ↓ 49% <br/> (0.51; 0.37 to 0.71) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Phenytoin <br/> (UDP-G Induction) </td><td align="justify" class="Rrule" valign="top"> <br/> 200 mg once daily x <br/> 10 days </td><td align="justify" class="Rrule" valign="top"> <br/> 200 mg (tablets) once <br/> daily × 10 days <span class="Sup">†</span></td><td align="justify" class="Rrule" valign="top"> <br/> ↓ 41% <br/> (0.59; 0.44 to 0.79) </td><td align="justify" class="Rrule" valign="top"> <br/> ↓ 50% <br/> (0.50; 0.36 to 0.71) </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"> <br/> <span class="Sup">*</span>Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for C <span class="Sub">max</span>or AUC. <br/> <span class="Sup">†</span>The tablet refers to a non-commercial tablet formulation without polymer. </td> </tr> </tbody> </table></div>

In vitrostudies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 28[see Contraindications (4)and Drug Interactions (7.1) including recommendations]. Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and Patients

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="799.33"> <col width="26.6222961730449%"/> <col width="20.4658901830283%"/> <col width="21.9633943427621%"/> <col width="15.8069883527454%"/> <col width="15.1414309484193%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Coadministered Drug</span> <br/> (Postulated Mechanism of <br/> Interaction is Inhibition of <br/> CYP3A4 by posaconazole) </td><td align="justify" class="Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Coadministered</span> <br/> <span class="Bold">Drug</span> <br/> <span class="Bold">Dose/Schedule</span></td><td align="justify" class="Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Posaconazole</span> <br/> <span class="Bold">Dose/Schedule</span></td><td align="justify" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Effect on</span> <br/> <span class="Bold">Bioavailability of</span> <br/> <span class="Bold">Coadministered Drugs</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Change in</span> <br/> <span class="Bold">Mean</span> <br/> <span class="Bold">C <span class="Sub">max</span></span>(ratio <br/> estimate*; <br/> 90% CI of <br/> the ratio <br/> estimate) </td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">Change in</span> <br/> <span class="Bold">Mean AUC</span> <br/> (ratio <br/> estimate*; <br/> 90% CI of <br/> the ratio <br/> estimate) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Sirolimus </td><td align="justify" class="Rrule" valign="top"> <br/> 2 mg single oral dose </td><td align="justify" class="Rrule" valign="top"> <br/> 400 mg (oral suspension) <br/> twice daily x 16 days </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 572% <br/> (6.72; 5.62 to 8.03) </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 788% <br/> (8.88; 7.26 to 10.9) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Cyclosporine </td><td align="justify" class="Rrule" valign="top"> <br/> Stable maintenance <br/> dose in heart transplant <br/> recipients </td><td align="justify" class="Rrule" valign="top"> <br/> 200 mg (tablets) once daily <br/> x 10 days <span class="Sup">†</span></td><td align="justify" class="Rrule" colspan="2" valign="top"> <br/> ↑ cyclosporine whole blood trough <br/> concentrations <br/> Cyclosporine dose reductions of up to 29% <br/> were required </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Tacrolimus </td><td align="justify" class="Rrule" valign="top"> <br/> 0.05 mg/kg single oral <br/> dose </td><td align="justify" class="Rrule" valign="top"> <br/> 400 mg (oral suspension) <br/> twice daily × 7 days </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 121% <br/> (2.21; 2.01 to 2.42) </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 358% <br/> (4.58; 4.03 to 5.19) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> Simvastatin </td><td align="justify" class="Rrule" rowspan="2" valign="top"> <br/> 40 mg single oral dose </td><td align="justify" class="Rrule" valign="top"> <br/> 100 mg (oral suspension) <br/> once daily x 13 days </td><td align="justify" class="Rrule" valign="top"> <br/> Simvastatin <br/> ↑ 841% <br/> (9.41, 7.13 to 12.44) <br/> Simvastatin Acid <br/> ↑ 817% <br/> (9.17, 7.36 to 11.43) </td><td align="justify" class="Rrule" valign="top"> <br/> Simvastatin <br/> ↑ 931% <br/> (10.31, 8.40 to 12.67) <br/> Simvastatin Acid <br/> ↑634% <br/> (7.34, 5.82 to 9.25) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 200 mg (oral suspension) <br/> once daily x 13 days </td><td align="justify" class="Rrule" valign="top"> <br/> Simvastatin <br/> ↑ 1041% <br/> (11.41, 7.99 to 16.29) <br/> Simvastatin Acid <br/> ↑851% (9.51, 8.15 to 11.10) </td><td align="justify" class="Rrule" valign="top"> <br/> Simvastatin <br/> ↑ 960% <br/> (10.60, 8.63 to 13.02) <br/> Simvastatin Acid <br/> ↑ 748% (8.48, 7.04 to 10.23) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Midazolam </td><td align="justify" class="Rrule" valign="top"> <br/> 0.4 mg single <br/> intravenous dose <span class="Sup">‡</span> <br/>   <br/> 0.4 mg single <br/> intravenous dose <span class="Sup">‡</span> <br/>   <br/> 2 mg single oral dose <span class="Sup">‡</span> <br/>   <br/> 2 mg single oral dose <span class="Sup">‡</span></td><td align="justify" class="Rrule" valign="top"> <br/> 200 mg (oral suspension) <br/> twice daily x 7 days <br/> 400 mg (oral suspension) <br/> twice daily x 7 days <br/> 200 mg (oral suspension) <br/> once daily x 7 days <br/> 400 mg (oral suspension) <br/> twice daily x 7 days </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 30% <br/> (1.3; 1.13 to 1.48) <br/>   <br/> ↑62% <br/> (1.62; 1.41 to 1.86) <br/>   <br/> ↑ 169% <br/> (2.69; 2.46 to 2.93) <br/>   <br/> ↑ 138% <br/> (2.38; 2.13 to 2.66) </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 362% <br/> (4.62; 4.02 to 5.3) <br/>   <br/> ↑524% <br/> (6.24; 5.43 to 7.16) <br/>   <br/> ↑ 470% <br/> (5.70; 4.82 to 6.74) <br/>   <br/> ↑ 397% <br/> (4.97; 4.46 to 5.54) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Rifabutin </td><td align="justify" class="Rrule" valign="top"> <br/> 300 mg once daily x 17 days </td><td align="justify" class="Rrule" valign="top"> <br/> 200 mg (tablets) once daily <br/> × 10 days <span class="Sup">†</span></td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 31% <br/> (1.31; 1.10 to 1.57) </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 72% <br/> (1.72;1.51 to 1.95) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Phenytoin </td><td align="justify" class="Rrule" valign="top"> <br/> 200 mg once daily PO x 10 days </td><td align="justify" class="Rrule" valign="top"> <br/> 200 mg (tablets) once daily <br/> x 10 days <span class="Sup">†</span></td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 16% <br/> (1.16; 0.85 to 1.57) </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 16% <br/> (1.16; 0.84 to 1.59) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Ritonavir </td><td align="justify" class="Rrule" valign="top"> <br/> 100 mg once daily x 14 days </td><td align="justify" class="Rrule" valign="top"> <br/> 400 mg (oral suspension) <br/> twice daily x 7 days </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 49% <br/> (1.49; 1.04 to 2.15) </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 80% <br/> (1.8;1.39 to 2.31) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Atazanavir </td><td align="justify" class="Rrule" valign="top"> <br/> 300 mg once daily <br/> x 14 days </td><td align="justify" class="Rrule" valign="top"> <br/> 400 mg (oral suspension) <br/> twice daily x 7 days </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 155% <br/> (2.55; 1.89 to 3.45) </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 268% <br/> (3.68; 2.89 to 4.70) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/>   <br/> Atazanavir/ <br/> ritonavir boosted <br/> regimen </td><td align="justify" class="Rrule" valign="top"> <br/>   <br/> 300 mg/100 mg once daily x 14 days </td><td align="justify" class="Rrule" valign="top"> <br/>   <br/> 400 mg (oral suspension) <br/> twice daily x 7 days </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 53% <br/>   <br/> (1.53; 1.13 to 2.07) </td><td align="justify" class="Rrule" valign="top"> <br/> ↑ 146% <br/>   <br/> (2.46; 1.93 to 3.13) </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"> <br/> <span class="Sup">*</span>Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C <span class="Sub">max</span>or AUC. <br/> <span class="Sup">†</span>The tablet refers to a non-commercial tablet formulation without polymer. <br/> <span class="Sup">‡</span>The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole. </td> </tr> </tbody> </table></div>

Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg once daily. Excretion: Following administration of Noxafil oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug). Posaconazole injection is eliminated with a mean terminal half-life (t½) of 27 hours and a total body clearance (CL) of 7.3 L/h. Specific Populations No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Race/Ethnicity: In a population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure. Patients Weighing More Than 120 kg: Weight has a clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)]. Pediatric Patients The mean pharmacokinetic parameters after multiple-dose administration of posaconazole injection in neutropenic pediatric patients 2 to less than 18 years of age are shown in Table 29.Patients were enrolled into 2 age groups and received posaconazole injection doses at 6 mg/kg (0.6 to 1 times the recommended dose) with a maximum 300 mg dose once daily (twice daily on Day 1) [see Adverse Reactions (6.1)]. Table 29: Summary of Steady-State Geometric Mean Pharmacokinetic Parameters (% Geometric CV) After Multiple Dosing with Posaconazole Injection 6 mg/kg* in Pediatric Patients with Neutropenia or Expected Neutropenia 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="799.33"> <col width="10.8153078202995%"/> <col width="10.648918469218%"/> <col width="6.65557404326123%"/> <col width="13.8103161397671%"/> <col width="11.3144758735441%"/> <col width="10.4825291181364%"/> <col width="11.6472545757072%"/> <col width="13.477537437604%"/> <col width="11.1480865224626%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Age Group</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">Dose</span> <br/> <span class="Bold">Type</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">N</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">AUC <span class="Sub">0-24 hr</span></span> <br/> <span class="Bold">(ng·hr/mL)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">Cav</span><span class="Sup">†</span> <br/> <span class="Bold">(ng/mL)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">C <span class="Sub">max</span></span> <br/> <span class="Bold">(ng/mL)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">C <span class="Sub">min</span></span> <br/> <span class="Bold">(ng/mL)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">T <span class="Sub">max</span></span><span class="Sup">‡</span> <br/> <span class="Bold">(hr)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">CL/F</span><span class="Sup">§</span> <br/> <span class="Bold">(L/hr)</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 2 to &lt;7 <br/> years </td><td align="justify" class="Rrule" valign="top"> <br/> IV </td><td align="justify" class="Rrule" valign="top"> <br/> 17 </td><td align="justify" class="Rrule" valign="top"> <br/> 31100 <br/> (48.9) </td><td align="justify" class="Rrule" valign="top"> <br/> 1300 <br/> (48.9) </td><td align="justify" class="Rrule" valign="top"> <br/> 3060 <br/> (54.1) </td><td align="justify" class="Rrule" valign="top"> <br/> 626 <br/> (104.8) </td><td align="justify" class="Rrule" valign="top"> <br/> 1.75 <br/> (1.57 to 1.83) </td><td align="justify" class="Rrule" valign="top"> <br/> 3.27 <br/> (49.3) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> 7 to 17 <br/> years </td><td align="justify" class="Rrule" valign="top"> <br/> IV </td><td align="justify" class="Rrule" valign="top"> <br/> 24 </td><td align="justify" class="Rrule" valign="top"> <br/> 44200 <br/> (41.5) </td><td align="justify" class="Rrule" valign="top"> <br/> 1840 <br/> (41.5) </td><td align="justify" class="Rrule" valign="top"> <br/> 3340 <br/> (39.4) </td><td align="justify" class="Rrule" valign="top"> <br/> 1160 <br/> (60.4) </td><td align="justify" class="Rrule" valign="top"> <br/> 1.77 <br/> (1.33 to 6.00) </td><td align="justify" class="Rrule" valign="top"> <br/> 4.76 <br/> (55.7) </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="9" valign="top"> <br/> IV= Posaconazole injection; AUC <span class="Sub">0-24</span>= Area under the plasma concentration-time curve from time zero to 24 hr; C <span class="Sub">max</span>= maximum observed concentration; C <span class="Sub">min</span>= minimum observed plasma concentration; T <span class="Sub">max</span>= time of maximum observed concentration; CL /F = apparent total body clearance <br/> <span class="Sup">*</span>0.6 to 1 times the recommended dose <br/> <span class="Sup">†</span>Cav = time-averaged concentrations (i.e., AUC <span class="Sub">0-24 hr</span>/24hr) <br/> <span class="Sup">‡</span>Median (minimum-maximum) <br/> <span class="Sup">§</span>Clearance (CL for IV) </td> </tr> </tbody> </table></div>

