POSACONAZOLE tablet, delayed release

Posaconazole by

Drug Labeling and Warnings

Posaconazole by is a Prescription medication manufactured, distributed, or labeled by Amneal Pharmaceuticals NY LLC, Amneal Pharmaceuticals, LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    1.2 Prophylaxis of Invasive Aspergillus and Candida Infections

    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 as follows:

    • Posaconazole delayed-release tablets: adults and pediatric patients 2 years of age and older who weigh greater than 40 kg

    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.


  • 2 DOSAGE AND ADMINISTRATION

    2.1 Important Administration Instructions

    Noxafil injection, posaconazole delayed-release tablets, Noxafil oral suspension and Noxafil PowderMix for delayed-release oral suspension are supplied in different dose strengths of posaconazole, are approved for different indications, age groups and weights; have different dosages and duration of therapy; and have different preparation and administration instructions.

    Therefore, select the recommended dosage form based on the indication, age group, and weight and carefully follow the recommended dosage, preparation and administration instructions described for each product [see Dosage and Administration (2.2 to 2.11)], and the following important administration instructions described below.

    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

    • Swallow tablets whole. Do not divide, crush, or chew.
    • Administer with or without food [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].
    • For patients who cannot eat a full meal, posaconazole delayed-release tablets should be used instead of Noxafil oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Noxafil oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.

    2.2 Recommended Dosage of Posaconazole Delayed-Release Tablets in Adult Patients

    The recommended dosage of posaconazole delayed-release tablets in adult patients 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 is shown in Table 1 [see Dosage and Administration (2.7, 2.9) and Clinical Pharmacology (12.3)].

    Table 1: Recommended Dosage of Posaconazole Delayed-Release Tablets in Adult Patients

    Dosage

    Duration of Therapy

    Prophylaxis of Invasive Aspergillus and Candida Infections

    Posaconazole Delayed-Release Tablets:
    Loading dose:
    300 mg (three 100 mg delayed-release tablets) twice a day on the first day.

    Maintenance dose:
    300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day.

    Loading dose:
    1 day

    Maintenance dose:
    Duration of therapy is based on recovery from neutropenia or immunosuppression

    2.3 Recommended Dosage of Posaconazole Delayed-Release Tablets for the Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients 2 Years of Age and Older

    Posaconazole delayed-release tablets

    The recommended dosage of posaconazole delayed-release tablets in pediatric patients 2 years of age and older who weigh greater than 40 kg for the prophylaxis of invasive Aspergillus and Candida infections is shown in Table 2 [see Dosage and Administration (2.7, 2.9) and Clinical Pharmacology (12.3)].

    Posaconazole delayed-release tablets are not recommended for use in pediatric patients who weigh 40 kg or less because the recommended dosage cannot be achieved with this dosage form.

    Table 2: Recommended Dosage of Posaconazole Delayed-Release Tablets for the Prophylaxis of Invasive Aspergillus and Candida

    Infections in Pediatric Patients (2 Years of Age and Older)

    Recommended Pediatric Dosage by Formulation

    Duration of Therapy

    Posaconazole Delayed-Release Tablets (patients weighing greater than 40 kg):
    Loading dose:
    300 mg (three 100 mg delayed-release tablets) twice a day on the first day.

    Maintenance dose:
    300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day.

    Prophylaxis of invasive Aspergillus and Candida infections:
    Duration of therapy is based on recovery from neutropenia or immunosuppression.
    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.

    2.7 Administration Instructions for Posaconazole Delayed-Release Tablets

    • Swallow the posaconazole delayed-release tablets whole. Do not divide, crush, or chew.
    • Administer posaconazole delayed-release tablets orally with or without food [see Clinical Pharmacology (12.3)].
    • Posaconazole delayed-release tablets should be used only for the prophylaxis indication [see Dosage and Administration (2.1)].

    2.9 Non-substitutability between Noxafil Oral Suspension and Other Formulations

    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)].

    2.11 Dosage Modifications in Patients with Renal Impairment

    The recommended dosage of posaconazole delayed-release tablets is the same in patients with renal impairment compared to those with normal renal function.


  • 3 DOSAGE FORMS AND STRENGTHS

    Posaconazole Delayed-Release Tablets

    Posaconazole delayed-release tablets are available as yellow, oblong, film coated, unscored tablets, debossed with "AC71" on one side and plain on other side containing 100 mg of posaconazole.

  • 4 CONTRAINDICATIONS

    4.1 Hypersensitivity

    Posaconazole delayed-release tablets are contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.

    4.2 Use with Sirolimus

    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 (7.2) and Clinical Pharmacology (12.3)].

    4.3 QT Prolongation with Concomitant Use with CYP3A4 Substrates

    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)].

    4.4 HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4

    Co-administration 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 (7.2) and Clinical Pharmacology (12.3)].

    4.5 Use with Ergot Alkaloids

    Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.2)].

    4.6 Use with Venetoclax

    Co-administration 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 (7.2)].

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Calcineurin-Inhibitor Toxicity

    Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.2) 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.

    5.2 Arrhythmias and QT Prolongation

    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)].

    5.3 Electrolyte Disturbances

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

    5.4 Pseudoaldosteronism

    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.

    5.5 Hepatic Toxicity

    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.

    5.6 Renal Impairment

    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 (2.11) and Use in Specific Populations (8.6)].

