{ "meta": { "disclaimer": "Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service.", "terms": "https://open.fda.gov/terms/", "license": "https://open.fda.gov/license/", "last_updated": "2026-09-23", "results": { "skip": 0, "limit": 1, "total": 1 } }, "results": [ { "spl_product_data_elements": [ "POSACONAZOLE posaconazole POSACONAZOLE POSACONAZOLE HYPROMELLOSE ACETATE SUCCINATE 06081224 (3 MM2/S) MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (90000 WAMW) CROSCARMELLOSE SODIUM SILICON DIOXIDE MAGNESIUM STEARATE POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL 3350 TALC FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE M;100 convex" ], "recent_major_changes": [ "RECENT MAJOR CHANGES Warnings and Precautions, Pseudoaldosteronism (5.4) 10/2024 Indications and Usage ( 1.2 ) 01/2026 Dosage and Administration ( 2 ) 01/2026" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Posaconazole delayed-release tablets are an azole antifungal indicated as follows: 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: ( 1.2 ) Posaconazole delayed-release tablets : adults and pediatric patients 13 years of age and older 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 13 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." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Posaconazole delayed-release tablets are not substitutable with Noxafil ® Oral Suspension 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. ( 2.1 , 2.2 , 2.3 ) Administer posaconazole delayed-release tablets with or without food. ( 2.1 ) See the full prescribing information for important administration instructions and preparation instructions for posaconazole delayed-release tablets ( 2.7 , 2.9 ). For adult and pediatric patients aged 13 years of age and older, see the Full Prescribing Information for dosing recommendations for posaconazole delayed-release tablets based on the indication, age, and weight associated with the dosage form ( 1.2 , 2.1 , 2.2 , 2.3 ) 2.1 Important Administration Instructions Non-substitutable Posaconazole delayed-release tablets are not substitutable with Noxafil ® Oral Suspension 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. 2.2 Recommended Dosage of Posaconazole Delayed-Release Tablets in Adult Patients The recommended dosage of posaconazole delayed-release tablets in adult patients for 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 (ages 13 to less than 18 years of age) Posaconazole delayed-release tablets The recommended dosage of posaconazole delayed-release tablets in pediatric patients 13 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 (13 to less than 18 years of age) 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 tablets whole. Do not divide, crush, or chew. Administer posaconazole delayed-release tablets with or without food [see Clinical Pharmacology (12.3) ] . 2.9 Non-Substitutability Between Noxafil ® Oral Suspension and Other Formulations Posaconazole delayed-release tablets are not substitutable with Noxafil ® Oral Suspension 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." ], "dosage_and_administration_table": [ "
Table 1: Recommended Dosage of Posaconazole Delayed-Release Tablets in Adult Patients
DosageDuration 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
", "
Table 2: Recommended Dosage of Posaconazole Delayed-Release Tablets for the Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (13 to less than 18 years of age)
Recommended Pediatric Dosage by FormulationDuration 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.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Posaconazole delayed-release tablets are available as yellow, modified, oval, convex tablets debossed with a logo \"M\" inside a square on one side and \"100\" on the opposite side containing 100 mg of posaconazole. Posaconazole delayed-release tablet: 100 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS Known hypersensitivity to posaconazole or other azole antifungal agents. ( 4.1 ) Coadministration of posaconazole delayed-release tablets with the following drugs is contraindicated; posaconazole delayed-release tablets increase concentrations and toxicities of: Sirolimus ( 4.2 , 7.2 ) CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) ( 4.3 , 5.2 , 7.2 ) HMG-CoA Reductase Inhibitors Primarily Metabolized through CYP3A4 ( 4.4 , 7.2 ) Ergot alkaloids ( 4.5 , 7.2 ) Venetoclax: In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp-up phase ( 4.6 , 5.11 , 7.2 ) 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 delayed-release tablets are contraindicated with sirolimus. Concomitant administration of posaconazole delayed-release tablets 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 delayed-release tablets are contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole delayed-release tablets 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 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 (7.2) 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 Coadministration of posaconazole delayed-release tablets 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) ] ." ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Calcineurin-Inhibitor Toxicity : Posaconazole delayed-release tablets increase concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. ( 5.1 ) Arrhythmias and QTc Prolongation : Posaconazole delayed-release tablets have been shown to prolong the QTc interval and cause cases of TdP. Administer with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs known to prolong QTc interval and metabolized through CYP3A4. ( 5.2 , 7.2 ) Electrolyte Disturbances : Monitor and correct, especially those involving potassium (K + ), magnesium (Mg ++ ), and calcium (Ca ++ ), before and during posaconazole delayed-release tablets therapy. ( 5.3 ) Pseudoaldosteronism : Manifested by the onset or worsening of hypertension, and abnormal laboratory findings. Monitor blood pressure and potassium levels, and manage as necessary. ( 5.4 ) Hepatic Toxicity : Elevations in liver tests may occur. Discontinuation should be considered in patients who develop abnormal liver tests or monitor liver tests during treatment. ( 5.5 ) Concomitant Use with Midazolam : Posaconazole delayed-release tablets can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. ( 5.7 , 7.2 ) Vincristine Toxicity : Concomitant administration of azole antifungals, including posaconazole delayed-release tablets, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole delayed-release tablets, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. ( 5.8 , 7.2 ) Breakthrough Fungal Infections : Monitor patients with severe diarrhea or vomiting when receiving posaconazole delayed-release tablets. ( 5.10 ) Venetoclax Toxicity : Concomitant administration of posaconazole delayed-release tablets with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. ( 4.6 , 5.11 , 7.2 ) 5.1 Calcineurin-Inhibitor Toxicity Concomitant administration of posaconazole delayed-release tablets 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 (18-85 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 delayed-release tablets, 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, Noxafil ® Oral Suspension, and Noxafil ® PowderMix for Delayed-Release Oral Suspension, 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 delayed-release tablets 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 delayed-release tablets, 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 delayed-release tablets, 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 delayed-release tablets, 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 delayed-release tablets 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 delayed-release tablets with venetoclax [see Drug Interactions (7.2) ] . Refer to the venetoclax prescribing information for dosing instructions." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2) ] Electrolyte Disturbances [see Warnings and Precautions (5.3) ] Pseudoaldosteronism [see Warnings and Precautions (5.4) ] Hepatic Toxicity [see Warnings and Precautions (5.5) ] Common adverse reactions in studies with posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Par Health at 1-800-778-7898 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole delayed-release tablets 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 P osaconazole 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 postchemotherapy, 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 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 Tablets 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 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" ], "adverse_reactions_table": [ "
Adverse ReactionsPosaconazole delayed-release tablet (300 mg) n=210 (%)
Percentage of Patients Reporting any Adverse Reaction 99
Diarrhea29
Pyrexia28
Nausea27
Hypokalemia22
Cough17
Edema Peripheral16
Rash 16
Epistaxis14
Headache14
Mucosal Inflammation14
Thrombocytopenia14
Vomiting13
Abdominal Pain11
Hypertension11
Anemia10
Asthenia10
Chills10
Constipation10
Hypomagnesemia10
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Table 15 and Table 17 include drugs with clinically important drug interactions when administered concomitantly with posaconazole delayed-release tablets 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 posaconazole delayed-release tablets [ Clinical Pharmacology (12.3) ] . Consult the labeling of concomitantly used drugs to obtain further information about interactions with posaconazole. Interaction Drug Interaction Rifabutin, phenytoin, efavirenz, cimetidine Avoid coadministration unless the benefit outweighs the risks ( 7.1 , 7.2 ) Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity ( 7.2 ) Digoxin Monitor digoxin plasma concentrations ( 7.2 ) Fosamprenavir Monitor for breakthrough fungal infections ( 7.1 ) 7.1 Effects of Other Drugs on Posaconazole Delayed-Release Tablets 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 delayed-release tablets 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 Delayed-Release Tablets When Administered Concomitantly with Other Drugs UDP-Glucuronidase Inducers Mechanism and Clinical Effect(s) Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of posaconazole delayed-release tablets 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 delayed-release tablets 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 Delayed-Release Tablets on Other Drugs Posaconazole is a strong CYP3A4 inhibitor. Therefore, concomitant use of posaconazole delayed-release tablets 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 Delayed-Release Tablets 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 delayed-release tablets. 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 Delayed-Release Tablets Additional clinical studies demonstrated that no clinically important effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with Noxafil 200 mg once daily; therefore, no dose adjustments are required for these drugs when coadministered with Noxafil 200 mg once daily. No clinically relevant effects on the pharmacokinetics of posaconazole delayed-release tablets were observed during concomitant use with antacids, H 2 -receptor antagonists and proton pump inhibitors, and metoclopramide [see Clinical Pharmacology (12.3) ] . No dosage adjustment of posaconazole delayed-release tablets 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, H 2 -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)." ], "drug_interactions_table": [ "
Interaction DrugInteraction
Rifabutin, phenytoin, efavirenz, cimetidine Avoid coadministration unless the benefit outweighs the risks (7.1, 7.2)
Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity (7.2)
Digoxin Monitor digoxin plasma concentrations (7.2)
Fosamprenavir Monitor for breakthrough fungal infections (7.1)
", "
UDP-Glucuronidase Inducers
Mechanism and Clinical Effect(s) Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of posaconazole delayed-release tablets 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 delayed-release tablets 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.
", "
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 delayed-release tablets. 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.