Based on a population pharmacokinetic model evaluating posaconazole pharmacokinetics and predicting exposures in pediatric patients, the exposure of steady-state posaconazole average concentration greater than or equal to 700 ng/mL in approximately 90% of patients is attained with the recommended dose of posaconazole injection. The population pharmacokinetic analysis of posaconazole in pediatric patients suggests that age, sex, renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics of posaconazole.

Mechanism of Action: Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole. Resistance: Clinical isolates of Candida albicansand Candida glabratawith decreased susceptibility to   posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known. Antimicrobial Activity: Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitroand in clinical infections [see I ndications and Usage (1)] . Microorganisms: Aspergillus spp. and Candida spp. Susceptibility Testing: For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Carcinogenesis No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times the exposure achieved with a 400 mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400 mg twice daily oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with a 400 mg twice daily oral suspension regimen. Mutagenesis Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study. Impairment of Fertility  Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 x the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 x the 400 mg twice daily oral suspension regimen).

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in a separate study of 10-week-old dogs dosed with intravenous posaconazole for 13 weeks with a 9-week recovery period or a follow-up study of 31-week-old dogs dosed for 3 months.

Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems.

The first study (Noxafil Oral Suspension Study 1) was a randomized, double-blind trial that compared Noxafil oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may have met more than one of these criteria). This assessed all patients while on study therapy plus 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (80 days, Noxafil oral suspension; 77 days, fluconazole). Table 32contains the results from Noxafil Oral Suspension Study 1. Table 32: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Noxafil Oral Suspension Study 1

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <colgroup> <col width="59%"/> <col width="20%"/> <col width="19%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold">Posaconazole</span> <br/> <span class="Bold">n=301</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Fluconazole</span> <br/> <span class="Bold">n=299</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold"><span class="Italics">On therapy plus 7 days</span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Clinical Failure*</span></td><td align="center" class="Rrule" valign="top">50 (17%)</td><td align="center" class="Rrule" valign="top">55 (18%)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Failure due to:</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Proven/Probable IFI</td><td align="center" class="Rrule" valign="top">7 (2%)</td><td align="center" class="Rrule" valign="top">22 (7%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">( <span class="Italics">Aspergillus</span>) </td><td align="right" class="Rrule" valign="top">3 (1%)</td><td align="right" class="Rrule" valign="top">17 (6%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">( <span class="Italics">Candida</span>) </td><td align="right" class="Rrule" valign="top">1 (&lt;1%)</td><td align="right" class="Rrule" valign="top">3 (1%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">(Other)</td><td align="right" class="Rrule" valign="top">3 (1%)</td><td align="right" class="Rrule" valign="top">2 (1%)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">All Deaths</td><td align="center" class="Rrule" valign="top">22 (7%)</td><td align="center" class="Rrule" valign="top">24 (8%)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Proven/probable fungal infection prior to death</td><td align="right" class="Rrule" valign="top">2 (&lt;1%)</td><td align="right" class="Rrule" valign="top">6 (2%)</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">SAF <span class="Sup">†</span></td><td align="center" class="Rrule" valign="top">27 (9%)</td><td align="center" class="Rrule" valign="top">25 (8%)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold"><span class="Italics">Through 16 weeks</span></span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">Clinical Failure <span class="Sup">*, ‡</span></span></td><td align="center" class="Rrule" valign="top">99 (33%)</td><td align="center" class="Rrule" valign="top">110 (37%)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Failure due to:</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Proven/Probable IFI</td><td align="center" class="Rrule" valign="top">16 (5%)</td><td align="center" class="Rrule" valign="top">27 (9%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">( <span class="Italics">Aspergillus</span>) </td><td align="right" class="Rrule" valign="top">7 (2%)</td><td align="right" class="Rrule" valign="top">21 (7%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">( <span class="Italics">Candida</span>) </td><td align="right" class="Rrule" valign="top">4 (1%)</td><td align="right" class="Rrule" valign="top">4 (1%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">(Other)</td><td align="right" class="Rrule" valign="top">5 (2%)</td><td align="right" class="Rrule" valign="top">2 (1%)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">All Deaths <br/> Proven/probable fungal infection prior to death </td><td align="center" class="Rrule" valign="top">58 (19%) <br/> 10 (3%) </td><td align="center" class="Rrule" valign="top">59 (20%) <br/> 16 (5%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">SAF <span class="Sup">†</span></td><td align="center" class="Rrule" valign="top">26 (9%)</td><td align="center" class="Rrule" valign="top">30 (10%)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Event free lost to follow-up <span class="Sup">§</span></td><td align="center" class="Rrule" valign="top">24 (8%)</td><td align="center" class="Rrule" valign="top">30 (10%)</td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Sup">*</span>Patients may have met more than one criterion defining failure. <br/> <span class="Sup">†</span>Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage &gt;4 consecutive days). <br/> <span class="Sup">‡</span>95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%). <br/> <span class="Sup">§</span>Patients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. These patients were considered failures. </td> </tr> </tbody> </table></div>

The second study (Noxafil Oral Suspension Study 2) was a randomized, open-label study that compared Noxafil oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Noxafil Oral Suspension Study 1, efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). This study assessed patients while on treatment plus 7 days and 100 days postrandomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 33contains the results from Noxafil Oral Suspension Study 2.

Table 33: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Noxafil Oral Suspension Study 2

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <colgroup> <col width="33%"/> <col width="33%"/> <col width="33%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">Posaconazole</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Fluconazole/Itraconazole</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">n=304</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">n=298</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="4" valign="top"><span class="Bold"><span class="Italics">On therapy plus 7 days</span></span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">Clinical Failure <span class="Sup">*,†</span></span></td><td class="Rrule" valign="top">82 (27%)</td><td class="Rrule" colspan="2" valign="top">126 (42%)</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Failure due to:</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Proven/Probable IFI</td><td align="center" class="Rrule" valign="top">7 (2%)</td><td align="center" class="Rrule" colspan="2" valign="top">25 (8%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">( <span class="Italics">Aspergillus</span>) </td><td align="right" class="Rrule" valign="top">2 (1%)</td><td align="right" class="Rrule" colspan="2" valign="top">20 (7%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">( <span class="Italics">Candida</span>) </td><td align="right" class="Rrule" valign="top">3 (1%)</td><td align="right" class="Rrule" colspan="2" valign="top">2 (1%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">(Other)</td><td align="right" class="Rrule" valign="top">2 (1%)</td><td align="right" class="Rrule" colspan="2" valign="top">3 (1%)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">All Deaths <br/> Proven/probable fungal <br/> infection prior to death </td><td align="center" class="Rrule" valign="top">17 (6%) <br/> 1 (&lt;1%) </td><td align="center" class="Rrule" colspan="2" valign="top">25 (8%) <br/> 2 (1%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">SAF <span class="Sup">‡</span></td><td align="center" class="Rrule" valign="top">67 (22%)</td><td align="center" class="Rrule" colspan="2" valign="top">98 (33%)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="4" valign="top"><span class="Bold"><span class="Italics">Through 100 days postrandomization</span></span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">Clinical Failure <span class="Sup">†</span></span></td><td align="center" class="Rrule" valign="top">158 (52%)</td><td align="center" class="Rrule" colspan="2" valign="top">191 (64%)</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Failure due to:</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Proven/Probable IFI</td><td align="center" class="Rrule" valign="top">14 (5%)</td><td align="center" class="Rrule" colspan="2" valign="top">33 (11%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">( <span class="Italics">Aspergillus</span>) </td><td align="right" class="Rrule" valign="top">2 (1%)</td><td align="right" class="Rrule" colspan="2" valign="top">26 (9%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">( <span class="Italics">Candida</span>) </td><td align="right" class="Rrule" valign="top">10 (3%)</td><td align="right" class="Rrule" colspan="2" valign="top">4 (1%)</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">(Other)</td><td align="right" class="Rrule" valign="top">2 (1%)</td><td align="right" class="Rrule" colspan="2" valign="top">3 (1%)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">All Deaths <br/> Proven/probable fungal <br/> infection prior to death </td><td align="center" class="Rrule" valign="top">44 (14%) <br/> 2 (1%) </td><td align="center" class="Rrule" colspan="2" valign="top">64 (21%) <br/> 16 (5%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">SAF <span class="Sup">‡</span></td><td align="center" class="Rrule" valign="top">98 (32%)</td><td align="center" class="Rrule" colspan="2" valign="top">125 (42%)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Event free lost to follow-up <span class="Sup">§</span></td><td align="center" class="Rrule" valign="top">34 (11%)</td><td align="center" class="Rrule" colspan="2" valign="top">24 (8%)</td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="4" valign="top"><span class="Sup">*</span>95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%). <br/> <span class="Sup">†</span>Patients may have met more than one criterion defining failure. <br/> <span class="Sup">‡</span>Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage &gt;3 consecutive days). <br/> <span class="Sup">§</span>Patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures. </td> </tr> </tbody> </table></div>

In summary, 2 clinical studies of prophylaxis were conducted with the Noxafil oral suspension. As seen in the accompanying tables ( Tables 32 and 33), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Noxafil Oral Suspension Study 1 ( Table 32), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole–comparator -11.5% to 3.7%) while in Noxafil Oral Suspension Study 2 ( Table 33) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole–comparator -22.9% to -7.8%). All-cause mortality was similar at 16 weeks for both treatment arms in Noxafil Oral Suspension Study 1 [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in Noxafil Oral Suspension Study 2 [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated fewer breakthrough infections caused by Aspergillusspecies in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.