    5.7 Midazolam Toxicity

    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 (7.2) and Clinical Pharmacology (12.3)].

    5.8 Vincristine Toxicity

    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 (7.2)].

    5.10 Breakthrough Fungal Infections

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

    5.11 Venetoclax Toxicity

    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 co-administering posaconazole with venetoclax [see Drug Interactions (7.2)]. Refer to the venetoclax prescribing information for dosing instructions.

  • 6 ADVERSE REACTIONS

    The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling:

    6.1 CLINICAL TRIALS EXPERIENCE

    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 with Posaconazole Delayed-Release Tablets for Prophylaxis of Invasive Aspergillus and Candida Infections

    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 to 78 years, 17% of patients were ≥65 years of age), and were 93% White and 16% Hispanic. Posaconazole delayed-release tablets were given for a median duration of 28 days. In this study, 20 adult patients received 200 mg daily dosage (this is not a recommended dosage [see Dosage and Administration (2.2)]) and 210 adult patients received 300 mg daily dosage (following twice daily dosing on Day 1 in each cohort). Table 9 presents adverse reactions (incidence of ≥10%) observed in patients treated with the posaconazole delayed-release tablets 300 mg daily dosage in the Posaconazole Delayed-Release Tablet Study.

    The most frequently reported adverse reactions (>25%) in patients treated 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%).

    Table 9: Adverse Reactions in at least 10% of Adults Receiving Posaconazole Delayed-Release Tablets (300 mg Daily Dosage) for the Prophylaxis of Invasive Aspergillus and Candida infections

    Adverse Reactions

    Posaconazole delayed-release tablet
    (300 mg)
    n=210
    (%)

    Percentage of Patients Reporting any Adverse Reaction

    99

    Diarrhea

    29

    Pyrexia

    28

    Nausea

    27

    Hypokalemia

    22

    Cough

    17

    Edema Peripheral

    16

    Rash

    16

    Epistaxis

    14

    Headache

    14

    Mucosal Inflammation

    14

    Thrombocytopenia

    14

    Vomiting

    13

    Abdominal Pain

    11

    Hypertension

    11

    Anemia

    10

    Asthenia

    10

    Chills

    10

    Constipation

    10

    Hypomagnesemia

    10

    Additional Adverse Reactions Reported in Less Than 5% of Posaconazole-Treated Patients in Clinical Trials

    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

    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.

    6.2 Postmarketing Experience

    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 or establish a causal relationship to drug exposure.

    Endocrine Disorders: Pseudoaldosteronism

  • 7 DRUG INTERACTIONS

    Table 15 and Table 17 include drugs with clinically important drug interactions when administered concomitantly with posaconazole and Noxafil PowderMix and instructions for preventing or managing them.

    These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy [see Clinical Pharmacology (12.3)].

    The following information was derived from data with Noxafil oral suspension or another posaconazole tablet formulation unless otherwise noted. All clinically important drug interactions with Noxafil oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to clinically important drug interactions with Noxafil injection, posaconazole delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension [Clinical Pharmacology (12.3)].

    Consult the labeling of concomitantly used drugs to obtain further information about interactions with posaconazole.

    7.1 Effects of Other Drugs on Posaconazole and Noxafil PowderMix

    Posaconazole is primarily metabolized via UDP-glucuronosyltransferase and is a substrate of p-­glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Concomitant use of posaconazole with drugs that can decrease the plasma posaconazole concentrations should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

    Table 15: Drug Interactions Affecting Posaconazole and Noxafil PowderMix When Administered Concomitantly with Other Drugs

    UDP-Glucuronidase Inducers

    Mechanism and Clinical Effect(s)

    Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of posaconazole with UDP-glucuronidase inducers may decrease posaconazole exposure [see Clinical Pharmacology (12.3)], which may reduce the effectiveness of posaconazole.

    Prevention or Management

    Efavirenz

    Avoid concomitant use of posaconazole with efavirenz, unless the benefit outweighs the risks.

    Rifabutin

    Avoid concomitant use of posaconazole with rifabutin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor closely for breakthrough fungal infections. See Table 17 for rifabutin monitoring considerations when posaconazole affects rifabutin via CYP3A4 inhibition.

    Phenytoin

    Avoid concomitant use of posaconazole with phenytoin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor for breakthrough fungal infections. See Table 17 for phenytoin monitoring considerations when posaconazole affects phenytoin via CYP3A4 inhibition.

    Fosamprenavir

    Mechanism and Clinical Effect(s)

    Concomitant use of posaconazole with fosamprenavir may lead to decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of posaconazole.

    Prevention or Management

    If concomitant use of posaconazole with fosamprenavir is needed, monitor closely for breakthrough fungal infections.

    7.2 Effects of Posaconazole and Noxafil PowderMix on Other Drugs

    Posaconazole is a strong CYP3A4 inhibitor. Therefore, concomitant use of posaconazole may increase plasma concentrations of drugs that are CYP3A4 substrates [see Clinical Pharmacology (12.3)].

    Table 17: Drug Interactions Affecting Drugs Administered Concomitantly with Posaconazole and Noxafil PowderMix

    Digoxin

    Clinical Effect(s)

    Increased digoxin plasma concentrations have been reported in patients who received concomitant posaconazole and digoxin.

    Prevention or Management

    Monitor digoxin plasma concentrations during concomitant use of posaconazole .

