USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1)Pediatrics: Safety and effectiveness in patients younger than years of age have not been established. (8.4)Severe Renal Impairment: Monitor closely for breakthrough fungal infections. (8.6). Pregnancy: Based on animal data, may cause fetal harm. (8.1). Pediatrics: Safety and effectiveness in patients younger than years of age have not been established. (8.4). Severe Renal Impairment: Monitor closely for breakthrough fungal infections. (8.6). 8.1 Pregnancy. Risk SummaryBased on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of Noxafil in pregnant women are insufficient to establish 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 Noxafil 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 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 through 15) at doses >=27 mg/kg (>=1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, reduction in body weight gain of females and reduction in litter size were seen.. 8.2 Lactation. Risk SummaryThere 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 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 mothers clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition.. 8.4 Pediatric Use. The posaconazole dosage forms (delayed-release tablets and oral suspension) are different products; are approved for different pediatric indications, age groups, and weights; have different dosing regimens; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the pediatric indication, age group, and weight [see Dosage and Administration (2.1)]. Treatment of Invasive AspergillosisThe safety and effectiveness of Posaconazole delayed-release tablets have been established for the treatment of invasive aspergillosis in pediatric patients years of age and older.Use of posaconazole for these pediatric indications is supported by evidence from adequate and well-controlled studies of Noxafil in adults and safety and pharmacokinetic (PK) data from pediatric studies [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. The safety of Noxafil in pediatric patients for these pediatric indications was consistent with the known safety profile of Noxafil in adults [see Adverse Reactions (6.1)]. The safety and effectiveness of posaconazole have not been established in pediatric patients less than years of age. Prophylaxis of Invasive Aspergillus and Candida InfectionsThe safety and effectiveness of Posaconazole delayed-release tablets have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients years of age and older who are at high risk of developing these infections due to being severely immunocompromised.The safety and effectiveness of Posaconazole oral suspension 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 for these pediatric indications is supported by adequate and well-controlled studies of Noxafil in adults and pediatric patients aged 13 years and older and additional PK and safety data in pediatric patients 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 years of age.Treatment of Oropharyngeal Candidiasis, including Refractory to Itraconazole and/or FluconazoleThe safety and effectiveness of Posaconazole oral suspension have been established for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients 13 years of age and older.Use of Posaconazole oral suspension for this pediatric indication is supported by adequate and well controlled studies in adults and pediatric patients 13 years of age and older [see Clinical studies (14.4)]. Posaconazole delayed-release tablets are not approved for the treatment of oropharyngeal candidiasis in pediatric patients. Posaconazole oral suspension is the only dosage form approved for the treatment of OPC and rOPC in pediatric patients [see Dosage and Administration (2.4)]. The safety and effectiveness of Posaconazole oral suspension for the treatment of OPC and rOPC have not been established in pediatric patients less than 13 years of age.. 8.5 Geriatric Use. No overall differences in the safety of Noxafil delayed-release tablets and Noxafil oral suspension 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 Noxafil-treated geriatric patients compared to Noxafil-treated younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].Of the 230 patients treated with Noxafil delayed-release tablets, 38 (17%) patients were >65 years of age.Of the 605 patients treated with Noxafil oral suspension in Noxafil Oral Suspension Study and Study (prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised), 63 (10%) patients were >=65 years of age.In studies of Noxafil for an unapproved indication, 48 patients treated with Noxafil oral suspension (greater than or equal to 800 mg/day (eight times the maximum recommended maintenance dosage for the treatment of OPC)) were >=65 years of age.Of the 288 patients treated with Noxafil injection or Noxafil delayed-release tablets in the Aspergillosis