Posaconazole Injection Posaconazole injection is available as a clear, colorless to yellow sterile liquid in single-dose Type I glass vials closed with serum rubber stopper and flip off seal (NDC 31722-370-31) containing 300 mg of posaconazole in 16.7 mL of solution (18 mg of posaconazole per mL).

Posaconazole Injection Posaconazole injection vial should be stored refrigerated at 2° to 8°C (36° to 46°F). Storage conditions for the diluted solution are presented in another section of the prescribing information [see Dosage and Administration (2.4)].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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Drug Interactions Advise patients to inform their physician immediately if they: • develop severe diarrhea or vomiting. • are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4. • are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath. • are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole. Serious and Potentially Serious Adverse Reactions Advise patients to inform their physician immediately if they: • notice a change in heart rate or heart rhythm or have a heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions. • are pregnant, plan to become pregnant, or are nursing. • have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu. • have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.

{ "type": "p", "children": [], "text": "\nDrug Interactions\n Advise patients to inform their physician immediately if they: \n • develop severe diarrhea or vomiting. \n • are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4. \n • are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath. \n • are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole. \n \nSerious and Potentially Serious Adverse Reactions\n Advise patients to inform their physician immediately if they: \n • notice a change in heart rate or heart rhythm or have a heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions. \n • are pregnant, plan to become pregnant, or are nursing. \n • have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu. \n • have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.\n\n " }

Manufactured for:  Camber Pharmaceuticals, Inc.  Piscataway, NJ 08854.

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Manufactured by:

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  Aspiro Pharma Limited Survey No. 321, Biotech Park, Phase – III Karkapatla Village, Markook (Mandal) Siddipet, Telangana-502281, India

{ "type": "p", "children": [], "text": " \n \n Aspiro Pharma Limited\n Survey No. 321, Biotech Park, Phase – III \n Karkapatla Village, Markook (Mandal) \n Siddipet, Telangana-502281, India\n\n " }

Issued: 01/2025

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<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="799.33"> <col width="100%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Patient Information</span> <br/> Posaconazole <br/> (poe″ sa kon′ a zole) <br/> injection </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">What is Posaconazole Injection?</span> <br/> Posaconazole is a prescription medicine used in adults and children to help prevent fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called <span class="Italics">Aspergillus</span>or <span class="Italics">Candida</span>. Posaconazole injection is used in people who have an increased chance of getting these infections due to a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a low white blood cell count due to chemotherapy for blood cancers (hematologic malignancies). <br/> <span class="Bold">Posaconazole injection</span>is used for: <ul class="Disc"> <li>prevention of fungal infections in adults and children 2 years of age and older.</li> </ul> <br/> It is not known if posaconazole injection is safe and effective in children under 2 years of age. </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Who should not take posaconazole?</span> <br/> <span class="Bold">Do not take posaconazole if you:</span> <ul class="Disc"> <li>are allergic to posaconazole, any of the ingredients in posaconazole or other azole antifungal medicines. See the end of this leaflet for a complete list of ingredients in posaconazole.</li> <li>are taking any of the following medicines: <br/> o sirolimus <br/> o pimozide <br/> o quinidine <br/> o certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin) <br/> o ergot alkaloids (ergotamine, dihydroergotamine) </li> <li>have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.</li> </ul> <br/> Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. Do not start taking a new medicine without talking to your healthcare provider or pharmacist. </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">What should I tell my healthcare provider before taking posaconazole?</span> <br/> <span class="Bold"> </span> <br/> <span class="Bold"> </span><span class="Bold">Before you take posaconazole, tell your healthcare provider if you:</span> <ul class="Disc"> <li>are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.</li> <li>are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause a decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole.</li> <li>are taking midazolam, a hypnotic and sedative medicine.</li> <li>are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat cancer).</li> <li>are taking venetoclax, a medicine used to treat cancer.</li> <li>have or had liver problems.</li> <li>have or had kidney problems.</li> <li>have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.</li> <li>are pregnant or plan to become pregnant. It is not known if posaconazole will harm your unborn baby.</li> <li>are breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole or breastfeed. You should not do both.</li> </ul> <br/> <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. Posaconazole can affect the way other medicines work, and other medicines can affect the way posaconazole work, and can cause serious side effects. <br/> Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them with you to show your healthcare provider or pharmacist when you get a new medicine. </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">How will I take posaconazole?</span> <ul class="Disc"> <li>Take posaconazole exactly as your healthcare provider tells you to take it.</li> <li>Your healthcare provider will tell you how much posaconazole to take and when to take it.</li> <li>Take posaconazole for as long as your healthcare provider tells you to take it.</li> <li>If you take too much posaconazole, call your healthcare provider or go to the nearest hospital emergency room right away.</li> <li>Posaconazole injection is usually given over 30 to 90 minutes through a plastic tube placed in your vein.</li> </ul> <br/> Follow the instructions from your healthcare provider on how much posaconazole you should take and when to take it. </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">What are the possible side effects of posaconazole?</span> <br/> <span class="Bold">Posaconazole may cause serious side effects, including:</span> <ul class="Disc"> <li> <span class="Bold">drug interactions with cyclosporine or tacrolimus.</span>If you take posaconazole with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath. </li> <li> <span class="Bold">problems with the electrical system of your heart (arrhythmias and QTc prolongation).</span>Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular. </li> <li> <span class="Bold">changes in body salt (electrolytes) levels in your blood.</span>Your healthcare provider should check your electrolytes while you are taking posaconazole. </li> <li> <span class="Bold">new or worsening high blood pressure and low potassium levels in your blood (pseudoaldosteronism).</span>Your healthcare provider should check your blood pressure and potassium levels. </li> <li> <span class="Bold">liver problems.</span>Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of posaconazole. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole. Call your healthcare provider right away if you have any of the following symptoms of liver problems: <br/>  o itchy skin                                    o feeling very tired <br/>  o nausea or vomiting                    o flu-like symptoms <br/>  o yellowing of your eyes or skin </li> <li> <span class="Bold">increased amounts of midazolam in your blood.</span>If you take posaconazole with midazolam, posaconazole increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole. </li> </ul> <br/> <span class="Bold">The most common side effects of posaconazole in adults include:</span> <br/> • diarrhea                  • headache <br/> • nausea                   • coughing <br/> • fever                       • low potassium levels in the blood <br/> • vomiting <br/> <span class="Bold">The most common side effects of posaconazole in children include:</span> <br/> • fever                                                            • itching <br/> • fever with low white blood cell                     • high blood pressure <br/> count (febrile neutropenia) <br/> • vomiting                                                       • low potassium levels in the blood <br/> • redness and sores of the lining of the <br/> mouth, lips, throat, stomach, and <br/> genitals (mucositis or stomatitis) <br/>   <br/> Tell your healthcare provider if you have any side effect that bothers you or that does not go away. <br/> These are not all the possible side effects of posaconazole. For more information, ask your healthcare provider or pharmacist. <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="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">How should I store posaconazole?</span>  <br/> Store posaconazole injection refrigerated at 36°F to 46°F (2°C to 8°C). <br/> Safely throw away medicine that is out of date or no longer needed. <br/> <span class="Bold">Keep posaconazole and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">General information about the safe and effective use of posaconazole.</span> <br/>   <br/> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use posaconazole for a condition for which it was not prescribed. Do not give posaconazole to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about posaconazole that is written for health professionals. </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">What are the ingredients in posaconazole?</span> <br/> <span class="Bold">Active ingredient:</span>posaconazole <br/> <span class="Bold">Inactive ingredients: posaconazole injection:</span>betadex sulfobutyl ether sodium (SBECD), edetate sodium, hydrochloric acid, sodium hydroxide, and water for injection. <br/>  Manufactured for: <br/> Camber Pharmaceuticals, Inc. <br/> Piscataway, NJ 08854. <br/>   <br/> <br/> Manufactured by:  <br/> <br/> <span class="Bold">Aspiro Pharma Limited</span> <br/> Survey No. 321, Biotech Park, Phase – III <br/> Karkapatla Village, Markook (Mandal) <br/> Siddipet, Telangana-502281, India  <br/> <br/> For more information, call 1-866-495-1995. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"799.33\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"top\">\n<br/>\n<span class=\"Bold\">Patient Information</span>\n<br/> Posaconazole \n <br/> (poe″ sa kon′ a zole) \n <br/> injection\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">\n<br/>\n<span class=\"Bold\">What is Posaconazole Injection?</span>\n<br/> Posaconazole is a prescription medicine used in adults and children to help prevent fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called\n \n <span class=\"Italics\">Aspergillus</span>or\n \n <span class=\"Italics\">Candida</span>. Posaconazole injection is used in people who have an increased chance of getting these infections due to a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a low white blood cell count due to chemotherapy for blood cancers (hematologic malignancies). \n <br/>\n<span class=\"Bold\">Posaconazole injection</span>is used for:\n \n <ul class=\"Disc\">\n<li>prevention of fungal infections in adults and children 2 years of age and older.</li>\n</ul>\n<br/> It is not known if posaconazole injection is safe and effective in children under 2 years of age.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">\n<br/>\n<span class=\"Bold\">Who should not take posaconazole?</span>\n<br/>\n<span class=\"Bold\">Do not take posaconazole if you:</span>\n<ul class=\"Disc\">\n<li>are allergic to posaconazole, any of the ingredients in posaconazole or other azole antifungal medicines. See the end of this leaflet for a complete list of ingredients in posaconazole.</li>\n<li>are taking any of the following medicines: \n <br/> o sirolimus \n <br/> o pimozide \n <br/> o quinidine \n <br/> o certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin) \n <br/> o ergot alkaloids (ergotamine, dihydroergotamine)\n </li>\n<li>have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.</li>\n</ul>\n<br/> Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. Do not start taking a new medicine without talking to your healthcare provider or pharmacist.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">\n<br/>\n<span class=\"Bold\">What should I tell my healthcare provider before taking posaconazole?</span>\n<br/>\n<span class=\"Bold\"> </span>\n<br/>\n<span class=\"Bold\"> </span><span class=\"Bold\">Before you take posaconazole, tell your healthcare provider if you:</span>\n<ul class=\"Disc\">\n<li>are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.</li>\n<li>are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause a decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole.</li>\n<li>are taking midazolam, a hypnotic and sedative medicine.</li>\n<li>are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat cancer).</li>\n<li>are taking venetoclax, a medicine used to treat cancer.</li>\n<li>have or had liver problems.</li>\n<li>have or had kidney problems.</li>\n<li>have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.</li>\n<li>are pregnant or plan to become pregnant. It is not known if posaconazole will harm your unborn baby.</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole or breastfeed. You should not do both.</li>\n</ul>\n<br/>\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. Posaconazole can affect the way other medicines work, and other medicines can affect the way posaconazole work, and can cause serious side effects. \n <br/> Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them with you to show your healthcare provider or pharmacist when you get a new medicine.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">\n<br/>\n<span class=\"Bold\">How will I take posaconazole?</span>\n<ul class=\"Disc\">\n<li>Take posaconazole exactly as your healthcare provider tells you to take it.</li>\n<li>Your healthcare provider will tell you how much posaconazole to take and when to take it.</li>\n<li>Take posaconazole for as long as your healthcare provider tells you to take it.</li>\n<li>If you take too much posaconazole, call your healthcare provider or go to the nearest hospital emergency room right away.</li>\n<li>Posaconazole injection is usually given over 30 to 90 minutes through a plastic tube placed in your vein.</li>\n</ul>\n<br/> Follow the instructions from your healthcare provider on how much posaconazole you should take and when to take it.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">\n<br/>\n<span class=\"Bold\">What are the possible side effects of posaconazole?</span>\n<br/>\n<span class=\"Bold\">Posaconazole may cause serious side effects, including:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">drug interactions with cyclosporine or tacrolimus.</span>If you take posaconazole with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.\n \n </li>\n<li>\n<span class=\"Bold\">problems with the electrical system of your heart (arrhythmias and QTc prolongation).</span>Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.\n \n </li>\n<li>\n<span class=\"Bold\">changes in body salt (electrolytes) levels in your blood.</span>Your healthcare provider should check your electrolytes while you are taking posaconazole.\n \n </li>\n<li>\n<span class=\"Bold\">new or worsening high blood pressure and low potassium levels in your blood (pseudoaldosteronism).</span>Your healthcare provider should check your blood pressure and potassium levels.\n \n </li>\n<li>\n<span class=\"Bold\">liver problems.</span>Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of posaconazole. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole. Call your healthcare provider right away if you have any of the following symptoms of liver problems: \n <br/>  o itchy skin                                    o feeling very tired \n <br/>  o nausea or vomiting                    o flu-like symptoms \n <br/>  o yellowing of your eyes or skin\n \n </li>\n<li>\n<span class=\"Bold\">increased amounts of midazolam in your blood.</span>If you take posaconazole with midazolam, posaconazole increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole.\n \n </li>\n</ul>\n<br/>\n<span class=\"Bold\">The most common side effects of posaconazole in adults include:</span>\n<br/> • diarrhea                  • headache \n <br/> • nausea                   • coughing \n <br/> • fever                       • low potassium levels in the blood \n <br/> • vomiting \n <br/>\n<span class=\"Bold\">The most common side effects of posaconazole in children include:</span>\n<br/> • fever                                                            • itching \n <br/> • fever with low white blood cell                     • high blood pressure \n <br/> count (febrile neutropenia) \n <br/> • vomiting                                                       • low potassium levels in the blood \n <br/> • redness and sores of the lining of the \n <br/> mouth, lips, throat, stomach, and \n <br/> genitals (mucositis or stomatitis) \n <br/>   \n <br/> Tell your healthcare provider if you have any side effect that bothers you or that does not go away. \n <br/> These are not all the possible side effects of posaconazole. For more information, ask your healthcare provider or pharmacist. \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 </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">\n<br/>\n<span class=\"Bold\">How should I store posaconazole?</span>  \n <br/> Store posaconazole injection refrigerated at 36°F to 46°F (2°C to 8°C). \n <br/> Safely throw away medicine that is out of date or no longer needed. \n <br/>\n<span class=\"Bold\">Keep posaconazole and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">\n<br/>\n<span class=\"Bold\">General information about the safe and effective use of posaconazole.</span>\n<br/>   \n <br/> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use posaconazole for a condition for which it was not prescribed. Do not give posaconazole to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about posaconazole that is written for health professionals.\n \n </td>\n</tr>\n<tr class=\"Last\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">\n<br/>\n<span class=\"Bold\">What are the ingredients in posaconazole?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span>posaconazole \n <br/>\n<span class=\"Bold\">Inactive ingredients: posaconazole injection:</span>betadex sulfobutyl ether sodium (SBECD), edetate sodium, hydrochloric acid, sodium hydroxide, and water for injection. \n <br/>  Manufactured for: \n <br/> Camber Pharmaceuticals, Inc. \n <br/> Piscataway, NJ 08854. \n <br/>   \n <br/>\n<br/> Manufactured by:  \n <br/>\n<br/>\n<span class=\"Bold\">Aspiro Pharma Limited</span>\n<br/> Survey No. 321, Biotech Park, Phase – III \n <br/> Karkapatla Village, Markook (Mandal) \n <br/> Siddipet, Telangana-502281, India  \n <br/>\n<br/> For more information, call 1-866-495-1995.\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 01/2025