    Glipizide

    Clinical Effect(s)

    No dosage modification of glipizide is needed when used concomitantly with posaconazole. However, glucose concentrations decrease in some patients concomitantly administered posaconazole and glipizide.

    Prevention or Management

    Increase monitoring of glucose concentrations when used concomitantly.

    CYP3A Substrates

    Immunosuppressants that are CYP3A4 Substrates

    Mechanism and Clinical Effect(s)

    Posaconazole is a strong CYP3A4 inhibitor. Therefore, plasma concentrations of CYP3A4 substrates may be increased by posaconazole use [see Clinical Pharmacology (12.3)].

    Prevention or Management

    Sirolimus

    Posaconazole is contraindicated with sirolimus [see Clinical Pharmacology (12.3)].

    Tacrolimus

    • At initiation of posaconazole treatment, reduce the tacrolimus dosage to approximately one-third of the original tacrolimus dosage.
    • Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dosage should be modified accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

    Cyclosporine

    • At initiation of posaconazole treatment reduce the cyclosporine dosage to approximately three-fourths of the original dosage.
    • Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dosage should be modified accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

    CYP3A4 Substrates that Prolong QTc Interval

    Mechanism and Clinical Effect(s)

    Concomitant use of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of the CYP3A4 substrates leading to QTc interval prolongation and torsades de pointes [see Warnings and Precautions (5.2)].

    Prevention or Management

    Pimozide

    Concomitant use with posaconazole is contraindicated.

    Quinidine

    HMG-CoA Reductase Inhibitors (Statins) that are CYP3A4 Substrates

    Mechanism and Clinical Effect(s)

    Concomitant use of posaconazole with simvastatin increased simvastatin plasma concentrations which can lead to rhabdomyolysis [see Clinical Pharmacology (12.3)].

    Prevention or Management

    Atorvastatin, Lovastatin, Simvastatin

    Concomitant use with posaconazole is contraindicated.

    Benzodiazepines that are CYP3A4 Substrates

    Mechanism and Clinical Effect(s)

    Concomitant use of posaconazole with midazolam increased midazolam plasma concentrations which could potentiate and prolong hypnotic and sedative effects [see Clinical Pharmacology (12.3)].

    Prevention or Management

    Midazolam, Alprazolam, Triazolam

    Closely monitor for adverse reactions associated with high plasma concentrations of benzodiazepines that are CYP3A4 substrates during concomitant use, and a benzodiazepine receptor antagonist should be available to reverse effects [see Warnings and Precautions (5.7)].

    Calcium Channel Blockers that are CYP3A4 Substrates

    Mechanism and Clinical Effect(s)

    Posaconazole may increase the plasma concentrations of calcium channel blockers that are substrates of CYP3A4.

    Prevention or Management

    Verapamil, Diltiazem, Nifedipine, Nicardipine, Felodipine

    Monitor frequently for adverse reactions and toxicity with concomitant use of posaconazole with calcium channel blockers that are CYP3A4 substrates. Dosage reduction of the calcium channel blocker may be needed.

    Anti-HIV Drugs that are CYP3A4 Substrates

    Mechanism and Clinical Effect(s)

    Ritonavir and atazanavir are CYP3A4 substrates and posaconazole increased plasma concentrations of these drugs [see Clinical Pharmacology (12.3)].

    Prevention or Management

    Ritonavir and Atazanavir

    Monitor frequently for adverse reactions and toxicity of ritonavir and atazanavir during concomitant use.

    Antineoplastic Drugs that are CYP3A4 Substrates

    Mechanism and Clinical Effect(s)

    Posaconazole may increase plasma concentrations of oncology drugs that are CYP3A4 substrates, which may increase the risk of serious adverse reactions.

    Prevention or Management

    Venetoclax

    CLL/SLL patients: Concomitant use of posaconazole with venetoclax during initiation and ramp-up phase is contraindicated.

    AML patients: With concomitant use, venetoclax dosage reduction and safety monitoring is recommended across all dosing phases [see Warnings and Precautions (5.11)].

    Vinca alkaloids (e.g., vincristine, vinblastine)

    Reserve concomitant use for patients with no alternative antifungal treatment options [see Warnings and Precautions (5.8)].

    Ergot Alkaloids

    Mechanism and Clinical Effect(s)

    Most of the ergot alkaloids are CYP3A4 substrates. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.

    Prevention or Management

    Ergotamine, Dihydroergot amine

    Concomitant use with posaconazole is contraindicated.

    Phenytoin

    Mechanism and Clinical Effect(s)

    Phenytoin is a CYP3A4 substrate. Concomitant use of posaconazole with phenytoin increased phenytoin plasma concentrations [see Clinical Pharmacology (12.3)].

    Prevention or Management

    Avoid concomitant use of posaconazole with phenytoin unless the benefit outweighs the risk. frequently monitor phenytoin concentrations and consider a dosage reduction of phenytoin. See Table 15 for additional monitoring considerations when phenytoin affects posaconazole via UDP-glucuronosyltransferase inhibition.

    Rifabutin

    Mechanism and Clinical Effect(s)

    Rifabutin is a CYP3A4 substrate. Concomitant use of posaconazole with rifabutin increased rifabutin plasma concentrations [see Clinical Pharmacology (12.3)].