Treatment Study, 85 (29%) patients were >=65 years of age.. Of the 230 patients treated with Noxafil delayed-release tablets, 38 (17%) patients were >65 years of age.. Of the 605 patients treated with Noxafil oral suspension in Noxafil Oral Suspension Study and Study (prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised), 63 (10%) patients were >=65 years of age.. In studies of Noxafil for an unapproved indication, 48 patients treated with Noxafil oral suspension (greater than or equal to 800 mg/day (eight times the maximum recommended maintenance dosage for the treatment of OPC)) were >=65 years of age.. Of the 288 patients treated with Noxafil injection or Noxafil delayed-release tablets in the Aspergillosis Treatment Study, 85 (29%) patients were >=65 years of age.. 8.6 Renal Impairment. Posaconazole Oral Suspension and Posaconazole Delayed-Release TabletsNo dosage adjustment is required for patients with eGFR 20 mL/minute/1.73 m2 or higher.Due to variability in posaconazole exposure, closely monitor patients with eGFR less than 20 mL/minute/1.73 m2 for breakthrough fungal infections. [see Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. No dose adjustment is recommended of posaconazole in patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) [see Pharmacology (12.3)]. However, specific hepatic impairment study has not been conducted with the Posaconazole delayed-release tablets.. 8.8 Sex. No adjustment in the dosage of posaconazole is necessary based on sex.. 8.9 Race. No adjustment in the dosage of posaconazole is necessary based on race.. 8.10 Weight. Pharmacokinetic modeling suggests that patients who weigh greater than 120 kg may have lower posaconazole plasma drug exposure. Therefore, consider closely monitoring for breakthrough fungal infections particularly when using Posaconazole oral suspension in patients weighing greater than 120 kg [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Calcineurin-Inhibitor Toxicity: Posaconazole increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. (5.1)Arrhythmias and QTc Prolongation: Posaconazole has 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 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 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, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole, for patients receiving 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 and Posaconazole oral suspension. (5.9)Venetoclax Toxicity: Concomitant administration of posaconazole 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, 5.10, 7.2). Calcineurin-Inhibitor Toxicity: Posaconazole increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. (5.1). Arrhythmias and QTc Prolongation: Posaconazole has 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 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 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, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole, for patients receiving 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 and Posaconazole oral suspension. (5.9). Venetoclax Toxicity: Concomitant administration of posaconazole 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, 5.10, 7.2). 5.1 Calcineurin-Inhibitor Toxicity. Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.. 5.2Arrhythmias 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 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 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 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. decrease in the QTc(F) interval (-3 msec) was also observed in 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 Noxafil had QTc(F) interval >=500 msec or an increase >=60 msec in their QTc(F) interval from baseline.Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)].. 5.3 Electrolyte Disturbances. Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.. 5.4 Pseudoaldosteronism Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11-deoxycortisol), has been reported with posaconazole use in the postmarket setting. Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldosteronism may include discontinuation of posaconazole, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists.. 5.5Hepatic 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 Posaconazole oral suspension 800 mg daily (400 mg twice daily or 200 mg four times 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 and Posaconazole oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)]. 5.7Midazolam Toxicity. Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].. 5.8Vincristine Toxicity. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.2)].. 5.9Breakthrough Fungal Infections. Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving Posaconazole delayed-release tablets or Posaconazole oral suspension.. 5.10 Venetoclax Toxicity. Concomitant administration of posaconazole, strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of posaconazole during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications (4.6)]. Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients.For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax [see Drug Interactions (7.2)]. Refer to the venetoclax prescribing information for dosing instructions.