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration. \n Issued: 01/2025\n " }

Posaconazole Injection 300 mg /16.7 mL (18 mg/mL) container label

{ "type": "p", "children": [], "text": "Posaconazole Injection 300 mg /16.7 mL (18 mg/mL) container label" }

Posaconazole Injection 300 mg /16.7 mL (18 mg/mL) Carton label

{ "type": "p", "children": [], "text": "Posaconazole Injection 300 mg /16.7 mL (18 mg/mL) Carton label" }

Posaconazole delayed-release tablets are indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies (14.1)] as follows: Posaconazole delayed-release tablets: adults and pediatric patients 13 years of age and older. Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.'s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp & Dohme Corp.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Non-substitutable Noxafil® oral suspension is not substitutable with posaconazole delayed-release tablets or Noxafil® powdermix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2,2.3). Posaconazole delayed-release tablets

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 1: Dosing Regimens in Adult Patients </span> </caption> <col width="17%"/> <col width="41%"/> <col width="42%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Indication</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Dose and Frequency </span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Duration of Therapy</span> <br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Prophylaxis of invasive <span class="Italics">Aspergillus </span> and <span class="Italics">Candida </span> infections<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Underline">Posaconazole Delayed-Release Tablets:</span> <br/> <br/> <span class="Underline">Loading dose:</span> 300 mg (three 100 mg delayed-release tablets) twice a day on the first day.<br/> <span class="Underline">Maintenance dose</span> : 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Underline">Posaconazole Delayed-Release Tablets:</span> <br/> <br/> <span class="Underline">Loading dose:</span> <br/> 1 day<br/> <span class="Underline">Maintenance dose</span> :<br/> Duration of therapy is based on recovery from neutropenia or immunosuppression.<br/> </p> </td> </tr> </tbody> </table></div>

The recommended dosing regimen of posaconazole for pediatric patients 13 to less than 18 years of age is shown in Table 2[see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

<div class="scrollingtable"><table width="95%"> <caption> <span> Table 2: Posaconazole delayed-release tablet Dosing Regimens for Pediatric Patients (Ages 13 to less than 18 years of age)  </span> </caption> <col width="27%"/> <col width="46%"/> <col width="26%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Indication</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">  Recommended Pediatric Dosage</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">  Duration of Therapy</span> <br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Prophylaxis of invasive <span class="Italics">Aspergillus</span>  and<br/> <span class="Italics">Candida</span>  infections<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Posaconazole Delayed-Release Tablets:<br/> <br/> <span class="Underline">Loading dose:</span> <br/> 300 mg twice daily on the first day.<br/> <span class="Underline">Maintenance dose:</span> 300 mg once daily.<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Duration of therapy is based on recovery from neutropenia or immunosuppression.<br/> </p> </td> </tr> </tbody> </table></div>

Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.'s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp & Dohme Corp.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Posaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powdermix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2, 2.3)].

The pharmacokinetics of posaconazole delayed-release tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

Posaconazole delayed-release tablets are available as yellow-coated, capsule shaped tablets, debossed with "100P" on one side and plain on the other side, containing 100 mg of posaconazole.

{ "type": "p", "children": [], "text": "Posaconazole delayed-release tablets are available as yellow-coated, capsule shaped tablets, debossed with \"100P\" on one side and plain on the other side, containing 100 mg of posaconazole." }

Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.

Posaconazole is contraindicated with sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].

Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].

Coadministration of Posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Warnings and Precautions (5.10) and Drug Interactions (7.16)].

Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole.

Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered posaconazole oral suspension 400 mg twice daily with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.

Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)].

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.

Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the posaconazole oral suspension 800 mg daily (400 mg twice daily or 200 mg four times a day) in clinical trials.

Liver tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.

Due to the variability in exposure with Posaconazole delayed-release tablets, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2.9) and Use in Specific Populations (8.6)].

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].

Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.10)].

Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole delayed-release tablets.

Concomitant administration of posaconazole, a strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of posaconazole during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications (4.6)]. Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax [see Drug Interactions (7.16)]. Refer to the venetoclax prescribing information for dosing instructions.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trial Experience in Adults

Clinical Trial Experience with Posaconazole Delayed-Release Tablets for Prophylaxis

The safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole delayed-release tablets when given as antifungal prophylaxis (Posaconazole Delayed-Release Tablet Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range 19-78 years, 17% of patients were ≥65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in each cohort).