    Prevention or Management

    Avoid concomitant use of posaconazole with rifabutin unless the benefit outweighs the risk. Frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) during concomitant use are recommended. See Table 15 for additional monitoring considerations when rifabutin affects posaconazole via UDP-glucuronosyltransferase inhibition.

    7.3 Absence of Clinically Important Interaction with Posaconazole and Noxafil PowderMix

    Additional clinical studies demonstrated that no clinically important 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 drugs when co-administered with posaconazole 200 mg once daily.

    No clinically relevant effects on the pharmacokinetics of posaconazole delayed-release tablets were observed during concomitant use with antacids, H2-receptor antagonists and proton pump inhibitors, and metoclopramide [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required during concomitant use with these drugs.

    No clinically relevant effects on the pharmacokinetics of Noxafil oral suspension were observed during concomitant use with antacids, H2-receptor antagonists (other than cimetidine), and loperamide [see Clinical Pharmacology (12.3)]. No dosage adjustment of Noxafil oral suspension is required during concomitant use with these drugs (other than cimetidine).

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    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 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, doses of ≥ 3 times the clinical exposure caused an increase in resorptions (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 populations 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.

    8.2 Lactation

    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.

    8.4 Pediatric Use

    The three posaconazole dosage forms (injection, delayed-release tablets, oral suspension) and one Noxafil PowderMix (for delayed-release oral suspension) dosage form are different products; are approved for different pediatric indications, age groups, and weights; have different dosing regimens; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the pediatric indication, age group, and weight [see Dosage and Administration (2.1)].

    Prophylaxis of Invasive Aspergillus and Candida Infections

    The safety and effectiveness of posaconazole delayed-release tablets have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 2 years of age and older who are at high risk of developing these infections due to being severely immunocompromised. Use of posaconazole for these pediatric indications is supported by adequate and well controlled studies of posaconazole in adults and pediatric patients aged 2 years of age and older and additional PK and safety data in pediatric patients 2 years of age and older [see Clinical Pharmacology (12.3) and Clinical studies (14)].

    The safety and effectiveness of posaconazole have not been established in pediatric patients less 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.

    8.5 Geriatric Use

    No overall differences in the safety or effectiveness of posaconazole delayed-release tablets have been observed between geriatric patients and younger adult patients in the clinical trials; therefore, the recommended dosage in geriatric patients is the same as that for younger adult patients. No clinically meaningful differences in posaconazole pharmacokinetics were observed in posaconazole-treated geriatric patients compared to posaconazole-treated younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].

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

    8.6 Renal Impairment

    Posaconazole Delayed-Release Tablets

    No dosage adjustment is required for patients with eGFR 20 mL/minute/1.73 m2 or higher. Due to variability in posaconazole exposure, closely monitor patients with eGFR less than 20 mL/minute/1.73 m2 for breakthrough fungal infections [see Clinical Pharmacology (12.3)].

    8.7 Hepatic Impairment

    No dosage adjustment is recommended for posaconazole delayed-release tablets in patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) [see Clinical Pharmacology (12.3)].

    However, a specific hepatic impairment study has not been conducted with the posaconazole delayed-release tablets.

    8.8 Sex

    No adjustment in the dosage of posaconazole is necessary based on sex.

    8.9 Race

    No adjustment in the dosage of posaconazole is necessary based on race.

    8.10 Weight

    Pharmacokinetic modeling suggests that patients who weigh greater than 120 kg may have lower posaconazole plasma drug exposure. Therefore, consider closely monitoring for breakthrough fungal infections [see Clinical Pharmacology (12.3)].

  • 10 OVERDOSAGE

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

    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 1200 mg twice daily Noxafil oral suspension for 3 days. No related adverse reactions were noted by the investigator.

    Posaconazole is not removed by hemodialysis.

  • 11 DESCRIPTION

    Posaconazole delayed-release tablets contain posaconazole, an azole antifungal agent.

    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-2­hydroxypropyl]-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:

    Structural Formula

    Posaconazole is a white powder with a low aqueous solubility.

    Posaconazole Delayed-Release Tablets

    Posaconazole delayed-release tablet, for oral use, are yellow, oblong, film coated, unscored tablets containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, ferrosoferric oxide black, hydroxypropylcellulose, hypromellose acetate succinate, iron oxide yellow, Macrogol/PEG 3350, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol partially hydrolyzed, talc and titanium dioxide.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

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

    12.2 Pharmacodynamics

    Exposure Response Relationship: Prophylaxis of invasive Aspergillus and Candida Infections in Adults Who Are at High Risk of Developing These Infections Due to Being Severely Immunocompromised

    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 posaconazole exposures 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 18). 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 18: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials

    Prophylaxis in AML/MDS*

    Prophylaxis in GVHD†

    Cavg Range (ng/mL)

    Treatment Failure‡ (%)

    Cavg Range (ng/mL)

    Treatment Failure‡ (%)

    Quartile 1

    90 to 322

    54.7

    22 to 557

    44.4

    Quartile 2

    322 to 490

    37.0

    557 to 915

    20.6

    Quartile 3

    490 to 734

    46.8

    915 to 1563

    17.5

    Quartile 4

    734 to 2200

    27.8

    1563 to 3650

    17.5

    Cavg = the average posaconazole concentration when measured at steady-state

    * Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS

    † HSCT recipients with GVHD

    ‡ Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections

    12.3 Pharmacokinetics

    General Pharmacokinetic Characteristics

    General Pharmacokinetic Characteristics of Posaconazole Delayed-Release Tablets

    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 21.