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Pregnancy : Based on animal data, may cause fetal harm. ( 8.1 ) Pediatrics : Safety and effectiveness in patients younger than 2 years of age have not been established. ( 8.4 ) Severe renal impairment : Monitor closely for breakthrough fungal infections. ( 8.6 ) 8.1 Pregnancy Risk Summary Based on findings from animal data, posaconazole delayed-release tablets may cause fetal harm when administered to pregnant women. Available data for use of posaconazole delayed-release 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 delayed-release 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 Noxafil ® 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 Noxafil ® 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 Noxafil ® 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 delayed-release tablets and any potential adverse effects on the breastfed child from posaconazole delayed-release tablets or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of posaconazole delayed-release tablets have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 13 years of age and older who are at high risk of developing these infections due to being severely immunocompromised. Use of posaconazole delayed-release tablets for these pediatric indications is supported by adequate and well controlled studies of posaconazole delayed-release tablets in adults and pediatric patients aged 13 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 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. 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 delayed-release tablets-treated geriatric patients compared to posaconazole delayed-release tablets -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. Of the 288 patients treated with Noxafil ® injection or posaconazole delayed-release tablets in the Aspergillosis Treatment Study, 85 (29%) 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 m 2 or higher. Due to variability in posaconazole exposure, closely monitor patients with eGFR less than 20 mL/minute/1.73 m 2 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 delayed-release tablets is necessary based on sex. 8.9 Race No adjustment in the dosage of posaconazole delayed-release tablets 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 particularly when using posaconazole delayed-release tablets in patients weighing greater than 120 kg [see Clinical Pharmacology (12.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Based on findings from animal data, posaconazole delayed-release tablets may cause fetal harm when administered to pregnant women. Available data for use of posaconazole delayed-release 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 delayed-release 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 Noxafil ® 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 Noxafil ® 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 Noxafil ® 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." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of posaconazole delayed-release tablets have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 13 years of age and older who are at high risk of developing these infections due to being severely immunocompromised. Use of posaconazole delayed-release tablets for these pediatric indications is supported by adequate and well controlled studies of posaconazole delayed-release tablets in adults and pediatric patients aged 13 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 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." ], "geriatric_use": [ "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 delayed-release tablets-treated geriatric patients compared to posaconazole delayed-release tablets -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. Of the 288 patients treated with Noxafil ® injection or posaconazole delayed-release tablets in the Aspergillosis Treatment Study, 85 (29%) patients were ≥65 years of age." ], "overdosage": [ "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." ], "description": [ "11 DESCRIPTION Posaconazole delayed-release tablets contain posaconazole, an azole antifungal agent. Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3 R ,5 R )-5- (2,4-difluorophenyl)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 empirical formula of C 37 H 42 F 2 N 8 O 4 and a molecular weight of 700.8. The chemical structure is: Posaconazole is a white powder with a low aqueous solubility. Posaconazole delayed-release tablets are yellow, modified, oval, convex tablets containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: Hypromellose Acetate Succinate, Microcrystalline Cellulose, Hydroxypropyl Cellulose, Croscarmellose Sodium, Silicon Dioxide, and Magnesium Stearate. The color coating contains (Polyvinyl Alcohol, Titanium Dioxide, Polyethylene Glycol, Talc, Ferric Oxide Yellow, and Ferrosoferric Oxide). Chemical Structure" ], "clinical_pharmacology": [ "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 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 (C avg ) and prophylactic efficacy (Table 18). A lower C avg 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 (C avg ) in Prophylaxis Trials Prophylaxis in AML/MDS Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHD HSCT recipients with GVHD C avg Range (ng/mL) Treatment Failure Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%) C avg Range (ng/mL) Treatment Failure (%) Quartile 1 90-322 54.7 22-557 44.4 Quartile 2 322-490 37.0 557-915 20.6 Quartile 3 490-734 46.8 915-1563 17.5 Quartile 4 734-2200 27.8 1563-3650 17.5 C avg = the average posaconazole concentration when measured at steady state 12.3 Pharmacokinetics 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 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) 300 mg twice daily on Day 1, then 300 mg once daily thereafter N AUC 0-24 hr C av C av = time-averaged concentrations (i.e., AUC 0-24 hr /24hr) C max C min T max Median (minimum-maximum) (hr) t 1/2 CL/F (ng·hr/mL) (ng/mL) (ng/mL) (ng/mL) (hr) (L/hr) Healthy 12 51618 2151 2764 1785 4 31 7.5 Volunteers (25) (25) (21) (29) (3-6) (40) (26) Patients 50 37900 1580 2090 1310 4 (1.3-8.3) - 9.39 (42) (42) (38) (50) (45) CV = coefficient of variation expressed as a percentage (%CV); AUC 0-T = Area under the plasma concentration-time curve from time zero to 24 hr; C max = maximum observed concentration; C min = minimum observed plasma concentration; T max = time of maximum observed concentration; t 1/2; = terminal phase half-life; CL/F = Apparent total body clearance Absorption: Absorption of Posaconazole Delayed-Release Tablets When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with a median T max 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 C max 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) 48.5 g fat Fed/Fasting Pharmacokinetic Parameter N Mean (%CV) N Mean (%CV) GMR (90% CI) C max (ng/mL) 14 935 (34) 16 1060 (25) 1.16 (0.96, 1.41) AUC 0-72hr (hr∙ng/mL) 14 26200 (28) 16 38400 (18) 1.51 (1.33, 1.72) T max Median (Min, Max) reported for T max (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 Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226-295 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). Posaconazole delayed-release tablet is eliminated with a mean half-life (t 1/2; ) ranging between 26 to 31 hours. Specific Populations: No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication. Patients with Renal Impairment: After posaconazole delayed-release tablets oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m 2 or higher compared to those with eGFR>80 mL/minute/1.73 m 2 . Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m 2 treated with Noxafil ® oral suspension to those with eGFR >80 mL/minute/1.73 m 2 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 m 2 compared to those with eGFR>80 mL/minute/1.73 m 2 (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 C max 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 C avg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole delayed-release tablets 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: Prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 13 years of age and older: 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 C av 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 C avg 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 includes a summary of the drug effects of concomitant medications that may impact the absorption of posaconazole when administered as 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 Delayed-Release Tablets: Table 28: Summary of the Effects of Coadministered Drugs on Posaconazole Delayed-Release Tablets in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Posaconazole Delayed-Release Tablets Dose/Schedule Effect on Bioavailability of Posaconazole Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to posaconazole delayed-release tablets alone for C max or AUC. ; 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; 0.47-0.66) ↓ 50% (0.50; 0.43-0.60) 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 (0.71-0.89) ↓23% 0.77 (0.68-0.87) Rifabutin (UDP-G Induction) 300 mg once daily x 17 days 200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↓ 43% (0.57; 0.43-0.75) ↓ 49% (0.51; 0.37­-0.71) Phenytoin (UDP-G Induction) 200 mg once daily x 10 days 200 mg (tablets) once daily × 10 days ↓ 41% (0.59; 0.44-­0.79) ↓ 50% (0.50; 0.36­-0.71) 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 Coadministered Drug Administration Arms Change in C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to posaconazole delayed-release tablets alone for C max or AUC 0-last . ; 90% CI of the ratio estimate) Change in AUC 0-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 -1.26)↑ ↑4% (1.04; 0.90 -1.20) Ranitidine (Zantac ® ) (Alteration in gastric pH) 150 mg (morning dose of 150 mg Ranitidine twice daily) ↑4% (1.04; 0.88 -1.23)↑ ↓3% (0.97; 0.84 -1.12) Esomeprazole (Nexium ® ) (Increase in gastric pH) 40 mg (every morning for 5 days, Day -4 to 1) ↑2% (1.02; 0.88-1.17)↑ ↑5% (1.05; 0.89 -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) Effects of Posaconazole Delayed-Release Tablets on Other Drugs: Table 31: Summary of the Effects of Posaconazole Delayed-Release Tablets on Coadministered Drugs in Healthy Adult Volunteers and Patients Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Posaconazole Delayed-Release Tablets Dose/ Schedule Effect on Bioavailability of Coadministered Drugs Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to coadministered drug alone for C max or AUC. ; 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; 5.62-8.03) ↑ 788% (8.88; 7.26-10.9) Cyclosporine Stable maintenance 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 dose in heart transplant recipients 400 mg (oral suspension) twice daily × 7 days ↑ 121% (2.21; 2.01-2.42) ↑ 358% (4.58; 4.03-5.19) 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, 7.13-12.44) Simvastatin Acid ↑ 817% (9.17, 7.3611.43) Simvastatin ↑ 1041% (11.41, 7.99-16.29) Simvastatin Acid ↑851% (9.51, 8.15-11.10) Simvastatin ↑ 931% (10.31, 8.40-12.67) Simvastatin Acid ↑634% (7.34, 5.82-9.25) Simvastatin ↑ 960% (10.60, 8.63- 13.02) Simvastatin Acid ↑ 748% (8.48, 7.04-10.23) Midazolam 0.4-mg single intravenous dose The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole delayed-release tablets. 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; 1.13-1.48) ↑62% (1.62; 1.41-1.86) ↑ 169% (2.69; 2.46-2.93) ↑ 138% (2.38; 2.13-2.66) ↑ 362% (4.62; 4.02-5.3) ↑524% (6.24; 5.43-7.16) ↑ 470% (5.70; 4.82-6.74) ↑ 397% (4.97; 4.46-5.54) Rifabutin 300 mg once daily x 17 days 200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↑ 31% (1.31; 1.10-1.57) ↑ 72% (1.72;1.51-1.95) Phenytoin 200 mg once daily PO x 10 days 200 mg (tablets) once daily x 10 days ↑ 16% (1.16; 0.85-1.57) ↑ 16% (1.16; 0.84-1.59) Ritonavir 100 mg once daily x 14 days 400 mg (oral suspension) twice daily x 7 days ↑ 49% (1.49; 1.04-2.15) ↑ 80% (1.8;1.39-2.31) 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; 1.89-3.45) ↑ 53% (1.53; 1.13-2.07) ↑ 268% (3.68; 2.89-4.70) ↑ 146% (2.46; 1.93-3.13) 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." ], "clinical_pharmacology_table": [ "
Table 18: Noxafil® Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials
Prophylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHDHSCT recipients with GVHD
Cavg Range (ng/mL) Treatment FailureDefined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections(%) Cavg Range (ng/mL) Treatment Failure(%)
Quartile 190-32254.722-55744.4
Quartile 2322-49037.0557-91520.6
Quartile 3490-73446.8915-156317.5
Quartile 4734-220027.81563-365017.5
Cavg = the average posaconazole concentration when measured at steady state
", "
Table 21: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)300 mg twice daily on Day 1, then 300 mg once daily thereafter
N AUC0-24 hrCavCav = time-averaged concentrations (i.e., AUC0-24 hr/24hr) CmaxCminTmaxMedian (minimum-maximum) (hr)t1/2CL/F
(ng·hr/mL)(ng/mL)(ng/mL)(ng/mL) (hr)(L/hr)
Healthy12 516182151276417854317.5
Volunteers (25)(25)(21)(29)(3-6)(40)(26)
Patients 50379001580209013104 (1.3-8.3)-9.39
(42)(42)(38)(50) (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; t1/2; = terminal phase half-life; CL/F = Apparent total body clearance
", "
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 ConditionsFed Conditions (High-Fat Meal)48.5 g fat Fed/Fasting
Pharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)
Cmax (ng/mL)14 935 (34)161060 (25)1.16 (0.96, 1.41)
AUC0-72hr (hr∙ng/mL)1426200 (28)1638400 (18)1.51 (1.33, 1.72)
TmaxMedian (Min, Max) reported for Tmax (hr)145.00 (3.00, 8.00)166.00 (5.00, 24.00) N/A
GMR=Geometric least-squares mean ratio; CI=Confidence interval
", "
Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Posaconazole Delayed-Release Tablets Dose/Schedule Effect on Bioavailability of Posaconazole
Change in Mean Cmax(ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to posaconazole delayed-release tablets alone for Cmax or AUC. ; 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; 0.47-0.66) ↓ 50% (0.50; 0.43-0.60)