Table 9 presents adverse reactions observed in patients treated with 300 mg daily dose at an incidence of >10% in posaconazole delayed-release tablet study.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 9: Posaconazole Delayed-Release Tablet Study: Adverse Reactions in at Least 10% of Subjects Treated with 300 mg Daily Dose </span> </caption> <col width="73%"/> <col width="15%"/> <col width="12%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Body System</span></span> <br/> <br/> </p> </td><td class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> Posaconazole delayed-release tablet (300 mg)</span> <br/> <span class="Bold"> n=210 (%)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Subjects Reporting any Adverse Reaction<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 207<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (99)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">Blood and Lymphatic System Disorder</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anemia<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 22<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (10)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Thrombocytopenia<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 29<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (14)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">Gastrointestinal Disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Abdominal Pain<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 23<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (11)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Constipation<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 20<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (10)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 61<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (29)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Nausea<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 56<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (27)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 28<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (13)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">General Disorders and Administration Site Conditions</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Asthenia<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 20<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (10)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Chills<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 22<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (10)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Mucosal Inflammation<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 29<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (14)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Edema Peripheral<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 33<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (16)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pyrexia<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 59<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (28)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">Metabolism and Nutrition Disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypokalemia<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 46<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (22)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypomagnesemia<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 20<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (10)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">Nervous System Disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Headache<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 30<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (14)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">Respiratory, Thoracic and Mediastinal Disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Cough<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 35<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (17)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Epistaxis<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 30<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (14)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">Skin and Subcutaneous Tissue Disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Rash<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 34<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (16)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Italics">Vascular Disorders</span> <br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypertension<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 23<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> (11)<br/> </p> </td> </tr> </tbody> </table></div>

The most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea.

The most common adverse reaction leading to discontinuation of posaconazole delayed-release tablets 300 mg once daily was nausea (2%).

Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.'s NOXAFIL (posaconazole) products. However, due to Merck Sharp & Dohme Corp.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

The following adverse reaction has been identified during the post-approval use of posaconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Endocrine Disorders: Pseudoaldosteronism

Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3)].

Tacrolimus: Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus.  At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications (4.3) and Warnings and Precautions (5.2)].

Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 [see Contraindications (4.4) and Clinical Pharmacology (12.3)].

Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids [see Contraindications (4.5)].

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.

Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see Clinical Pharmacology (12.3)]. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.

Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see Clinical Pharmacology (12.3)].

Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.

Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.

No clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.

Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions [see Warnings and Precautions (5.7)]. Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.

Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.

Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide.

Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.

Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities [see Contraindications (4.6), Warnings and Precautions (5.10)]. Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

Risk Summary

Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses 5 times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of ≥ 3 times the clinical exposure caused an increase in resorptions in these rabbits (see Data). Based on animal 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. 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

Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy  volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.

Risk Summary

There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition.

The safety and effectiveness of posaconazole delayed-release tablets for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 13 years and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy.

Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 13 years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].

The safety and effectiveness of posaconazole have not been established in pediatric patients younger than 2 years of age.

Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.'s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp & Dohme Corp.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

No overall differences in the safety of posaconazole delayed-release tablets were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of posaconazole in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].

Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age.

No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

Following single-dose administration of 400 mg of the posaconazole oral suspension, there was no significant effect of mild (eGFR: 50-80 mL/min/1.73 m2, n=6) or moderate (eGFR: 20-49 mL/min/1.73 m2, n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR:  <20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2.9)]. Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the posaconazole delayed-release tablets.

After a single oral dose of posaconazole oral suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects  with  normal hepatic function. The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.

It is recommended that no dose adjustment of posaconazole delayed-release tablet is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2) and Warnings and Precautions (5.4)]. However, a specific study has not been conducted with posaconazole delayed-release tablets.

The pharmacokinetics of posaconazole are comparable in males and females. No adjustment in the dosage of posaconazole is necessary based on gender.

The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of Posaconazole is necessary based on race.

Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections [see Clinical Pharmacology (12.3)].

There is no experience with overdosage of posaconazole delayed-release tablets.

{ "type": "p", "children": [], "text": "There is no experience with overdosage of posaconazole delayed-release tablets." }

During the clinical trials, some patients received posaconazole oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg twice daily posaconazole oral suspension for 3 days. No related adverse reactions were noted by the investigator.

{ "type": "p", "children": [], "text": "During the clinical trials, some patients received posaconazole oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg twice daily posaconazole oral suspension for 3 days. No related adverse reactions were noted by the investigator." }

Posaconazole is not removed by hemodialysis.  

{ "type": "p", "children": [], "text": "Posaconazole is not removed by hemodialysis.  " }

Posaconazole is an azole antifungal agent. Posaconazole is available as delayed-release tablet intended for oral administration.

{ "type": "p", "children": [], "text": "Posaconazole is an azole antifungal agent. Posaconazole is available as delayed-release tablet intended for oral administration." }

Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5 - (1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2 - hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:

{ "type": "p", "children": [], "text": "Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5 - (1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2 - hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:" }

Posaconazole is a white powder with a low aqueous solubility.

{ "type": "p", "children": [], "text": "Posaconazole is a white powder with a low aqueous solubility." }

Posaconazole delayed-release tablets are yellow, coated, capsule-shaped tablets containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: partially neutralized methacrylic acid and ethyl acrylate copolymer, triethyl citrate, xylitol, hydroxypropyl cellulose, propyl gallate, cellulose, microcrystalline, silica, colloidal anhydrous, croscarmellose sodium, sodium stearyl fumarate and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, macrogol, polyethylene glycol, titanium dioxide, talc, and iron oxide yellow).

{ "type": "p", "children": [], "text": "Posaconazole delayed-release tablets are yellow, coated, capsule-shaped tablets containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: partially neutralized methacrylic acid and ethyl acrylate copolymer, triethyl citrate, xylitol, hydroxypropyl cellulose, propyl gallate, cellulose, microcrystalline, silica, colloidal anhydrous, croscarmellose sodium, sodium stearyl fumarate and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, macrogol, polyethylene glycol, titanium dioxide, talc, and iron oxide yellow)." }

Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].

Exposure Response Relationship Prophylaxis: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), a wide range of plasma exposures to posaconazole was noted following administration of posaconazole oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 17).  A lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 17: Posaconazole Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials </span> </caption> <col width="14%"/> <col width="20%"/> <col width="22%"/> <col width="22%"/> <col width="21%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></td><td class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> Prophylaxis in AML/MDS*</span> <br/> </p> </td><td class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> Prophylaxis in GVHD†</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> Cavg Range (ng/mL)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Treatment Failure‡ (%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Cavg Range (ng/mL)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Treatment Failure‡ (%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Quartile 1<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 90-322<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 54.7<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 22-557<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 44.4<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Quartile 2<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 322-490<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 37.0<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 557-915<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 20.6<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Quartile 3<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 490-734<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 46.8<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 915-1563<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 17.5<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Quartile 4<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 734-2200<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 27.8<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 1563-3650<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 17.5<br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> Cavg = the average posaconazole concentration when measured at steady state<br/> * Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS<br/> † HSCT recipients with GVHD<br/> ‡ Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections<br/> </p> </td> </tr> </tbody> </table></div>

General Pharmacokinetic Characteristics

Posaconazole delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of posaconazole delayed-release tablets 300 mg twice daily on Day 1, then 300 mg once daily thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 20.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 20: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)* </span> </caption> <col width="13%"/> <col width="5%"/> <col width="14%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <col width="13%"/> <col width="10%"/> <col width="11%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="9" valign="top">CV = coefficient of variation expressed as a percentage (%CV); AUC0-T = Area under the plasma concentration-time curve from time zero to 24 hr; Cmax = maximum observed concentration;  Cmin  = minimum observed plasma concentration; Tmax = time of maximum observed concentration; t½ = terminal phase half-life; CL /F = Apparent total body clearance</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> N</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> AUC 0-24 hr</span> <br/> <span class="Bold"> (ng·hr/mL)</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Cav† (ng/mL)</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> C max (ng/mL)</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> C min (ng/mL)</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> ‡Tmax(hr)</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> t 1/2 (hr)</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> CL/F</span> <br/> <span class="Bold"> (L/hr)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Healthy Volunteers<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 12<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 51618<br/> (25)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2151<br/> (25)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2764<br/> (21)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 1785<br/> (29)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 4<br/> (3-6)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 31<br/> (40)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 7.5<br/> (26)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Patients<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 50<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 37900<br/> (42)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 1580<br/> (42)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2090<br/> (38)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 1310<br/> (50)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 4 (1.3-8.3)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> -<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 9.39<br/> (45)<br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" colspan="9" valign="top"> <p class="First"> CV = coefficient of variation expressed as a percentage (%CV); AUC0-T = Area under the plasma concentration-time curve from time zero to 24 hr; Cmax = maximum observed concentration;  Cmin  = minimum observed plasma concentration; Tmax = time of maximum observed concentration; t½ = terminal phase half-life; CL /F = Apparent total body clearance<br/> *300 mg twice daily on Day 1, then 300 mg once daily thereafter<br/> † Cav = time-averaged concentrations (i.e., AUC0-24 hr/24hr)<br/> ‡ Median (minimum-maximum)<br/> </p> </td> </tr> </tbody> </table></div>

Absorption:

When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with a median Tmax of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 at the 300 mg dose (once daily after twice daily loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see Table 22).

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 22: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Posaconazole Delayed-Release Tablet to Healthy Subjects under Fasting and Fed Conditions </span> </caption> <col width="19%"/> <col width="11%"/> <col width="20%"/> <col width="10%"/> <col width="19%"/> <col width="20%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="6" valign="top">GMR=Geometric least-squares mean ratio; CI=Confidence interval</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> Fasting Conditions</span> <br/> </p> </td><td class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> Fed Conditions (High Fat Meal)*</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Fed/Fasting</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Pharmacokinetic Parameter</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> N</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Mean (%CV)</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> N</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Mean (%CV)</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> GMR (90% CI)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Cmax (ng/mL)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 14<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 935 (34)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 16<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 1060 (25)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 1.16 (0.96, 1.41)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> AUC<span class="Sub">0-72hr </span>(hr∙ng/mL)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 14<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 26200 (28)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 16<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 38400 (18)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 1.51 (1.33, 1.72)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Tmax† (hr)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 14<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 5.00 (3.00, 8.00)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 16<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 6.00 (5.00, 24.00)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> N/A<br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" colspan="6" valign="top"> <p class="First"> GMR=Geometric least-squares mean ratio; CI=Confidence interval<br/> * 48.5 g fat<br/> † Median (Min, Max) reported for Tmax<br/> </p> </td> </tr> </tbody> </table></div>

Concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 23).