    Table 21: Arithmetic Mean (%CV) of Steady-State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)*

    N

    AUC0-24 hr (ng·hr/mL)

    Cav† (ng/mL)

    Cmax (ng/mL)

    Cmin (ng/mL)

    ‡Tmax (hr)

    t1/2
    (hr)

    CL/F (L/hr)

    Healthy Volunteers

    12

    51618 (25)

    2151 (25)

    2764 (21)

    1785 (29)

    4 (3 to 6)

    31 (40)

    7.5 (26)

    Patients

    50

    37900 (42)

    1580 (42)

    2090 (38)

    1310 (50)

    4 (1.3­8.3)

    -

    9.39 (45)

    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; t&frac12; = terminal phase half-life; CL/F = Apparent total body clearance

    * 300 mg twice daily on Day 1, then 300 mg once daily thereafter

    † Cav = time-averaged concentrations (i.e., AUC0-24 hr/24 hr)

    ‡ Median (minimum-maximum)

    Absorption:

    Absorption of Posaconazole Delayed-Release Tablets

    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 are increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see Table 23).

    Table 23: 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

    Fasting Conditions

    Fed Conditions
    (High Fat Meal)*

    Fed/Fasting

    Pharmacokinetic Parameter

    N

    Mean (%CV)

    N

    Mean (%CV)

    GMR (90% CI)

    Cmax (ng/mL)

    14

    935 (34)

    16

    1060 (25)

    1.16 (0.96, 1.41)

    AUC0-72hr (hr∙ng/mL)

    14

    26200 (28)

    16

    38400 (18)

    1.51 (1.33, 1.72)

    Tmax† (hr)

    14

    5.00
    (3.00, 8.00)

    16

    6.00
    (5.00, 24.00)

    N/A

    GMR=Geometric least-squares mean ratio; CI=Confidence interval

    * 48.5 g fat

    † Median (Min, Max) reported for Tmax

    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 a substrate for p-glycoprotein (P-gp) efflux.

    In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4.

    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). Noxafil injection is eliminated with a mean terminal half-life (t&frac12;) of 27 hours and a total body clearance (CL) of 7.3 L/h.

    Posaconazole delayed-release tablet is eliminated with a mean half-life (t&frac12;) ranging between 26 to 31 hours.

    Noxafil oral suspension is eliminated with a mean half-life (t&frac12;) 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).

    Patients with Renal Impairment:

    After posaconazole oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m2 or higher compared to those with eGFR>80 mL/minute/1.73 m2. Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m2 treated with Noxafil oral suspension to those with eGFR >80 mL/minute/1.73 m2 treated with Noxafil oral suspension, the range of the AUC estimates was highly variable (CV=96%) in patients with eGFR less than 20 mL/minute/1.73 m2 compared to those with eGFR>80 mL/minute/1.73 m2 (CV<40%).Similar posaconazole pharmacokinetic results are expected after administration of posaconazole delayed-release tablets [see Use in Specific Populations (8.6)].

    Patients with Hepatic Impairment:

    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 [see Use in Specific Populations (8.7)].

    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 [see Use in Specific Populations (8.9)].

    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 2500 ng/mL was attained in approximately 50% of patients instead of the prespecified 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.

     

    Drug Interaction Studies:

    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 another tablet formulation, which affect posaconazole concentrations, is provided in Table 28.

    Table 30 include a summary of the drug effects of concomitant medications that may impact the absorption of posaconazole when administered as either the oral suspension or delayed-release tablets.

    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 31 [see Contraindications (4) and Drug Interactions (7.2) including recommendations].

    Effects of Other Drugs on Posaconazole:

    Table 28: Summary of the Effects of Co-administered Drugs on Posaconazolein Healthy Volunteers

    Co-administered Drug (Postulated Mechanism of Interaction)

    Co-administered Drug Dose/Schedule

    Posaconazole Dose/Schedule

    Effect on Bioavailability of Posaconazole

    Change in Mean Cmax (ratio estimate*; 90% CI of the ratio estimate)

    Change in Mean AUC (ratio estimate*; 90% CI of the ratio estimate)

    Efavirenz
    (UDP-G Induction)

    400 mg once
    daily × 10 and
    20 days

    400 mg (oral suspension) twice daily × 10 and
    20 days

    ↓45%
    (0.55; 0.47 to 0.66)

    ↓ 50%
    (0.50; 0.43 to 0.60)

    Fosamprenavir (unknown mechanism)

    700 mg twice
    daily x 10 days

    200 mg once daily on the 1st day,
    200 mg twice daily on the 2nd day,
    then 400 mg twice daily x 8 Days

    ↓21%
    0.79 (0.71 to 0.89)

    ↓23%
    0.77 (0.68 to 0.87)

    Rifabutin
    (UDP-G Induction)

    300 mg once
    daily x 17 days

    200 mg (tablets) once daily ×
    10 days†

    ↓ 43%
    (0.57; 0.43 to 0.75)

    ↓ 49%
    (0.51; 0.37 to ­0.71)

    Phenytoin
    (UDP-G Induction)

    200 mg once
    daily x 10 days

    200 mg (tablets) once daily ×
    10 days†

    ↓ 41%
    (0.59; 0.44 to ­0.79)

    ↓ 50%
    (0.50; 0.36 to ­0.71)

    * Ratio Estimate is the ratio of co-administered drug plus posaconazole to posaconazole alone for Cmax or AUC.