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 (0.71-0.89) ↓23% 0.77 (0.68-0.87)
Rifabutin (UDP-G Induction) 300 mg once daily x 17 days 200 mg (tablets) once daily × 10 daysThe tablet refers to a non-commercial tablet formulation without polymer.↓ 43% (0.57; 0.43-0.75) ↓ 49% (0.51; 0.37­-0.71)
Phenytoin (UDP-G Induction) 200 mg once daily x 10 days 200 mg (tablets) once daily × 10 days ↓ 41% (0.59; 0.44-­0.79) ↓ 50% (0.50; 0.36­-0.71)
", "
Coadministered Drug Administration Arms Change in Cmax(ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to posaconazole delayed-release tablets alone for Cmax or AUC0-last.; 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 -1.26)↑ ↑4% (1.04; 0.90 -1.20)
Ranitidine (Zantac®) (Alteration in gastric pH) 150 mg (morning dose of 150 mg Ranitidine twice daily) ↑4% (1.04; 0.88 -1.23)↑ ↓3% (0.97; 0.84 -1.12)
Esomeprazole (Nexium®) (Increase in gastric pH) 40 mg (every morning for 5 days, Day -4 to 1) ↑2% (1.02; 0.88-1.17)↑ ↑5% (1.05; 0.89 -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)
", "
Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Posaconazole Delayed-Release Tablets Dose/ Schedule Effect on Bioavailability of Coadministered Drugs
Change in Mean Cmax(ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to coadministered drug alone for Cmax or AUC.; 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; 5.62-8.03) ↑ 788% (8.88; 7.26-10.9)
Cyclosporine Stable maintenance200 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 dose in heart transplant recipients400 mg (oral suspension) twice daily × 7 days ↑ 121% (2.21; 2.01-2.42) ↑ 358% (4.58; 4.03-5.19)
Simvastatin 40-mg single oral dose 100 mg (oral suspension) once daily x 13 days200 mg (oral suspension) once daily x 13 days Simvastatin ↑ 841% (9.41, 7.13-12.44) Simvastatin Acid ↑ 817% (9.17, 7.3611.43) Simvastatin↑ 1041% (11.41, 7.99-16.29) Simvastatin Acid ↑851% (9.51, 8.15-11.10)Simvastatin ↑ 931% (10.31, 8.40-12.67) Simvastatin Acid ↑634% (7.34, 5.82-9.25) Simvastatin ↑ 960% (10.60, 8.63-13.02) Simvastatin Acid ↑ 748% (8.48, 7.04-10.23)
Midazolam 0.4-mg single intravenous doseThe mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole delayed-release tablets. 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 (oralsuspension) once daily x 7 days 400 mg (oral suspension) twice daily x 7 days↑ 30% (1.3; 1.13-1.48) ↑62% (1.62; 1.41-1.86)↑ 169% (2.69; 2.46-2.93)↑ 138% (2.38; 2.13-2.66)↑ 362% (4.62; 4.02-5.3) ↑524% (6.24; 5.43-7.16) ↑ 470% (5.70; 4.82-6.74)↑ 397% (4.97; 4.46-5.54)
Rifabutin 300 mg once daily x 17 days 200 mg (tablets) once daily × 10 daysThe tablet refers to a non-commercial tablet formulation without polymer. ↑ 31% (1.31; 1.10-1.57) ↑ 72% (1.72;1.51-1.95)
Phenytoin 200 mg once daily PO x 10 days 200 mg (tablets) once daily x 10 days ↑ 16% (1.16; 0.85-1.57) ↑ 16% (1.16; 0.84-1.59)
Ritonavir 100 mg once daily x 14 days 400 mg (oral suspension) twice daily x 7 days ↑ 49% (1.49; 1.04-2.15) ↑ 80% (1.8;1.39-2.31)
Atazanavir Atazanavir/ritonavir boosted regimen 300 mg once daily x 14 days300 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; 1.89-3.45) ↑ 53% (1.53; 1.13-2.07) ↑ 268% (3.68; 2.89-4.70) ↑ 146% (2.46; 1.93-3.13)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4) ] ." ], "pharmacodynamics": [ "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 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 (C avg ) and prophylactic efficacy (Table 18). A lower C avg 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 (C avg ) in Prophylaxis Trials Prophylaxis in AML/MDS Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHD HSCT recipients with GVHD C avg Range (ng/mL) Treatment Failure Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%) C avg Range (ng/mL) Treatment Failure (%) Quartile 1 90-322 54.7 22-557 44.4 Quartile 2 322-490 37.0 557-915 20.6 Quartile 3 490-734 46.8 915-1563 17.5 Quartile 4 734-2200 27.8 1563-3650 17.5 C avg = the average posaconazole concentration when measured at steady state" ], "pharmacodynamics_table": [ "
Table 18: Noxafil® Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials
Prophylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHDHSCT recipients with GVHD
Cavg Range (ng/mL) Treatment FailureDefined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections(%) Cavg Range (ng/mL) Treatment Failure(%)
Quartile 190-32254.722-55744.4
Quartile 2322-49037.0557-91520.6
Quartile 3490-73446.8915-156317.5
Quartile 4734-220027.81563-365017.5
Cavg = the average posaconazole concentration when measured at steady state
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics 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 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) 300 mg twice daily on Day 1, then 300 mg once daily thereafter N AUC 0-24 hr C av C av = time-averaged concentrations (i.e., AUC 0-24 hr /24hr) C max C min T max Median (minimum-maximum) (hr) t 1/2 CL/F (ng·hr/mL) (ng/mL) (ng/mL) (ng/mL) (hr) (L/hr) Healthy 12 51618 2151 2764 1785 4 31 7.5 Volunteers (25) (25) (21) (29) (3-6) (40) (26) Patients 50 37900 1580 2090 1310 4 (1.3-8.3) - 9.39 (42) (42) (38) (50) (45) CV = coefficient of variation expressed as a percentage (%CV); AUC 0-T = Area under the plasma concentration-time curve from time zero to 24 hr; C max = maximum observed concentration; C min = minimum observed plasma concentration; T max = time of maximum observed concentration; t 1/2; = terminal phase half-life; CL/F = Apparent total body clearance Absorption: Absorption of Posaconazole Delayed-Release Tablets When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with a median T max 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 C max 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) 48.5 g fat Fed/Fasting Pharmacokinetic Parameter N Mean (%CV) N Mean (%CV) GMR (90% CI) C max (ng/mL) 14 935 (34) 16 1060 (25) 1.16 (0.96, 1.41) AUC 0-72hr (hr∙ng/mL) 14 26200 (28) 16 38400 (18) 1.51 (1.33, 1.72) T max Median (Min, Max) reported for T max (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 Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226-295 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). Posaconazole delayed-release tablet is eliminated with a mean half-life (t 1/2; ) ranging between 26 to 31 hours. Specific Populations: No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication. Patients with Renal Impairment: After posaconazole delayed-release tablets oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m 2 or higher compared to those with eGFR>80 mL/minute/1.73 m 2 . Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m 2 treated with Noxafil ® oral suspension to those with eGFR >80 mL/minute/1.73 m 2 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 m 2 compared to those with eGFR>80 mL/minute/1.73 m 2 (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 C max 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 C avg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole delayed-release tablets 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: Prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 13 years of age and older: 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 C av 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 C avg 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 includes a summary of the drug effects of concomitant medications that may impact the absorption of posaconazole when administered as 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 Delayed-Release Tablets: Table 28: Summary of the Effects of Coadministered Drugs on Posaconazole Delayed-Release Tablets in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Posaconazole Delayed-Release Tablets Dose/Schedule Effect on Bioavailability of Posaconazole Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to posaconazole delayed-release tablets alone for C max or AUC. ; 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; 0.47-0.66) ↓ 50% (0.50; 0.43-0.60) 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 (0.71-0.89) ↓23% 0.77 (0.68-0.87) Rifabutin (UDP-G Induction) 300 mg once daily x 17 days 200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↓ 43% (0.57; 0.43-0.75) ↓ 49% (0.51; 0.37­-0.71) Phenytoin (UDP-G Induction) 200 mg once daily x 10 days 200 mg (tablets) once daily × 10 days ↓ 41% (0.59; 0.44-­0.79) ↓ 50% (0.50; 0.36­-0.71) 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 Coadministered Drug Administration Arms Change in C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to posaconazole delayed-release tablets alone for C max or AUC 0-last . ; 90% CI of the ratio estimate) Change in AUC 0-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 -1.26)↑ ↑4% (1.04; 0.90 -1.20) Ranitidine (Zantac ® ) (Alteration in gastric pH) 150 mg (morning dose of 150 mg Ranitidine twice daily) ↑4% (1.04; 0.88 -1.23)↑ ↓3% (0.97; 0.84 -1.12) Esomeprazole (Nexium ® ) (Increase in gastric pH) 40 mg (every morning for 5 days, Day -4 to 1) ↑2% (1.02; 0.88-1.17)↑ ↑5% (1.05; 0.89 -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) Effects of Posaconazole Delayed-Release Tablets on Other Drugs: Table 31: Summary of the Effects of Posaconazole Delayed-Release Tablets on Coadministered Drugs in Healthy Adult Volunteers and Patients Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Posaconazole Delayed-Release Tablets Dose/ Schedule Effect on Bioavailability of Coadministered Drugs Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to coadministered drug alone for C max or AUC. ; 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; 5.62-8.03) ↑ 788% (8.88; 7.26-10.9) Cyclosporine Stable maintenance 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 dose in heart transplant recipients 400 mg (oral suspension) twice daily × 7 days ↑ 121% (2.21; 2.01-2.42) ↑ 358% (4.58; 4.03-5.19) 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, 7.13-12.44) Simvastatin Acid ↑ 817% (9.17, 7.3611.43) Simvastatin ↑ 1041% (11.41, 7.99-16.29) Simvastatin Acid ↑851% (9.51, 8.15-11.10) Simvastatin ↑ 931% (10.31, 8.40-12.67) Simvastatin Acid ↑634% (7.34, 5.82-9.25) Simvastatin ↑ 960% (10.60, 8.63- 13.02) Simvastatin Acid ↑ 748% (8.48, 7.04-10.23) Midazolam 0.4-mg single intravenous dose The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole delayed-release tablets. 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; 1.13-1.48) ↑62% (1.62; 1.41-1.86) ↑ 169% (2.69; 2.46-2.93) ↑ 138% (2.38; 2.13-2.66) ↑ 362% (4.62; 4.02-5.3) ↑524% (6.24; 5.43-7.16) ↑ 470% (5.70; 4.82-6.74) ↑ 397% (4.97; 4.46-5.54) Rifabutin 300 mg once daily x 17 days 200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↑ 31% (1.31; 1.10-1.57) ↑ 72% (1.72;1.51-1.95) Phenytoin 200 mg once daily PO x 10 days 200 mg (tablets) once daily x 10 days ↑ 16% (1.16; 0.85-1.57) ↑ 16% (1.16; 0.84-1.59) Ritonavir 100 mg once daily x 14 days 400 mg (oral suspension) twice daily x 7 days ↑ 49% (1.49; 1.04-2.15) ↑ 80% (1.8;1.39-2.31) 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; 1.89-3.45) ↑ 53% (1.53; 1.13-2.07) ↑ 268% (3.68; 2.89-4.70) ↑ 146% (2.46; 1.93-3.13)" ], "pharmacokinetics_table": [ "
Table 21: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)300 mg twice daily on Day 1, then 300 mg once daily thereafter
N AUC0-24 hrCavCav = time-averaged concentrations (i.e., AUC0-24 hr/24hr) CmaxCminTmaxMedian (minimum-maximum) (hr)t1/2CL/F
(ng·hr/mL)(ng/mL)(ng/mL)(ng/mL) (hr)(L/hr)
Healthy12 516182151276417854317.5
Volunteers (25)(25)(21)(29)(3-6)(40)(26)
Patients 50379001580209013104 (1.3-8.3)-9.39
(42)(42)(38)(50) (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; t1/2; = terminal phase half-life; CL/F = Apparent total body clearance
", "
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 ConditionsFed Conditions (High-Fat Meal)48.5 g fat Fed/Fasting
Pharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)
Cmax (ng/mL)14 935 (34)161060 (25)1.16 (0.96, 1.41)
AUC0-72hr (hr∙ng/mL)1426200 (28)1638400 (18)1.51 (1.33, 1.72)
TmaxMedian (Min, Max) reported for Tmax (hr)145.00 (3.00, 8.00)166.00 (5.00, 24.00) N/A
GMR=Geometric least-squares mean ratio; CI=Confidence interval
", "
Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Posaconazole Delayed-Release Tablets Dose/Schedule Effect on Bioavailability of Posaconazole
Change in Mean Cmax(ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to posaconazole delayed-release tablets alone for Cmax or AUC. ; 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; 0.47-0.66) ↓ 50% (0.50; 0.43-0.60)
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 (0.71-0.89) ↓23% 0.77 (0.68-0.87)
Rifabutin (UDP-G Induction) 300 mg once daily x 17 days 200 mg (tablets) once daily × 10 daysThe tablet refers to a non-commercial tablet formulation without polymer.↓ 43% (0.57; 0.43-0.75) ↓ 49% (0.51; 0.37­-0.71)
Phenytoin (UDP-G Induction) 200 mg once daily x 10 days 200 mg (tablets) once daily × 10 days ↓ 41% (0.59; 0.44-­0.79) ↓ 50% (0.50; 0.36­-0.71)
", "
Coadministered Drug Administration Arms Change in Cmax(ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to posaconazole delayed-release tablets alone for Cmax or AUC0-last.; 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 -1.26)↑ ↑4% (1.04; 0.90 -1.20)