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 23: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy Volunteers </span> </caption> <col width="30%"/> <col width="29%"/> <col width="22%"/> <col width="20%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Coadministered Drug</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Administration Arms</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Change in C<span class="Sub">max</span>  </span> (ratio estimate*; 90% CI of the ratio estimate)<br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Change in AUC<span class="Sub">0-last</span>  </span> (ratio estimate*; 90% CI of the ratio estimate)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Mylanta® Ultimate strength liquid (Increase in gastric pH)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 25.4 meq/5 mL, 20 mL<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑6%<br/> (1.06; 0.90 -1.26)↑<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑4%<br/> (1.04; 0.90 -1.20)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Ranitidine (Zantac®) (Alteration in gastric pH)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 150 mg (morning dose of 150 mg Ranitidine twice daily)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑4%<br/> (1.04; 0.88 -1.23)↑<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓3%<br/> (0.97; 0.84 -1.12)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Esomeprazole (Nexium®) (Increase in gastric pH)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 40 mg (every morning for 5 days, Day -4 to 1)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑2%<br/> (1.02; 0.88-1.17)↑<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑5%<br/> (1.05; 0.89 -1.24)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Metoclopramide (Reglan®) (Increase in gastric motility)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 15 mg four times daily for 2 days (Day -1 and 1)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓14% (0.86, 0.73,1.02)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓7%<br/> (0.93, 0.803,1.07)<br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> * Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for C<span class="Sub">max</span> or AUC<span class="Sub">0-last</span>.<br/> </p> </td> </tr> </tbody> </table></div>

Distribution:

Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.

Metabolism:

Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.

Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers </span> </caption> <col width="21%"/> <col width="20%"/> <col width="20%"/> <col width="21%"/> <col width="20%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold"> Coadministered Drug (Postulated</span> <br/> <span class="Bold"> Mechanism of Interaction)</span> <br/> </p> </td><td class="Botrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold"> Coadministered Drug Dose/Schedule</span> <br/> </p> </td><td class="Botrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold"> Posaconazole Dose/Schedule</span> <br/> </p> </td><td class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> Effect on Bioavailability of Posaconazole</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Change in Mean Cmax</span> <br/> (ratio estimate*; 90%<br/> CI of the ratio estimate)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Change in Mean AUC</span> <br/> (ratio estimate*; 90%<br/> CI of the ratio estimate)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Efavirenz<br/> (UDP-G Induction)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 400 mg once daily × 10 and 20 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 400 mg (oral suspension) twice daily × 10 and 20 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓45%<br/> (0.55; 0.47-0.66)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓45%<br/> (0.55; 0.47-0.66)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Fosamprenavir (unknown mechanism)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 700 mg twice daily x 10 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily x 8 Days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓21%<br/> 0.79 (0.71-0.89)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓23%<br/> 0.77 (0.68-0.87)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Rifabutin<br/> (UDP-G Induction)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 300 mg once daily x 17 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 200 mg (tablets) once daily<br/> × 10 days†<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓ 43%<br/> (0.57; 0.43-0.75)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓ 49%<br/> (0.51; 0.37-0.71)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Phenytoin<br/> (UDP-G Induction)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 200 mg once daily x 10 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 200 mg (tablets) once daily<br/> × 10 days†<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓ 41%<br/> (0.59; 0.44-0.79)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↓ 50%<br/> (0.50; 0.36-0.71)<br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> * Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC.<br/> † The tablet refers to a non-commercial tablet formulation without polymer.<br/> </p> </td> </tr> </tbody> </table></div>

In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 28 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Volunteers and Patients </span> </caption> <col width="17%"/> <col width="19%"/> <col width="21%"/> <col width="21%"/> <col width="21%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold"> Coadministered Drug </span> (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)<br/> </p> </td><td class="Botrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold"> Coadministered Drug Dose/Schedule</span> <br/> </p> </td><td class="Botrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold"> Posaconazole Dose/ Schedule</span> <br/> </p> </td><td class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold"> Effect on Bioavailability of Coadministered</span> <br/> <span class="Bold"> Drugs</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Change in Mean Cmax</span> <br/> (ratio estimate*;<br/> 90% CI of the ratio estimate)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Change in Mean AUC</span> <br/> (ratio estimate*; 90% CI of the ratio estimate)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Sirolimus<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2-mg single oral dose<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 400 mg (oral suspension)<br/> twice daily x 16 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 572%<br/> (6.72; 5.62-8.03)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 788%<br/> (8.88; 7.26-10.9)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Cyclosporine<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Stable maintenance dose in heart transplant recipients<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 200 mg (tablets)<br/> once daily x 10 days†<br/> </p> </td><td class="Botrule Rrule" colspan="2" valign="top"> <p class="First"> ↑ cyclosporine whole blood trough concentrations<br/> Cyclosporine dose reductions of up to 29% were required<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Tacrolimus<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 0.05-mg/kg single oral dose<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 400 mg (oral suspension)<br/> twice daily × 7 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 121%<br/> (2.21; 2.01-2.42)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 358%<br/> (4.58; 4.03-5.19)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> Simvastatin<br/> </p> </td><td class="Botrule Rrule" rowspan="2" valign="top"> <p class="First"> 40-mg single oral dose<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> 100 mg (oral suspension)<br/> once daily x 13 days<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> Simvastatin<br/> ↑ 841%<br/> (9.41, 7.13-12.44)<br/> Simvastatin Acid<br/> ↑ 817%<br/> (9.17, 7.36-11.43)<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> Simvastatin<br/> ↑ 931%<br/> (10.31, 8.40-12.67)<br/> Simvastatin Acid<br/> ↑ 634%<br/> (7.34, 5.82-9.25)<br/> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> 200 mg (oral suspension)<br/> once daily x 13 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Simvastatin<br/> ↑ 1041%<br/> (11.41, 7.99-16.29)<br/> Simvastatin Acid<br/> ↑ 851%<br/> (9.51, 8.15-11.10)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> Simvastatin<br/> ↑ 960%<br/> (10.60, 8.63-13.02)<br/> Simvastatin Acid<br/> ↑748%<br/> (8.48, 7.04-10.23)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="4" valign="top"> <p class="First"> Midazolam<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> 0.4-mg single<br/> intravenous dose‡<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> 200 mg (oral suspension)<br/> twice daily x 7 days<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> ↑ 30%<br/> (1.3; 1.13-1.48)<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> ↑ 362%<br/> (4.62; 4.02-5.3)<br/> </p> </td> </tr> <tr> <td class="Rrule" valign="top"> <p class="First"> 0.4-mg single<br/> intravenous dose‡<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> 400 mg (oral suspension)<br/> twice daily x 7 days<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> ↑62<br/> (1.62; 1.41-1.86)<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> ↑524%<br/> (6.24; 5.43-7.16)<br/> </p> </td> </tr> <tr> <td class="Rrule" valign="top"> <p class="First"> 2-mg single oral dose‡<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> 200 mg (oral suspension) once daily x 7 days<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> ↑ 169%<br/> (2.69; 2.46-2.93)<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> ↑ 470%<br/> (5.70; 4.82-6.74)<br/> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> 2-mg single oral dose‡<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 400 mg (oral suspension) twice daily x 7 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 138%<br/> (2.38; 2.13-2.66)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 397%<br/> (4.97; 4.46-5.54)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Rifabutin<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 300 mg once daily x 17 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 200 mg (tablets)<br/> once daily × 10 days†<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 31%<br/> (1.31; 1.10-1.57)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 72%<br/> (1.72;1.51-1.95)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Phenytoin<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 200 mg once daily PO x 10 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 200 mg (tablets) <br/> once daily x 10 days†<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 16%<br/> (1.16; 0.85-1.57)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 16%<br/> (1.16; 0.84-1.59)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Ritonavir<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 100 mg once daily x 14 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 400 mg (oral suspension) twice daily x 7 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 49%<br/> (1.49; 1.04-2.15)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 80%<br/> (1.8;1.39-2.31)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> Atazanavir<br/> Atazanavir/<br/> ritonavir boosted<br/> regimen<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> 300 mg once daily x 14 days<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> 400 mg (oral suspension)<br/> twice daily x 7 days<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> ↑ 155%<br/> (2.55; 1.89-3.45)<br/> </p> </td><td class="Rrule" valign="top"> <p class="First"> ↑ 268%<br/> (3.68; 2.89-4.70)<br/> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> 300 mg/100 mg once daily x 14 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 400 mg (oral suspension)<br/> twice daily x 7 days<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 53%<br/> (1.53; 1.13-2.07)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> ↑ 146%<br/> (2.46; 1.93-3.13)<br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> * Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.<br/> † The tablet refers to a non-commercial tablet formulation without polymer.<br/> ‡ The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole.<br/> </p> </td> </tr> </tbody> </table></div>

Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg once daily.

Excretion:

Following administration of Noxafil® oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug). Posaconazole delayed-release tablet is eliminated with a mean half-life (t½) ranging between 26 to 31 hours.

Specific Patients

No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis).

Race/Ethnicity:

In a population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure.

Patients Weighing More Than 120 kg:

Weight has a clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)].

Pediatric Patients

A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of Noxafil oral suspension for prophylaxis of invasive fungal infections. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (≥18 years of age). In a study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with Noxafil oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2,500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.

Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.'s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp & Dohme Corp.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Mechanism of Action:

Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.

Resistance:

Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.

Antimicrobial Activity:

Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].

Microorganisms:

Aspergillus spp. and Candida spp.

Susceptibility Testing:

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see:

https://www.fda.gov/STIC.

Carcinogenesis

No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times the exposure achieved with a 400-mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400-mg twice daily oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with a 400-mg twice daily oral suspension regimen.

Mutagenesis

Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study.

Impairment of Fertility

Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 x the 400-mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 x the 400-mg twice daily oral suspension regimen).

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5 -month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in a separate study of 10-week old dogs dosed with intravenous posaconazole for 13 weeks with a 9-week recovery period or a follow-up study of 31-week old dogs dosed for 3 months.

Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems.