ADVERSE REACTIONS SECTION.

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)] 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 are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Common adverse reactions in studies with posaconazole are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Noxafil cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Treatment of Invasive Aspergillosis in Adults and Adolescents (Noxafil Injection and Noxafil Delayed-Release Tablets)The safety of Noxafil injection and Noxafil delayed-release tablets was assessed in randomized, double-blind, active-controlled clinical study of Noxafil injection and Noxafil delayed-release tablets versus voriconazole for treatment of invasive aspergillosis (Aspergillosis Treatment Study). total of 575 adult and pediatric patients 14 years of age and older (288 in the Noxafil group, 287 in voriconazole group (voriconazole for injection or voriconazole tablets)) with proven, probable or possible invasive aspergillosis were included. The median duration of treatment was 67 days for Noxafil injection or Noxafil delayed-release tablet and 64 days for voriconazole (voriconazole for injection). In this study, with 55% to 60% of patients started intravenous treatment with Noxafil (Noxafil injection) or voriconazole (voriconazole for injection). The median duration of the first instance of intravenous treatment (before switching to oral treatment or discontinuing or completing study treatment) was days for both groups. Table presents adverse reactions reported at an incidence of >=10% in either one of the treatment groups in the Aspergillosis Treatment Study.Adverse reactions leading to treatment discontinuation were reported for 34% of patients. The most commonly reported adverse reactions (>2% of patients) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the Noxafil group, and septic shock and acute myeloid leukemia in the voriconazole group. The most frequently reported adverse reactions in the Noxafil-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%).Table 5: Adverse Reactions in at least 10% of Adults and Adolescents Receiving Noxafil Injection or Noxafil Delayed-Release Tablets for the Treatment of Invasive AspergillosisAdverse ReactionsNoxafil injection or Noxafil delayed-release tablets n=288(%)Voriconazole for injection or Voriconazole tablets n=287(%) Percentage of Patients Reporting any Adverse Reaction97.697.6Hypokalemia28.517.1Pyrexia28.125.1Nausea22.617.8Diarrhea18.118.1Vomiting18.113.6Alanine aminotransferase increased14.612.9Febrile neutropenia14.613.2Aspartate aminotransferase increased13.212.5Pneumonia12.59.1Headache12.28.7Constipation11.18.0Edema peripheral11.18.4Epistaxis11.15.9Cough10.48.4Abdominal pain10.18.4Hypomagnesemia10.16.3Clinical Trial Experience with Noxafil Delayed-Release Tablets for Prophylaxis of Invasive Aspergillus and Candida InfectionsThe safety of Noxafil delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in non-comparative pharmacokinetic and safety trial of Noxafil delayed-release tablets when given as antifungal prophylaxis (Noxafil Delayed-Release Tablet Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had mean age of 51 years (range: 19-78 years, 17% of patients were >=65 years of age), and were 93% White and 16% Hispanic. Noxafil delayed-release tablets were given for median duration of 28 days. In this study, 20 adult patients received 200 mg daily dose and 210 adult patients received 300 mg daily dosage (following twice daily dosing on Day in each cohort). Table presents adverse reactions (incidence of >10%) observed in patients treated with the Noxafil delayed-release tablets 300 mg daily dosage in the Noxafil Delayed-Release Tablet Study.The most frequently reported adverse reactions (>25%) in patients treated with Noxafil delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea. The most common adverse reaction leading to discontinuation of Noxafil delayed-release tablets 300 mg once daily was nausea (2%).Table 6: Adverse Reactions in at least 10% of Adults Receiving Noxafil Delayed-Release Tablets (300 mg Daily Dosage) for the Prophylaxis of Invasive Aspergillus and Candida infectionsAdverse ReactionsNoxafil delayed-releasetablet (300 mg) n=210(%)Percentage of Patients Reporting any Adverse Reaction99Diarrhea29Pyrexia28Nausea27Hypokalemia22Cough17Edema Peripheral16Rash16Epistaxis14Headache14Mucosal Inflammation14Thrombocytopenia14Vomiting13Abdominal Pain11Hypertension11Anemia10Asthenia10Chills10Constipation10Hypomagnesemia10. Clinical