Ranitidine (Zantac®) (Alteration in gastric pH) 150 mg (morning dose of 150 mg Ranitidine twice daily) ↑4% (1.04; 0.88 -1.23)↑ ↓3% (0.97; 0.84 -1.12)
Esomeprazole (Nexium®) (Increase in gastric pH) 40 mg (every morning for 5 days, Day -4 to 1) ↑2% (1.02; 0.88-1.17)↑ ↑5% (1.05; 0.89 -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)
", "
Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Posaconazole Delayed-Release Tablets Dose/ Schedule Effect on Bioavailability of Coadministered Drugs
Change in Mean Cmax(ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole delayed-release tablets to coadministered drug alone for Cmax or AUC.; 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; 5.62-8.03) ↑ 788% (8.88; 7.26-10.9)
Cyclosporine Stable maintenance200 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 dose in heart transplant recipients400 mg (oral suspension) twice daily × 7 days ↑ 121% (2.21; 2.01-2.42) ↑ 358% (4.58; 4.03-5.19)
Simvastatin 40-mg single oral dose 100 mg (oral suspension) once daily x 13 days200 mg (oral suspension) once daily x 13 days Simvastatin ↑ 841% (9.41, 7.13-12.44) Simvastatin Acid ↑ 817% (9.17, 7.3611.43) Simvastatin↑ 1041% (11.41, 7.99-16.29) Simvastatin Acid ↑851% (9.51, 8.15-11.10)Simvastatin ↑ 931% (10.31, 8.40-12.67) Simvastatin Acid ↑634% (7.34, 5.82-9.25) Simvastatin ↑ 960% (10.60, 8.63-13.02) Simvastatin Acid ↑ 748% (8.48, 7.04-10.23)
Midazolam 0.4-mg single intravenous doseThe mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole delayed-release tablets. 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 (oralsuspension) once daily x 7 days 400 mg (oral suspension) twice daily x 7 days↑ 30% (1.3; 1.13-1.48) ↑62% (1.62; 1.41-1.86)↑ 169% (2.69; 2.46-2.93)↑ 138% (2.38; 2.13-2.66)↑ 362% (4.62; 4.02-5.3) ↑524% (6.24; 5.43-7.16) ↑ 470% (5.70; 4.82-6.74)↑ 397% (4.97; 4.46-5.54)
Rifabutin 300 mg once daily x 17 days 200 mg (tablets) once daily × 10 daysThe tablet refers to a non-commercial tablet formulation without polymer. ↑ 31% (1.31; 1.10-1.57) ↑ 72% (1.72;1.51-1.95)
Phenytoin 200 mg once daily PO x 10 days 200 mg (tablets) once daily x 10 days ↑ 16% (1.16; 0.85-1.57) ↑ 16% (1.16; 0.84-1.59)
Ritonavir 100 mg once daily x 14 days 400 mg (oral suspension) twice daily x 7 days ↑ 49% (1.49; 1.04-2.15) ↑ 80% (1.8;1.39-2.31)
Atazanavir Atazanavir/ritonavir boosted regimen 300 mg once daily x 14 days300 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; 1.89-3.45) ↑ 53% (1.53; 1.13-2.07) ↑ 268% (3.68; 2.89-4.70) ↑ 146% (2.46; 1.93-3.13)
" ], "microbiology": [ "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." ], "nonclinical_toxicology": [ "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 Noxafil ® Oral Suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400 mg twice daily Noxafil ® 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 Noxafil ® 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 Noxafil ® 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 Noxafil ® Oral Suspension regimen)." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "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 Noxafil ® Oral Suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400 mg twice daily Noxafil ® 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 Noxafil ® 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 Noxafil ® 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 Noxafil ® Oral Suspension regimen)." ], "clinical_studies": [ "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, posaconazole; 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-Versus-Host Disease (GVHD): Noxafil ® Oral Suspension Study 1 Posaconazole n=301 Fluconazole n=299 On therapy plus 7 days Clinical Failure Patients may have met more than one criterion defining 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 Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days). 27 (9%) 25 (8%) Through 16 weeks Clinical Failure , 95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%). 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 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. 24 (8%) 30 (10%) 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 95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%). , Patients may have met more than one criterion defining 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 Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days). 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 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. 34 (11%) 24 (8%) 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." ], "clinical_studies_table": [ "
Table 34: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-Versus-Host Disease (GVHD): Noxafil® Oral Suspension Study 1
Posaconazole n=301 Fluconazole n=299
On therapy plus 7 days
Clinical FailurePatients may have met more than one criterion defining failure. 50 (17%) 55 (18%)
Failure due to:
Proven/Probable IFI7 (2%)22 (7%)
(Aspergillus)3 (1%)17 (6%)
(Candida)1 (<1%)3 (1%)
(Other)3 (1%)2 (1%)
All Deaths22 (7%)24 (8%)
Proven/probable fungal infection prior to death2 (<1%)6 (2%)
SAFUse of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days). 27 (9%)25 (8%)
Through 16 weeks
Clinical Failure ,95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%). 99 (33%)110 (37%)
Failure due to:
Proven/Probable IFI16 (5%)27 (9%)
(Aspergillus)7 (2%)21 (7%)
(Candida)4 (1%)4 (1%)
(Other)5 (2%)2 (1%)
All Deaths58 (19%)59 (20%)
Proven/probable fungal infection prior to death 10 (3%)16 (5%)
SAF 26 (9%)30 (10%)
Event free lost to follow-upPatients 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. 24 (8%)30 (10%)
", "
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 Failure95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%). , Patients may have met more than one criterion defining failure. 82 (27%)126 (42%)
Failure due to:
Proven/Probable IFI7 (2%)25 (8%)
(Aspergillus)2 (1%)20 (7%)
(Candida)3 (1%)2 (1%)
(Other)2 (1%)3 (1%)
All Deaths17 (6%)25 (8%)
Proven/probable fungal infection prior to death1 (<1%)2 (1%)
SAFUse of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days). 67 (22%)98 (33%)
Through 100 days post-randomization
Clinical Failure 158 (52%)191 (64%)
Failure due to:
Proven/Probable IFI14 (5%)33 (11%)
(Aspergillus)2 (1%)26 (9%)
(Candida)10 (3%)4 (1%)
(Other)2 (1%)3 (1%)
All Deaths44 (14%)64 (21%)
Proven/probable fungal infection prior to death 2 (1%)16 (5%)
SAF 98 (32%)125 (42%)