The first study (Noxafil® Oral Suspension Study 1) was a randomized, double-blind trial that compared Noxafil® oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may have met more than one of these criteria). This assessed all patients while on study therapy plus 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (80 days, posaconazole; 77 days, fluconazole). Table 32 contains the results from Noxafil® Oral Suspension Study 1.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 32: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Noxafil<span class="Sup">®</span> Oral Suspension Study 1 </span> </caption> <col width="48%"/> <col width="25%"/> <col width="26%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Posaconazole n=301</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Fluconazole n=299</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">On therapy plus 7 days</span></span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Clinical Failure*</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 50 (17%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 55 (18%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Failure due to:</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Proven/Probable IFI<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 7 (2%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 22 (7%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (<span class="Italics">Aspergillus</span> )<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 3 (1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 17 (6%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (<span class="Italics">Candida</span> )<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 1 (&lt;1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 3 (1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (Other)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 3 (1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2 (1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> All Deaths<br/> Proven/probable fungal<br/> infection prior to death<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 22 (7%)<br/> 2 (&lt;1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 24 (8%)<br/> 6 (2%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> SAF†<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 27 (9%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 25 (8%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Through 16 weeks</span></span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Clinical Failure*,‡</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 99 (33%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 110 (37%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Failure due to:</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Proven/Probable IFI<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 16 (5%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 27 (9%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (<span class="Italics">Aspergillus</span> )<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 7 (2%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 21 (7%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (<span class="Italics">Candida</span> )<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 4 (1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 4 (1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (Other)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 5 (2%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2 (1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> All Deaths<br/> Proven/probable fungal<br/> infection prior to death<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 58 (19%)<br/> 10 (3%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 59 (20%)<br/> 16 (5%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> SAF†<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 26 (9%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 30 (10%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Event free lost to follow-up§<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 24 (8%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 30 (10%)<br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> * Patients may have met more than one criterion defining failure.<br/> † Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage &gt;4 consecutive days).<br/> ‡ 95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%).<br/> § Patients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. These patients were considered failures.<br/> </p> </td> </tr> </tbody> </table></div>

The second study (Noxafil® Oral Suspension Study 2) was a randomized, open-label study that compared Noxafil® oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Noxafil® Oral Suspension Study 1, efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). This study assessed patients while on treatment plus 7 days and 100 days postrandomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 33 contains the results from Noxafil® Oral Suspension Study 2.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 33: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Noxafil<span class="Sup">®</span> Oral Suspension Study 2 </span> </caption> <col width="40%"/> <col width="28%"/> <col width="31%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Posaconazole n=304</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Fluconazole/Itraconazole n=298</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">On therapy plus 7 days</span></span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Clinical Failure*,†</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 82 (27%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 126 (42%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Failure due to:</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Proven/Probable IFI<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 7 (2%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 25 (8%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (<span class="Italics">Aspergillus</span> )<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2 (1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 20 (7%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (<span class="Italics">Candida</span> )<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 3 (1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2 (1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (Other)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2 (1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 3 (1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> All Deaths<br/> Proven/probable fungal<br/> infection prior to death<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 17 (6%)<br/> 1 (&lt;1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 25 (8%)<br/> 2 (1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> SAF‡<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 67 (22%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 98 (33%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Through 100 days postrandomization</span></span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Clinical Failure†</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 158 (52%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 191 (64%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold"> Failure due to:</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Proven/Probable IFI<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 14 (5%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 33 (11%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (<span class="Italics">Aspergillus</span> )<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2 (1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 26 (9%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (<span class="Italics">Candida</span> )<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 10 (3%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 4 (1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> (Other)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 2 (1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 3 (1%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> All Deaths<br/> Proven/probable fungal<br/> infection prior to death<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 44 (14%)<br/> 2 (1%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 64 (21%)<br/> 16 (5%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> SAF‡<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 98 (32%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 125 (42%)<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Event free lost to follow-up§<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 34 (11%)<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> 24 (8%)<br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> * 95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%).<br/> † Patients may have met more than one criterion defining failure.<br/> ‡ Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage &gt;3 consecutive days).<br/> § Patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures.<br/> </p> </td> </tr> </tbody> </table></div>

In summary, 2 clinical studies of prophylaxis were conducted with the Noxafil® oral suspension. As seen in the accompanying tables (Tables 32 and 33), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Noxafil® Oral Suspension Study 1 (Table 32), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole–comparator -11.5% to 3.7%) while in Noxafil® Oral Suspension Study 2 (Table 33) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole–comparator -22.9% to   7.8%).

All-cause mortality was similar at 16 weeks for both treatment arms in Noxafil® Oral Suspension Study 1 [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in Noxafil® Oral Suspension Study 2 [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.

Posaconazole delayed-release tablets are available as yellow-coated, capsule shaped tablets, debossed with "100P" on one side and plain on the other side.

Cartons of 20 delayed-release tablets (10 delayed-release each blister pack x 2), NDC 0904-7149-10 

Cartons of 30 delayed-release tablets (10 delayed-release each blister pack x 3), NDC 0904-7149-04

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

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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Important Administration Instructions

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Advise patients that posaconazole delayed-release tablets must be swallowed whole and not divided, crushed, or chewed.

{ "type": "p", "children": [], "text": "Advise patients that posaconazole delayed-release tablets must be swallowed whole and not divided, crushed, or chewed." }

Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

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Drug Interactions

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Advise patients to inform their physician immediately if they:

{ "type": "p", "children": [], "text": "Advise patients to inform their physician immediately if they:" }

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

Serious and Potentially Serious Adverse Reactions

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Advise patients to inform their physician immediately if they:

{ "type": "p", "children": [], "text": "Advise patients to inform their physician immediately if they:" }

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Manufactured by:

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AET Laboratories Private Limited

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Telangana state, 502319,

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India

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Manufactured for:

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Lupin Pharmaceuticals, Inc.

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Naples, FL 34108

{ "type": "p", "children": [], "text": "Naples, FL 34108" }

United States

{ "type": "p", "children": [], "text": "United States" }

Packaged and Distributed by:

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MAJOR® PHARMACEUTICALS

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

Indianapolis, IN 46268 USA

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

Refer to package label for Distributor's NDC Number

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December 2024

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

The trademarks referenced herein are owned by their respective companies.

{ "type": "p", "children": [], "text": "The trademarks referenced herein are owned by their respective companies." }

All rights reserved.