Trials Safety Experience with Noxafil Oral SuspensionThe safety of Noxafil oral suspension has been assessed in 1,844 patients, including:605 patients in the active-controlled prophylaxis studies for the prophylaxis of invasive Aspergillus and Candida infections557 patients in the active-controlled OPC studies (not refractory to itraconazole or fluconazole)239 patients in refractory OPC studies (refractory to itraconazole or fluconazole) (rOPC), and443 patients in other patient populationsThese studies included immunocompromised patients (e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection), as well as non-neutropenic patients. This patient population was 71% male, had mean age of 42 years (range: 8-84 years, 6% of patients were >=65 years of age and 1% was <18 years of age), and were 64% White, 14% Black, and 16% Hispanic. Noxafil oral suspension therapy was given to 171 patients for >=6 months, including 58 patients who received Noxafil oral suspension therapy for >=12 months. Table presents adverse reactions observed at an incidence of >10% in the studies for prophylaxis of invasive Aspergillus and Candida infections. Table presents adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.Prophylaxis of Invasive Aspergillus and Candida Infections (Noxafil oral suspension)In the two randomized, comparative studies for prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised (Noxafil Oral Suspension Study and 2), the safety of Noxafil oral suspension 200 mg three times day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice day in severely immunocompromised patients. The most frequently reported adverse reactions (>30%) in these trials were fever, diarrhea, and nausea. The most common adverse reactions leading to discontinuation of Noxafil oral suspension were GI adverse reactions, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).Table 7: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida InfectionsAdverse ReactionsNoxafil Oral Suspension n=605(%)Fluconazole n=539(%) Itraconazole n=58(%) Percentage of Patients Reporting any Adverse Reaction9899100Fever454755Diarrhea423960Nausea383752Hypokalemia302652Thrombocytopenia292734Vomiting293241Headache282640Abdominal Pain272736Anemia252328Coughing242424Neutropenia232340Constipation211717Dyspnea202226Rigors201629Rash191843Hypertension18165Hypomagnesemia181619Fatigue17189Insomnia171719Musculoskeletal Pain161516Anorexia151728Edema Legs151219Epistaxis141421Hypotension141517Pharyngitis121121Tachycardia12145Arthralgia11129Dizziness11109Hyperglycemia11143Petechiae111016Pruritus111219Back Pain10127Bilirubinemia10919Dyspepsia10910Vaginal HemorrhagePercentages of sex-specific adverse reactions are based on the number of males/females. 10912Treatment of Nonrefractory OPC and Refractory OPC (Noxafil oral suspension)In two randomized comparative studies for the treatment of nonrefractory OPC, the safety of Noxafil oral suspension (less than or equal to 400 mg once daily) in 557 HIV-infected patients was compared to the safety of fluconazole (100 mg once daily) in 262 HIV-infected patients.An additional 239 HIV-infected patients with refractory OPC (rOPC) received Noxafil oral suspension in two non-comparative trials for rOPC. Of these patients, 149 received the 800 mg/day dosage and the remainder received the less than or equal to 400 mg once daily dosage.In the nonrefractory OPC and rOPC studies, the most common adverse reactions in patients treated with Noxafil oral suspension were fever, diarrhea, nausea, headache, vomiting, and coughing.Adverse reactions were reported more frequently in the studies of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions were reported in 55% (132/239) of Noxafil oral suspension-treated patients. The most commonly reported serious adverse reactions were fever (13%) and neutropenia (10%).Table 8: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Treatment of Nonrefractory and Refractory OPCAdverse ReactionsControlled OPC PoolRefractory OPC PoolNoxafil Oral SuspensionFluconazoleNoxafil Oral Suspensionn=557(%)n=262(%)n=239(%)OPC=oropharyngeal candidiasisPercentage of Patients that Reported any Adverse ReactionBased on patients reporting adverse reactions at least once during the study, without regard to relationship to treatment. Patients may have reported more than adverse reaction. 646792Diarrhea101329Nausea91129Headache8920Vomiting7728Fever6834Abdominal Pain5618Neutropenia4316Coughing3425Fatigue3513Herpes Simplex3311Pneumonia3210Rash3415Anemia2214Anorexia2219Asthenia2213Sweating Increased2210Candidiasis, Oral1<112Dehydration1311Dyspnea1312Insomnia1116Pain1111Weight Decrease1<114Rigors<1212. 605 patients in the active-controlled prophylaxis studies for the prophylaxis of invasive Aspergillus and Candida infections. 557 patients in the active-controlled OPC studies (not refractory to itraconazole or fluconazole). 