    † The tablet refers to a non-commercial tablet formulation without polymer.

    Posaconazole Delayed-Release Tablets: 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 30).

    Table 30: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy Volunteers

    Co-administered Drug

    Administration Arms

    Change in Cmax (ratio estimate*; 90% CI of the ratio estimate)

    Change in AUC0-last (ratio estimate*; 90% CI of the ratio estimate)

    Mylanta® Ultimate strength liquid (Increase in gastric pH)

    25.4 mEq/5 mL, 20 mL

    ↑6%
    (1.06; 0.90 to 1.26)↑

    ↑4%
    (1.04; 0.90 to 1.20)

    Ranitidine (Zantac®) (Alteration in gastric pH)

    150 mg (morning dose of 150 mg Ranitidine twice daily)

    ↑4%
    (1.04; 0.88 to 1.23)↑

    ↓3%
    (0.97; 0.84 to 1.12)

    Esomeprazole (Nexium®) (Increase in gastric pH)

    40 mg (every morning for 5 days, Day -4 to 1)

    ↑2%
    (1.02; 0.88 to 1.17)↑

    ↑5%
    (1.05; 0.89 to 1.24)

    Metoclopramide (Reglan®)
    (Increase in gastric motility)

    15 mg four times daily for 2 days (Day -1 and 1)

    ↓14%
    (0.86, 0.73,1.02)

    ↓7%
    (0.93, 0.803,1.07)

    * Ratio Estimate is the ratio of co-administered drug plus Noxafil to Noxafil alone for Cmax or AUC0-last.

    Effects of Posaconazoleand Noxafil PowderMix on Other Drugs:

    Table 31: Summary of the Effects of Posaconazoleon Co-administered Drugs in Healthy Adult Volunteers and Patients

    Co-administered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)

    Co-administered Drug Dose/Schedule

    PosaconazoleDose/ Schedule

    Effect on Bioavailability of Co-administered Drugs

    Change in Mean Cmax
    (ratio estimate*; 90% CI of the ratio estimate)

    Change in Mean AUC
    (ratio estimate*; 90% CI of the ratio estimate)

    Sirolimus

    2-mg single oral dose

    400 mg (oral suspension) twice daily x 16 days

    ↑ 572%
    (6.72; 5.62 to 8.03)

    ↑ 788%
    (8.88; 7.26 to 10.9)

    Cyclosporine

    Stable maintenance dose in heart transplant recipients

    200 mg (tablets) once daily x 10 days†

    ↑ Cyclosporine whole blood trough concentrations

    Cyclosporine dose reductions of up to 29% were required

    Tacrolimus

    0.05-mg/kg single oral dose

    400 mg (oral suspension) twice daily × 7 days

    ↑ 121%
    (2.21; 2.01 to 2.42)

    ↑ 358%
    (4.58; 4.03 to 5.19)

    Simvastatin

    40-mg single oral dose

    100 mg (oral suspension) once daily x 13 days

    200 mg (oral suspension) once daily x 13 days

    Simvastatin
    ↑ 841%
    (9.41, 7.13­ to 12.44) Simvastatin Acid
    ↑ 817%
    (9.17, 7.36 to ­11.43)

    Simvastatin
    ↑ 1041%
    (11.41, 7.99 to ­16.29) Simvastatin Acid ↑851%
    (9.51, 8.15­ to 11.10)

    Simvastatin
    ↑ 931%
    (10.31, 8.40 to ­12.67) Simvastatin Acid ↑634%
    (7.34, 5.82 to 9.25)

    Simvastatin
    ↑ 960%
    (10.60, 8.63 to ­13.02) Simvastatin Acid
    ↑ 748%
    (8.48, 7.04 to ­10.23)

    Midazolam

    0.4-mg single intravenous dose‡

    0.4-mg single intravenous dose‡

    2-mg single oral dose‡

    2-mg single oral dose‡

    200 mg (oral suspension) twice daily x 7 days

    400 mg (oral suspension) twice daily x 7 days

    200 mg (oral suspension) once daily x 7 days

    400 mg (oral suspension) twice daily x 7 days

    ↑ 30%
    (1.3; 1.13 to 1.48)

    ↑62%
    (1.62; 1.41 to 1.86)

    ↑ 169%
    (2.69; 2.46 to 2.93)

    ↑ 138%
    (2.38; 2.13 to 2.66)

    ↑ 362%
    (4.62; 4.02 to 5.3)

    ↑524%
    (6.24; 5.43 to 7.16)

    ↑ 470%
    (5.70; 4.82 to 6.74)

    ↑ 397%
    (4.97; 4.46 to 5.54)

    Rifabutin

    300 mg once daily x 17 days

    200 mg (tablets) once daily × 10 days†

    ↑ 31%
    (1.31; 1.10 to 1.57)

    ↑ 72%
    (1.72;1.51 to 1.95)

    Phenytoin

    200 mg once daily PO x 10 days

    200 mg (tablets) once daily x 10 days†

    ↑ 16%
    (1.16; 0.85 to 1.57)