Event free lost to follow-upPatients 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. 34 (11%)24 (8%)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Posaconazole delayed-release tablets are available as yellow, modified, oval, convex tablets debossed with a logo \"M\" inside a square on one side and \"100\" on the opposite side containing 100 mg of posaconazole. Bottles of 60 . . . . . . . . . . . . . . NDC 0406-7711-60 16.2 Storage and Handling 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]. Dispense in a tight, light-resistant container (as defined in USP) with a child-resistant closure." ], "spl_unclassified_section": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). 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. © 2026 Par Health, Inc. or one of its affiliates. Noxafil, Mylanta, Zantac, Nexium, and Reglan are trademarks of their respective owners. Manufactured for: SpecGx LLC Webster Groves, MO 63119 USA www.parhealth.com or call 1-800-778-7898 L20P21 Revised: 02/2026 Par Health™" ], "spl_patient_package_insert": [ "To obtain a printable copy of the Patient Information, visit www.parhealth.com/products Patient Information Posaconazole (poe'' sa kon' a zole) delayed-release tablets What are posaconazole delayed-release tablets? Posaconazole delayed-release tablets are a prescription medicine 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 malignancies). Posaconazole delayed-release tablets are used for: prevention of fungal infections in adults and children 13 years of age and older who weigh greater than 88 lbs (40 kg). It is not known if posaconazole delayed-release tablets are 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 work, 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 taking posaconazole delayed-release tablets and Noxafil ® Oral Suspension. Take posaconazole delayed-release tablets exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many posaconazole delayed-release tablets to take and when to take them. Take posaconazole delayed-release tablets for as long as your healthcare provider tells you to take them. If you take too many 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 many posaconazole delayed-release tablets you should take and when to take them. 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 nausea or vomiting yellowing of your eyes or skin feeling very tired flu-like symptoms 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? 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 they were 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: Hypromellose Acetate Succinate, Microcrystalline Cellulose, Hydroxypropyl Cellulose, Croscarmellose Sodium, Silicon Dioxide, and Magnesium Stearate. The color coating contains (Polyvinyl Alcohol, Titanium Dioxide, Polyethylene Glycol, Talc, Ferric Oxide Yellow, and Ferrosoferric Oxide). 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. © 2026 Par Health, Inc. or one of its affiliates. Noxafil, Mylanta, Zantac, Nexium, and Reglan are trademarks of their respective owners. Manufactured for: SpecGx LLC Webster Groves, MO 63119 USA www.parhealth.com or call 1-800-778-7898 Par Health™ This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 02/2026 X30000254" ], "spl_patient_package_insert_table": [ "
To obtain a printable copy of the Patient Information, visit www.parhealth.com/products
Patient Information Posaconazole (poe'' sa kon' a zole) delayed-release tablets
What are posaconazole delayed-release tablets?Posaconazole delayed-release tablets are a prescription medicine 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 malignancies).Posaconazole delayed-release tablets are used for:prevention of fungal infections in adults and children 13 years of age and older who weigh greater than 88 lbs (40 kg).It is not known if posaconazole delayed-release tablets are 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: sirolimuspimozidequinidinecertain 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 work, 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 taking posaconazole delayed-release tablets and Noxafil® Oral Suspension.Take posaconazole delayed-release tablets exactly as your healthcare provider tells you to take them.Your healthcare provider will tell you how many posaconazole delayed-release tablets to take and when to take them.Take posaconazole delayed-release tablets for as long as your healthcare provider tells you to take them.If you take too many 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 many posaconazole delayed-release tablets you should take and when to take them.
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 skinnausea or vomitingyellowing of your eyes or skinfeeling very tiredflu-like symptomsincreased 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:diarrheanauseafevervomitingheadachecoughinglow potassium levels in the bloodIf 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?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 they were 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: Hypromellose Acetate Succinate, Microcrystalline Cellulose, Hydroxypropyl Cellulose, Croscarmellose Sodium, Silicon Dioxide, and Magnesium Stearate. The color coating contains (Polyvinyl Alcohol, Titanium Dioxide, Polyethylene Glycol, Talc, Ferric Oxide Yellow, and Ferrosoferric Oxide).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.© 2026 Par Health, Inc. or one of its affiliates.Noxafil, Mylanta, Zantac, Nexium, and Reglan are trademarks of their respective owners.Manufactured for:SpecGx LLC Webster Groves, MO 63119 USA www.parhealth.com or call 1-800-778-7898Par Health™
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 100 mg Label NDC 0406- 7711 -60 60 TABLETS Posaconazole Delayed-Release Tablets 100 mg Rx only ATTENTION: Noxafil™ Oral Suspension and Posaconazole Delayed-Release Tablets are NOT interchangeable due to differences in the dosing of each formulation. PHARMACIST: Dispense the Patient Information provided separately to each patient. Par Health™ L00P34 Rev 02/2026 PRINCIPAL DISPLAY PANEL - 100 mg Label" ], "set_id": "8412398b-c696-4f12-ba3a-da74dc8dadaf", "id": "2432a708-a147-4b42-972c-a118b280d3ac", "effective_time": "20260423", "version": "14", "openfda": { "application_number": [ "ANDA212226" ], "brand_name": [ "POSACONAZOLE" ], "generic_name": [ "POSACONAZOLE" ], "manufacturer_name": [ "SpecGx LLC" ], "product_ndc": [ "0406-7711" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "POSACONAZOLE" ], "rxcui": [ "1482908" ], "spl_id": [ "2432a708-a147-4b42-972c-a118b280d3ac" ], "spl_set_id": [ "8412398b-c696-4f12-ba3a-da74dc8dadaf" ], "package_ndc": [ "0406-7711-60" ], "is_original_packager": [ true ], "nui": [ "N0000175487", "M0002083" ], "pharm_class_epc": [ "Azole Antifungal [EPC]" ], "pharm_class_cs": [ "Azoles [CS]" ], "unii": [ "6TK1G07BHZ" ] } } ] }