239 patients in refractory OPC studies (refractory to itraconazole or fluconazole) (rOPC), and. 443 patients in other patient populations. Additional Adverse Reactions Reported in Less Than 5% of Noxafil-Treated Patients in Clinical TrialsOther clinically significant adverse reactions reported in less than 5% of patients in clinical trials of Noxafil are listed below:Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravatedEndocrine disorders: adrenal insufficiencyNervous system disorders: paresthesiaImmune system disorders: allergic reaction [see Contraindications (4.1)] Cardiac disorders: torsades de pointes [see Warnings and Precautions (5.2)] Vascular disorders: pulmonary embolismGastrointestinal disorders: pancreatitisLiver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundiceRenal Urinary System Disorders: renal failure acute. Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated. Endocrine disorders: adrenal insufficiency. Nervous system disorders: paresthesia. Immune system disorders: allergic reaction [see Contraindications (4.1)] Cardiac disorders: torsades de pointes [see Warnings and Precautions (5.2)] Vascular disorders: pulmonary embolism. Gastrointestinal disorders: pancreatitis. Liver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice. Renal Urinary System Disorders: renal failure acute. Liver Test Abnormalities in the Clinical Trials of Noxafil Oral SuspensionLiver Test Abnormalities in the Clinical Trials with Noxafil Oral Suspension for Prophylaxis of Invasive Aspergillus and Candida InfectionsIn the prophylaxis of invasive Aspergillus and Candida infections studies, the number and percentage of patients with changes in liver tests from Common Toxicity Criteria (CTC) Grade 0, 1, or at baseline to Grade or at the end of the studies is presented in Table 9. Table 9: Changes in Liver Test Results from CTC Grade 0, 1, or at Baseline to Grade or in Prophylaxis of Invasive Aspergillus and Candida Infections Studies (Noxafil Oral Suspension Study and Study 2)Number (%) of Patients with ChangeChange from Grade to at baseline to Grade or during the study. These data are presented in the form X/Y, where represents the number of patients who met the criterion as indicated, and represents the number of patients who had baseline observation and at least one post-baseline observation. CTC Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase.Noxafil Oral Suspension Study 1Laboratory ParameterNoxafil Oral Suspensionn=301Fluconazolen=299 AST11/266 (4)13/266 (5) ALT47/271 (17)39/272 (14) Bilirubin24/271 (9)20/275 (7) Alkaline Phosphatase9/271 (3)8/271 (3)Noxafil Oral Suspension Study 2Laboratory ParameterNoxafil Oral Suspension(n=304)Fluconazole/Itraconazole(n=298) AST9/286 (3)5/280 (2) ALT18/289 (6)13/284 (5) Bilirubin20/290 (7)25/285 (9) Alkaline Phosphatase4/281 (1)1/276 (<1)Liver Test Abnormalities in the Clinical Trials with Noxafil Oral Suspension for the Treatment of OPCThe number and percentage of patients treated for OPC with clinically significant liver test abnormalities at any time during the studies is provided in Table 10 (liver test abnormalities were present in some of these patients prior to initiation of the study drug).Table 10: Clinically Significant Liver Test Abnormalities without Regard to Baseline Value (Noxafil Oral Suspension Studies for the Treatment of OPC)Laboratory TestNonrefractory OPCRefractory OPCNoxafil Oral SuspensionFluconazoleNoxafil Oral Suspensionn=557 (%)n=262 (%)n=239 (%)ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.ALT 3.0 ULN16/537 (3)13/254 (5)25/226 (11)AST 3.0 ULN33/537 (6)26/254 (10)39/223 (17)Total Bilirubin 1.5 ULN15/536 (3)5/254 (2)9/197 (5)Alkaline Phosphatase 3.0 ULN17/535 (3)15/253 (6)24/190 (13)Liver Test Abnormalities in the Clinical Trials with Noxafil Oral Suspension for the Treatment of Invasive AspergillosisThe number and percentage of patients treated for invasive aspergillosis with clinically significant liver test abnormalities at any time during the Aspergillosis Treatment Study is provided in Table 11. Liver test abnormalities present prior to the initiation of study drug included ALT (22% of the patients), AST (13% of the patients), and bilirubin (13% of the patients).Table 11: Changes in Liver Test Results from CTC Grade 0, 1, or at Baseline to Grade or (Aspergillosis Treatment Study)Number (%) of Patients with ChangeChange from Grade to at baseline to Grade or during the study. These data are presented in the form n/N, where represents the number of patients who met the criterion as indicated, and represents the number of patients who had baseline observation and at least one post-baseline observation. Laboratory ParameterNoxafiln/N (%)Voriconazolen/N (%)N=Number of patients for given laboratory test with baseline value of CTC Grade 0, 1, or and at least one post-baseline value.CTC Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase. AST22/281 (8)21/285 (7) ALT29/281(10)23/282 (8) Bilirubin26/280 (9)25/284 (9) Alkaline Phosphatase12/282 (4)20/284 (7)In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma concentrations of posaconazole.Clinical Trials in Pediatric Patients Years of Age and OlderThe safety of Noxafil injection and Noxafil PowderMix (for delayed-release oral suspension) for prophylaxis of invasive fungal infections was evaluated in an open-label uncontrolled dose-ranging pharmacokinetic and safety study of Noxafil injection and Noxafil PowderMix (Pediatric Study 1, NCT02452034). In this study, 115 immunocompromised pediatric patients to less than 18 years of age with known or expected neutropenia initially received Noxafil injection (up to mg/kg twice daily for the first day and then up to mg/kg for at least days) and then 63 patients were transitioned to Noxafil PowderMix (up to mg/kg once daily). The mean overall treatment duration for all treated subjects was 21 days including mean duration of 14 days (range: to 28 days) on Noxafil injection and mean duration of 12 days (range: to 18 days) on Noxafil PowderMix for delayed-release oral suspension. In this study, the reported adverse reaction profile of Noxafil injection and Noxafil PowderMix in pediatric patients was consistent with the safety profile of Noxafil in adults. The safety of Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension for the treatment of invasive aspergillosis was evaluated in an open-label, non-comparative clinical study in 31 pediatric patients to less than 18 years of age with diagnosis of possible, probable, or proven invasive aspergillosis (Pediatric Study 2, NCT04218851). In this study, all 31 pediatric patients initially received Noxafil injection (6 mg/kg twice daily on the first day and then mg/kg once daily) for the treatment of invasive aspergillosis; 12 patients were transitioned to Noxafil delayed-release tablets (300 mg once daily) if they weighed >=40 kg, and 10 patients were transitioned to Noxafil PowderMix (based on weight) if they weighed 10 to 40 kg [see Dosage and Administration (2.3)]. The mean overall treatment duration was 50 days including 15 days (range: to 78 days) on Noxafil injection, 54 days (range: to 80 days) on Noxafil delayed-release tablets, and 44 days (range: to 76 days) on Noxafil PowderMix. The reported adverse reaction profile of Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix in pediatric patients was consistent with the known safety profile of Noxafil in adults. The most common adverse reactions that occurred in greater than 20% of pediatric patients who received any of the three formulations of Noxafil were vomiting, pyrexia, abdominal pain, liver test abnormalities, and hypertension.. 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish casual relationship to drug exposure.Endocrine Disorders: Pseudoaldosteronism.

CLINICAL PHARMACOLOGY SECTION.

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 ImmunocompromisedIn 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), wide range of plasma posaconazole exposures was noted following administration of Noxafil oral suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 15). lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.Table 15: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis TrialsProphylaxis 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 (%)Cavg the average posaconazole concentration when measured at steady stateQuartile 190-32254.722-55744.4Quartile 2322-49037.0557-91520.6Quartile 3490-73446.8915-156317.5Quartile 4734-220027.81563-365017.5Exposure Response Relationship: Treatment of Invasive Aspergillosis in Adult and Adolescent Patients:Across range of posaconazole plasma minimum concentrations (Cmin, range: 244 to 5663 ng/mL) following administration of Noxafil injection and Noxafil delayed-release tablets in adult and pediatric patients aged 14 years and older treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole Cmin and treatment efficacy [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. Similarly, across range of population pharmacokinetic model-predicted steady-state plasma average concentrations (Cavg, range: 589 to 6315 ng/mL), there was no association between posaconazole Cavg and treatment efficacy.. 