    ↑ 16%
    (1.16; 0.84 to 1.59)

    Ritonavir

    100 mg once daily x 14 days

    400 mg (oral suspension) twice daily x 7 days

    ↑ 49%
    (1.49; 1.04 to 2.15)

    ↑ 80%
    (1.8;1.39 to 2.31)

    Atazanavir

    Atazanavir/ ritonavir boosted regimen

    300 mg once daily x 14 days

    300 mg/100 mg once daily x 14 days

    400 mg (oral suspension) twice daily x 7 days

    400 mg (oral suspension) twice daily x 7 days

    ↑ 155%
    (2.55; 1.89 to 3.45)

    ↑ 53%
    (1.53; 1.13 to 2.07)

    ↑ 268%
    (3.68; 2.89 to 4.70)

    ↑ 146%
    (2.46; 1.93 to 3.13)

    * Ratio Estimate is the ratio of co-administered drug plus posaconazole to co-administered drug alone for Cmax or AUC.

    † The tablet refers to a non-commercial tablet formulation without polymer.

    ‡ The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during co-administration with posaconazole.

    12.4 MICROBIOLOGY

    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.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    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).

  • 14 CLINICAL STUDIES

    14.2 Prophylaxis of Aspergillus and Candida Infections with Noxafil Oral Suspension

    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 34 contains the results from Noxafil Oral Suspension Study 1.

    Table 34: 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

    Posaconazole
    n=301

    Fluconazole
    n=299

    On therapy plus 7 days

    Clinical Failure*

    50 (17%)

    55 (18%)

    Failure due to:

    Proven/Probable IFI

    7 (2%)

    22 (7%)

    (Aspergillus)

    3 (1%)

    17 (6%)

    (Candida)

    1 (<1%)

    3 (1%)

    (Other)

    3 (1%)

    2 (1%)

    All Deaths

    22 (7%)

    24 (8%)

    Proven/probable fungal infection prior to death

    2 (<1%)

    6 (2%)

    SAF†

    27 (9%)

    25 (8%)

    Through 16 weeks

    Clinical Failure*,‡

    99 (33%)

    110 (37%)

    Failure due to:

    Proven/Probable IFI

    16 (5%)

    27 (9%)

    (Aspergillus)

    7 (2%)

    21 (7%)

    (Candida)

    4 (1%)

    4 (1%)

    (Other)

    5 (2%)

    2 (1%)

    All Deaths

    58 (19%)

    59 (20%)

    Proven/probable fungal infection prior to death

    10 (3%)

    16 (5%)

    SAF†

    26 (9%)

    30 (10%)

    Event free lost to follow-up§

    24 (8%)

    30 (10%)

    * Patients may have met more than one criterion defining failure.

    † Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days).

    ‡ 95% confidence interval (posaconazole-fluconazole) = (-11.5%,+3.7%).

    § 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.

    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 post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 35 contains the results from Noxafil Oral Suspension Study 2.

    Table 35: 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

    Posaconazole
    n=304

    Fluconazole/Itraconazole
    n=298

    On therapy plus 7 days

    Clinical Failure*,†

    82 (27%)

    126 (42%)

    Failure due to:

    Proven/Probable IFI

    7 (2%)

    25 (8%)

    (Aspergillus)

    2 (1%)

    20 (7%)

    (Candida)

    3 (1%)

    2 (1%)

    (Other)

    2 (1%)

    3 (1%)

    All Deaths

    17 (6%)

    25 (8%)

    Proven/probable fungal infection prior to death

    1 (<1%)

    2 (1%)

    SAF‡

    67 (22%)

    98 (33%)

    Through 100 days post-randomization

    Clinical Failure†

    158 (52%)

    191 (64%)

    Failure due to:

    Proven/Probable IFI

    14 (5%)

    33 (11%)

    (Aspergillus)

    2 (1%)

    26 (9%)

    (Candida)

    10 (3%)

    4 (1%)

    (Other)

    2 (1%)

    3 (1%)

    All Deaths

    44 (14%)

    64 (21%)

    Proven/probable fungal infection prior to death

    2 (1%)

    16 (5%)

    SAF‡

    98 (32%)

    125 (42%)

    Event free lost to follow-up§

    34 (11%)

    24 (8%)

    * 95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%).

    † Patients may have met more than one criterion defining failure.

    ‡ Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days).

    § 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.

    In summary, 2 clinical studies of prophylaxis were conducted with the Noxafil oral suspension. As seen in the accompanying tables (Table 34 and Table 35), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Noxafil Oral Suspension Study 1 (Table 34), 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 35) 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.


  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1 How Supplied

    Posaconazole Delayed-Release Tablets

    Posaconazole delayed-release tablets 100 mg are available as yellow, oblong, film coated, unscored tablets, debossed with "AC71" on one side and plain on other side. They are supplied as follows:

    Bottles of 30 with child-resistant closure:                              NDC: 69238-1476-3.
    Bottles of 60 with child-resistant closure:                              NDC: 69238-1476-6.

    16.2 Storage and Handling

    Posaconazole Delayed-Release Tablets

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

  • 17 PATIENT COUNSELING INFORMATION

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

    Important Administration Instructions

    Posaconazole Delayed-Release Tablets

    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.

    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.

    The trademarks referenced herein are owned by their respective companies.