{ "type": "p", "children": [], "text": "All rights reserved." }

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First Toprule"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold"> Patient Information</span> <br/> <span class="Bold"> Posaconazole </span> (poe sa kon a zole)<span class="Bold"> delayed-release tablets</span> <br/> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> What is posaconazole delayed-release tablets?</span> <br/> Posaconazole delayed-release tablets are prescription medicines used in adults and children 13 years of age and older to help prevent fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Posaconazole delayed-release tablets are used in people who have an increased chance of getting these infections due to a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a low white blood cell count due to chemotherapy for blood cancers (hematologic malignancy).<br/> It is not known if posaconazole delayed-release tablets are safe and effective in children under 2 years of age.<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> Who should not take posaconazole delayed-release tablets?</span> <br/> <span class="Bold"> Do not take posaconazole delayed-release tablets if you:</span> <br/> •    are allergic to posaconazole, any of the ingredients in posaconazole delayed-release tablets, or other azole antifungal medicines. See the end of this leaflet for a complete list of ingredients in posaconazole delayed-release tablets.<br/> •    are taking any of the following medicines:<br/>     •    sirolimus<br/>     •    pimozide<br/>     •    quinidine<br/>     •    certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)<br/>     •    ergot alkaloids (ergotamine, dihydroergotamine)<br/> •    have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.<br/> Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. <br/> Do not start taking a new medicine without talking to your healthcare provider or pharmacist.<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> What should I tell my healthcare provider before taking posaconazole delayed-release tablets?</span> <br/> <br/> <span class="Bold"> Before you take posaconazole delayed-release tablets, tell your healthcare provider if you:</span> <br/> •    are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.<br/> •    are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause a decrease in the posaconazole delayed-release tablets <br/> •    levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole delayed-release tablets.<br/> •    are taking midazolam, a hypnotic and sedative medicine.<br/> •    are taking vincristine, vinblastine and other "vinca alkaloids" (medicines used to treat cancer).<br/> •    are taking venetoclax, a medicine used to treat cancer.<br/> •    have or had liver problems.<br/> •    have or had kidney problems.<br/> •    have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.<br/> •    are pregnant or plan to become pregnant. It is not known if posaconazole delayed-release tablets will harm your unborn baby.<br/> •    are breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole delayed-release tablets or breastfeed. You should not do both.<br/> <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. Posaconazole delayed-release tablets can affect the way other medicines work, and other medicines can affect the way posaconazole delayed-release tablets work and can cause serious side effects.<br/> Especially tell your healthcare provider if you take:<br/> •    rifabutin or phenytoin. If you are taking these medicines, you should not take posaconazole delayed-release tablets.<br/> Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.<br/> Know the medicines you take. Keep a list of them with you to show your healthcare provider or pharmacist when you get a new medicine.<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> How will I take posaconazole delayed-release tablets?</span> <br/> •    <span class="Bold"> Do not switch between posaconazole oral suspension and Posaconazole delayed-release tablets or posaconazole powdermix for delayed-release oral suspension.</span> <br/> •    Take posaconazole delayed-release tablets exactly as your healthcare provider tells you to take them.<br/> •    Your healthcare provider will tell you how many posaconazole delayed-release tablets to take and when to take it.<br/> •    Take posaconazole delayed-release tablets for as long as your healthcare provider tells you to take it.<br/> •    If you take too many posaconazole delayed-release tablets, call your healthcare provider or go to the nearest hospital emergency room right away.<br/> •    Take posaconazole delayed-release tablets with or without food.<br/> •    Take posaconazole delayed-release tablets whole. Do not break, crush, or chew posaconazole delayed-release tablets before swallowing. If you cannot swallow posaconazole delayed-release tablets whole, tell your healthcare provider. You may need a different medicine.<br/> •    If you miss a dose, take it as soon as you remember and then take your next scheduled dose at its regular time. If it is within 12 hours of your next dose, do not take the missed dose. Skip the missed dose and go back to your regular schedule. Do not double your next dose or take more than your prescribed dose.<br/> Follow the instructions from your healthcare provider on how many posaconazole delayed-release tablets you should take and when to take them.<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> What are the possible side effects of posaconazole delayed-release tablets?</span> <br/> <span class="Bold"> Posaconazole delayed-release tablets may cause serious side effects, including:</span> <br/> •    <span class="Bold"> drug interactions with cyclosporine or tacrolimus. </span> If you take posaconazole delayed-release tablets with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole delayed-release tablets. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.<br/> •    <span class="Bold"> problems with the electrical system of your heart (arrhythmias and QTc prolongation). </span> Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole delayed-release tablets, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.<br/> •    <span class="Bold"> changes in body salt (electrolytes) levels in your blood. </span> Your healthcare provider should check your electrolytes while you are taking posaconazole delayed-release tablets. <br/> •    <span class="Bold"> liver problems. </span> Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of posaconazole delayed-release tablets. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole delayed-release tablets. Call your healthcare provider right away if you have any of the following symptoms of liver problems:<br/>     •    itchy skin<br/>     •    nausea or vomiting<br/>     •    yellowing of your eyes<br/>     •    flu-like symptoms<br/>     •    feeling very tired<br/> <br/> •    <span class="Bold"> increased amounts of midazolam in your blood. </span> If you take posaconazole delayed-release tablets with midazolam, posaconazole delayed-release tablets increase the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole delayed-release tablets.<br/> <br/> <span class="Bold"> The most common side effects of posaconazole delayed-release tablets include:</span> <br/>     •    diarrhea<br/>     •    nausea<br/>     •    fever<br/>     •    vomiting<br/>     •    headache<br/>     •    coughing<br/>     •    low potassium levels in the blood<br/> If you take posaconazole delayed-release tablets, tell your healthcare provider right away if you have diarrhea or vomiting.<br/> Tell your healthcare provider if you have any side effect that bothers you or that does not go away.<br/> These are not all the possible side effects of posaconazole delayed-release tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> How should I store posaconazole delayed-release tablets?</span> <br/>     •    Store posaconazole delayed-release tablets at room temperature between 68°F to 77°F (20°C to 25°C).<br/>     •    Safely throw away medicine that is out of date or no longer needed.<br/> <span class="Bold"> Keep posaconazole delayed-release tablets and all medicines out of the reach of children.</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> General information about the safe and effective use of posaconazole delayed-release tablets.</span> <br/> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use posaconazole delayed-release tablets for a condition for which it was not prescribed. Do not give posaconazole delayed-release tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about posaconazole delayed-release tablets that is written for health professionals.<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"> What are the ingredients in posaconazole delayed-release tablets? </span> <br/> <span class="Bold"> Active ingredient: </span> posaconazole <br/> <span class="Bold"> Inactive ingredients: </span> partially neutralized methacrylic acid and ethyl acrylate copolymer, triethyl citrate, xylitol, hydroxypropyl cellulose, propyl gallate, cellulose, microcrystalline, silica, colloidal anhydrous, croscarmellose sodium, sodium stearyl fumarate and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, macrogol, polyethylene glycol, titanium dioxide, talc, and iron oxide yellow).<br/> <span class="Italics">Additional Pediatric Use information is approved for Merck Sharp &amp; Dohme Corp.'s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp &amp; Dohme Corp.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.</span> <br/> </p> </td> </tr> <tr class="Botrule Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Manufactured by:<br/> <span class="Bold"> AET Laboratories Private Limited</span> <br/> Telangana state, 502319,<br/> India<br/> Manufactured for:<br/> <span class="Bold"> Lupin Pharmaceuticals, Inc.</span> <br/> Naples, FL 34108<br/> United States</p> <p> <br/> <span class="Bold">Packaged and Distributed by:</span> </p> <p> <span class="Bold">MAJOR® PHARMACEUTICALS</span> </p> <p>Indianapolis, IN 46268 USA</p> <p>Refer to package label for Distributor's NDC Number</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Toprule\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"> Patient Information</span>\n<br/>\n<span class=\"Bold\"> Posaconazole </span> (poe sa kon a zole)<span class=\"Bold\"> delayed-release tablets</span>\n<br/>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"> What is posaconazole delayed-release tablets?</span>\n<br/> Posaconazole delayed-release tablets are prescription medicines used in adults and children 13 years of age and older to help prevent fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Posaconazole delayed-release tablets are used in people who have an increased chance of getting these infections due to a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a low white blood cell count due to chemotherapy for blood cancers (hematologic malignancy).<br/> It is not known if posaconazole delayed-release tablets are safe and effective in children under 2 years of age.<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"> Who should not take posaconazole delayed-release tablets?</span>\n<br/>\n<span class=\"Bold\"> Do not take posaconazole delayed-release tablets if you:</span>\n<br/> •    are allergic to posaconazole, any of the ingredients in posaconazole delayed-release tablets, or other azole antifungal medicines. See the end of this leaflet for a complete list of ingredients in posaconazole delayed-release tablets.<br/> •    are taking any of the following medicines:<br/>     •    sirolimus<br/>     •    pimozide<br/>     •    quinidine<br/>     •    certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)<br/>     •    ergot alkaloids (ergotamine, dihydroergotamine)<br/> •    have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.<br/> Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. <br/> Do not start taking a new medicine without talking to your healthcare provider or pharmacist.<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"> What should I tell my healthcare provider before taking posaconazole delayed-release tablets?</span>\n<br/>\n<br/>\n<span class=\"Bold\"> Before you take posaconazole delayed-release tablets, tell your healthcare provider if you:</span>\n<br/> •    are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.<br/> •    are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause a decrease in the posaconazole delayed-release tablets <br/> •    levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole delayed-release tablets.<br/> •    are taking midazolam, a hypnotic and sedative medicine.<br/> •    are taking vincristine, vinblastine and other \"vinca alkaloids\" (medicines used to treat cancer).<br/> •    are taking venetoclax, a medicine used to treat cancer.<br/> •    have or had liver problems.<br/> •    have or had kidney problems.<br/> •    have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.<br/> •    are pregnant or plan to become pregnant. It is not known if posaconazole delayed-release tablets will harm your unborn baby.<br/> •    are breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole delayed-release tablets or breastfeed. You should not do both.<br/>\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. Posaconazole delayed-release tablets can affect the way other medicines work, and other medicines can affect the way posaconazole delayed-release tablets work and can cause serious side effects.<br/> Especially tell your healthcare provider if you take:<br/> •    rifabutin or phenytoin. If you are taking these medicines, you should not take posaconazole delayed-release tablets.<br/> Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.<br/> Know the medicines you take. Keep a list of them with you to show your healthcare provider or pharmacist when you get a new medicine.<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"> How will I take posaconazole delayed-release tablets?</span>\n<br/> •    <span class=\"Bold\"> Do not switch between posaconazole oral suspension and Posaconazole delayed-release tablets or posaconazole powdermix for delayed-release oral suspension.</span>\n<br/> •    Take posaconazole delayed-release tablets exactly as your healthcare provider tells you to take them.<br/> •    Your healthcare provider will tell you how many posaconazole delayed-release tablets to take and when to take it.<br/> •    Take posaconazole delayed-release tablets for as long as your healthcare provider tells you to take it.<br/> •    If you take too many posaconazole delayed-release tablets, call your healthcare provider or go to the nearest hospital emergency room right away.<br/> •    Take posaconazole delayed-release tablets with or without food.<br/> •    Take posaconazole delayed-release tablets whole. Do not break, crush, or chew posaconazole delayed-release tablets before swallowing. If you cannot swallow posaconazole delayed-release tablets whole, tell your healthcare provider. You may need a different medicine.<br/> •    If you miss a dose, take it as soon as you remember and then take your next scheduled dose at its regular time. If it is within 12 hours of your next dose, do not take the missed dose. Skip the missed dose and go back to your regular schedule. Do not double your next dose or take more than your prescribed dose.<br/> Follow the instructions from your healthcare provider on how many posaconazole delayed-release tablets you should take and when to take them.<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"> What are the possible side effects of posaconazole delayed-release tablets?</span>\n<br/>\n<span class=\"Bold\"> Posaconazole delayed-release tablets may cause serious side effects, including:</span>\n<br/> •    <span class=\"Bold\"> drug interactions with cyclosporine or tacrolimus. </span> If you take posaconazole delayed-release tablets with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole delayed-release tablets. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.<br/> •    <span class=\"Bold\"> problems with the electrical system of your heart (arrhythmias and QTc prolongation). </span> Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole delayed-release tablets, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.<br/> •    <span class=\"Bold\"> changes in body salt (electrolytes) levels in your blood. </span> Your healthcare provider should check your electrolytes while you are taking posaconazole delayed-release tablets. <br/> •    <span class=\"Bold\"> liver problems. </span> Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of posaconazole delayed-release tablets. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole delayed-release tablets. Call your healthcare provider right away if you have any of the following symptoms of liver problems:<br/>     •    itchy skin<br/>     •    nausea or vomiting<br/>     •    yellowing of your eyes<br/>     •    flu-like symptoms<br/>     •    feeling very tired<br/>\n<br/> •    <span class=\"Bold\"> increased amounts of midazolam in your blood. </span> If you take posaconazole delayed-release tablets with midazolam, posaconazole delayed-release tablets increase the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole delayed-release tablets.<br/>\n<br/>\n<span class=\"Bold\"> The most common side effects of posaconazole delayed-release tablets include:</span>\n<br/>     •    diarrhea<br/>     •    nausea<br/>     •    fever<br/>     •    vomiting<br/>     •    headache<br/>     •    coughing<br/>     •    low potassium levels in the blood<br/> If you take posaconazole delayed-release tablets, tell your healthcare provider right away if you have diarrhea or vomiting.<br/> Tell your healthcare provider if you have any side effect that bothers you or that does not go away.<br/> These are not all the possible side effects of posaconazole delayed-release tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"> How should I store posaconazole delayed-release tablets?</span>\n<br/>     •    Store posaconazole delayed-release tablets at room temperature between 68°F to 77°F (20°C to 25°C).<br/>     •    Safely throw away medicine that is out of date or no longer needed.<br/>\n<span class=\"Bold\"> Keep posaconazole delayed-release tablets and all medicines out of the reach of children.</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"> General information about the safe and effective use of posaconazole delayed-release tablets.</span>\n<br/> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use posaconazole delayed-release tablets for a condition for which it was not prescribed. Do not give posaconazole delayed-release tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about posaconazole delayed-release tablets that is written for health professionals.<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"> What are the ingredients in posaconazole delayed-release tablets? </span>\n<br/>\n<span class=\"Bold\"> Active ingredient: </span> posaconazole <br/>\n<span class=\"Bold\"> Inactive ingredients: </span> partially neutralized methacrylic acid and ethyl acrylate copolymer, triethyl citrate, xylitol, hydroxypropyl cellulose, propyl gallate, cellulose, microcrystalline, silica, colloidal anhydrous, croscarmellose sodium, sodium stearyl fumarate and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, macrogol, polyethylene glycol, titanium dioxide, talc, and iron oxide yellow).<br/>\n<span class=\"Italics\">Additional Pediatric Use information is approved for Merck Sharp &amp; Dohme Corp.'s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp &amp; Dohme Corp.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr class=\"Botrule Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\"> Manufactured by:<br/>\n<span class=\"Bold\"> AET Laboratories Private Limited</span>\n<br/> Telangana state, 502319,<br/> India<br/> Manufactured for:<br/>\n<span class=\"Bold\"> Lupin Pharmaceuticals, Inc.</span>\n<br/> Naples, FL 34108<br/> United States</p>\n<p>\n<br/>\n<span class=\"Bold\">Packaged and Distributed by:</span>\n</p>\n<p>\n<span class=\"Bold\">MAJOR® PHARMACEUTICALS</span>\n</p>\n<p>Indianapolis, IN 46268 USA</p>\n<p>Refer to package label for Distributor's NDC Number</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration.                   Revised: December 2024

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

ID#: 40942

{ "type": "p", "children": [], "text": "ID#: 40942" }

MAJOR®

{ "type": "p", "children": [], "text": "MAJOR®" }

NDC 0904-7149-04

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Unit Dose

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Posaconazole

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

Delayed-Release

{ "type": "p", "children": [], "text": "\nDelayed-Release\n" }

Tablets

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

100 mg

{ "type": "p", "children": [], "text": "\n100 mg\n" }

30 TABLETS (3 x 10)

{ "type": "p", "children": [], "text": "30 TABLETS (3 x 10)" }

Rx only

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