12.3 Pharmacokinetics. General Pharmacokinetic Characteristics. General Pharmacokinetic Characteristics of Posaconazole Delayed-Release TabletsNoxafil 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 Noxafil 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 16.Table 16: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Noxafil Delayed-Release Tablets (300 mg)300 mg twice daily on Day 1, then 300 mg once daily thereafter NAUC0-24 hr (nghr/mL)CavCav time-averaged concentrations (i.e., AUC0-24 hr/24 hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Tmax Median (minimum-maximum) (hr)t1/2 (hr)CL/F(L/hr)CV coefficient of variation expressed as 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; 1/2 terminal phase half-life; CL/F Apparent total body clearanceHealthy Volunteers1251618(25)2151(25)2764(21)1785(29)4(3-6)31(40)7.5(26)Patients5037900(42)1580(42)2090(38)1310(50)4 (1.3-8.3)-9.39(45). General Pharmacokinetic Characteristics of Posaconazole Oral SuspensionDose-proportional increases in plasma exposure (AUC) to Noxafil oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections.The mean (%CV) [min-max] Noxafil oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times day and 400 mg twice daily of the oral suspension are provided in Table 17.Table 17: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Noxafil Oral Suspension 200 mg Three Times Day and 400 mg Twice DailyDoseOral suspension administration Cavg (ng/mL)AUCAUC (0-24 hr) for 200 mg three times day and AUC (0-12 hr) for 400 mg twice daily (nghr/mL)CL/F (L/hr)V/F (L)t 1/2 (hr)Cavg the average posaconazole concentration when measured at steady state200 mg three times dayHSCT recipients with GVHD (n=252)1103 (67)[21.5-3650]NDNot done ND ND ND 200 mg three times dayNeutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215)583 (65)[89.7-2200]15,900 (62)[4100-56,100]51.2 (54)[10.7-146]2425 (39)[828-5702]37.2 (39)[19.1-148]400 mg twice dailyFebrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects. (n=23)723 (86)[6.70-2256]9093 (80)[1564-26,794]76.1 (78)[14.9-256]3088 (84)[407-13,140]31.7 (42)[12.4-67.3]. Absorption:. Absorption of Posaconazole Delayed-Release TabletsWhen given orally in healthy volunteers, Noxafil delayed-release tablets are absorbed with median Tmax of to hours. Steady-state plasma concentrations are attained by Day at the 300 mg dose (once daily after twice daily loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of Noxafil delayed-release tablets are increased 16% and 51%, respectively, when given with high fat meal compared to fasted state (see Table 18).Table 18: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Noxafil Delayed-Release Tablet to Healthy Subjects under Fasting and Fed ConditionsFasting ConditionsFed Conditions(High Fat Meal)48.5 fat Fed/FastingPharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)GMR=Geometric least-squares mean ratio; CI=Confidence intervalCmax (ng/mL)14935 (34)161060 (25)1.16 (0.96, 1.41)AUC0-72hr (hrng/mL)1426200 (28)1638400 (18)1.51 (1.33, 1.72)Tmax Median (Min, Max) reported for Tmax (hr)145.00 (3.00, 8.00)166.00 (5.00, 24.00)N/A. Absorption of Posaconazole Oral SuspensionNoxafil oral suspension is absorbed with median Tmax of ~3 to hours. Steady-state plasma concentrations are attained at to 10 days following multiple-dose administration.Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when the oral suspension is administered with nonfat meal and approximately 4-times higher when administered with high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of Noxafil oral suspension 400 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when administered with liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 19). In addition, the effects of varying gastric administration conditions on the Cmax and AUC of Noxafil oral suspension in healthy volunteers have been investigated and are shown in Table 20.To assure attainment of adequate plasma concentrations, it is recommended to administer Posaconazole oral suspension during or immediately following full meal. In patients who cannot eat full meal, Posaconazole oral suspension should be taken with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).Table 19: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Noxafil Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted ConditionsDose (mg)Cmax (ng/mL)Tmax Median [min-max]. (hr)AUC (I)(nghr/mL)CL/F(L/hr)t 1/2 (hr)200 mg fasted(n=20)n=15 for AUC (I), CL/F, and 1/2 132 (50)[45-267]3.50[1.5-36The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between hrs and 36 hrs).]4179 (31)[2705-7269]51 (25)[28-74]23.5 (25)[15.3-33.7]200 mg nonfat(n=20) 378 (43)[131-834]4 [3-5]10,753 (35)[4579-17,092]21 (39)[12-44]22.2 (18)[17.4-28.7]200 mg high fat(54 gm fat)(n=20) 512 (34)[241-1016]5 [4-5]15,059 (26)[10,341-24,476]14 (24)[8.2-19]23.0 (19)[17.2-33.4]400 mg fasted(n=23)n=10 for AUC (I), CL/F, and 1/2 121 (75)[27-366]4 [2-12]5258 (48)[2834-9567]91 (40) [42-141]27.3 (26)[16.8-38.9]400 mg with liquid nutritional supplement(14 gm fat)(n=23) 355 (43)[145-720]5 [4-8]11,295 (40)[3865-20,592]43 (56)[19-103]26.0 (19)[18.2-35.0]Table 20: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Noxafil Oral Suspension in Healthy VolunteersIn subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when Noxafil was administered via an NG tube compared to when Noxafil was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when posaconazole is administered via an NG tube