    Distributed by:
    Amneal Pharmaceuticals LLC
    Bridgewater, NJ 08807

    Rev. 03-2026-03

  • Patient Information

     Posaconazole (poe”sa kon’a zole) Delayed-Release Tablets


    What are posaconazole delayed-release tablets?

    Posaconazole delayed-release tablets are prescription medicines 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 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 malignancies).

    Posaconazole delayed-release tablets are used for:

    • prevention of fungal infections in adults and children 2 years of age and older who weigh greater than 88 lbs (40 kg).

    It is not known if posaconazole delayed-release tablets is safe and effective in children under 2 years of age.

    Do not take posaconazole delayed-release tablets if you:

    • are allergic to posaconazole, any of the ingredients in posaconazole delayed-release tablets, or other azole antifungal medicines. See the end of this Patient Information leaflet for a complete list of ingredients in posaconazole delayed-release tablets.
    • are taking any of the following medicines:
    • sirolimus
    • pimozide
    • quinidine
    • certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)
    • 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.

    Before you take posaconazole delayed-release tablets, tell your healthcare provider about all of your medical conditions, including 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 delayed-release tablets.
    • 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 delayed-release tablets 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 delayed-release tablets 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 delayed-release tablets can affect the way other medicines work, and other medicines can affect the way posaconazole delayed-release tablets, and can cause serious side effects.

    Especially tell your healthcare provider if you take:

    • rifabutin or phenytoin. If you are taking these medicines, you should not take posaconazole delayed-release tablets.

    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.

    How should I take posaconazole delayed-release tablets?

    • Do not switch between Noxafil oral suspension and posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension.
    • Take posaconazole delayed-release tablets exactly as your healthcare provider tells you to take it.
    • Your healthcare provider will tell you how much posaconazole delayed-release tablets to take and when to take it.
    • Take posaconazole delayed-release tablets for as long as your healthcare provider tells you to take it.
    • If you take too much posaconazole delayed-release tablets, call your healthcare provider or go to the nearest hospital emergency room right away.
    • Posaconazole delayed-release tablets:
    • Take posaconazole delayed-release tablets with or without food.
    • 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.
    • 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.

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

    What are the possible side effects of posaconazole delayed-release tablets?

    Posaconazole delayed-release tablets may cause serious side effects, including:

    • drug interactions with cyclosporine or tacrolimus. 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.
    • 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 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.
    • changes in body salt (electrolytes) levels in your blood. Your healthcare provider should check your electrolytes while you are taking posaconazole delayed-release tablets.
    • ·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 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:
    • itchy skin
    • onausea or vomiting
    • flu-like symptoms
    • feeling very tired
    • yellowing of your eyes or skin
    • increased amounts of midazolam in your blood. If you take posaconazole delayed-release tablets with midazolam, posaconazole delayed-release tablets 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 delayed-release tablets.

    The most common side effects of posaconazole delayed-release tablets in adults include:

    • diarrhea
    • ·nausea
    • fever
    • ·vomiting
    • headache
    • coughing
    • low potassium levels in the blood

    If you take posaconazole delayed-release tablets, tell your healthcare provider right away if you have diarrhea or vomiting.

    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 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.

    How should I store posaconazole delayed-release tablets?

    Posaconazole delayed-release tablets

    • Store posaconazole delayed-release tablets at room temperature between 68°F to 77°F (20°C to 25°C).

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

    Keep posaconazole delayed-release tablets and all medicines out of the reach of children.

    General information about the safe and effective use of posaconazole delayed-release tablets.

    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.

    What are the ingredients in posaconazole delayed-release tablets?

    Active ingredient: posaconazole

    Inactive ingredients:

    Posaconazole delayed-release tablets: colloidal silicon dioxide, croscarmellose sodium, ferrosoferric oxide black, hydroxypropylcellulose, hypromellose acetate succinate, iron oxide yellow, Macrogol/PEG 3350, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide.

    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.

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

    Distributed by:
    Amneal Pharmaceuticals LLC
    Bridgewater, NJ 08807

    For more information, go to www.amneal.com or call 1-877-835-5472.

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

    Rev. 03-2026-03

  • PRINCIPAL DISPLAY PANEL

    30ct label
  • INGREDIENTS AND APPEARANCE
    POSACONAZOLE 
    posaconazole tablet, delayed release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 69238-1476
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    POSACONAZOLE (UNII: 6TK1G07BHZ) (POSACONAZOLE - UNII:6TK1G07BHZ) POSACONAZOLE100 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
    HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)  
    HYPROMELLOSE ACETATE SUCCINATE 06081224 (3 MM2/S) (UNII: 6N003M473W)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)  
    TALC (UNII: 7SEV7J4R1U)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    ColoryellowScoreno score
    ShapeOVAL (oblong) Size18mm
    FlavorImprint Code AC71
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 69238-1476-330 in 1 BOTTLE; Type 0: Not a Combination Product12/30/2022
    2NDC: 69238-1476-660 in 1 BOTTLE; Type 0: Not a Combination Product12/30/2022
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21662612/30/2022
    Labeler - Amneal Pharmaceuticals NY LLC (123797875)
    Establishment
    NameAddressID/FEIBusiness Operations
    Amneal Pharmaceuticals, LLC053542455analysis(69238-1476) , label(69238-1476) , manufacture(69238-1476) , pack(69238-1476)
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