because lower plasma exposure may be associated with an increased risk of treatment failure. Study DescriptionAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in AUC(ratio estimate; 90% CI of the ratio estimate)400-mg single dose with high-fat meal relative to fasted state (n=12)5 minutes before high-fat meal96%(1.96; 1.48-2.59)111%(2.11; 1.60-2.78)During high-fat meal339%(4.39; 3.32-5.80)382%(4.82; 3.66-6.35)20 minutes after high-fat meal333%(4.33; 3.28-5.73)387%(4.87; 3.70-6.42)400 mg twice daily and 200 mg four times daily for days in fasted state and with liquid nutritional supplement (BOOST(R)) (n=12)400 mg twice daily with BOOST65%(1.65; 1.29-2.11)66%(1.66; 1.30-2.13)200 mg four times daily with BOOSTNo EffectNo EffectDivided daily dose from 400 mg twice daily to 200 mg four times daily for days regardless of fasted conditions or with BOOST (n=12)Fasted state136%(2.36; 1.84-3.02)161%(2.61; 2.04-3.35)With BOOST137%(2.37; 1.86-3.04)157%(2.57; 2.00-3.30)400-mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)Ginger ale92%(1.92; 1.51-2.44)70%(1.70; 1.43-2.03)Esomeprazole32%(0.68; 0.53-0.86)30%(0.70; 0.59-0.83)400-mg single dose with prokinetic agent (metoclopramide 10 mg three times day for days) BOOST or an antikinetic agent (loperamide 4-mg single dose) BOOST (n=12)With metoclopramide BOOST21%(0.79; 0.72-0.87)19%(0.81; 0.72-0.91)With loperamide BOOST3%(0.97; 0.88-1.07)11%(1.11; 0.99-1.25)400-mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)Via NG tubeNG nasogastric 19%(0.81; 0.71-0.91)23%(0.77; 0.69-0.86). Distribution: Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.. Metabolism:Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 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 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 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 mean half-life (t 1/2 ranging between 26 to 31 hours. Posaconazole oral suspension is eliminated with mean half-life (t 1/2 of 35 hours (range: 20-66 hours).Specific PopulationsNo clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Patients with Renal Impairment:After Noxafil oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m2 or higher compared to those with eGFR >80 mL/minute/1.73 m2. Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m2 treated with Noxafil oral suspension to those with eGFR >80 mL/minute/1.73 m2 treated with Noxafil oral suspension, the range of the AUC estimates was highly variable (CV=96%) in patients with eGFR less than 20 mL/minute/1.73 m2 compared to those with eGFR >80 mL/minute/1.73 m2 (CV <40%).Similar posaconazole pharmacokinetic results are expected after administration of Posaconazole delayed-release tablets [see Use in Specific Populations (8.6)]. Patients with Hepatic Impairment:After single oral dose of Noxafil oral suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively [see Use in Specific Populations (8.7)]. Race/Ethnicity:In 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 clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)].Pediatric Patients:Treatment of invasive aspergillosis in pediatric patients years of age and older: total of 31 patients to less than 18 years of age (body weight of >=12 kg) received pediatric dosing based on body weight of Noxafil delayed-release tablets, Noxafil Injection, and Noxafil PowderMix for delayed-release oral suspension [see Dosage and Administration (2.3]. The mean population pharmacokinetic model parameters after multiple dose administration of Noxafil delayed-release tablets, Noxafil Injection, and Noxafil PowderMix for delayed-release oral suspension in pediatric patients to less than 18 years of age for the treatment of invasive aspergillosis (Pediatric Study 2) are shown in Table 21. [see Adverse Reactions (6.1)].Table 21: Summary of Steady-State Geometric Mean Pharmacokinetic ParametersParameter estimates reported only for N>2 (excludes single patient >=2 to <12 receiving tablet and patients >=12 to <18 years receiving PFS) (% Geometric CV) After Multiple Dosing with Noxafil Injection, Noxafil PowderMix for Delayed-Release Oral Suspension, and Noxafil Delayed-Release Tablets in Pediatric Patients being Treated for Invasive AspergillosisAge GroupDose TypeNSome patients had values (1 for IV dosing and for oral dosing) AUC0-24 hours (ng.hr/mL)Cav Cav time-averaged concentrations (i.e., AUC0-24 hours/24hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Tmax Median (minimum-maximum) (hr)CL/FClearance (CL for IV and CL/F for PFS or Tablet) (L/hr)IV Noxafil injection; PFS Noxafil PowderMix for delayed-release oral suspension; Tablet= Noxafil delayed-release tablets; AUC0-24 hours 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; CL/F apparent total body clearance2 to <12 yearsIV961900(49.8)2580 (49.8)3630 (30.8)1710 (82.2)1.50 (1.25-1.77)2.56 (47.8)PFS645200(30.2)1880 (30.2)2220 (26.5)1370 (41.8)7.00 (6.40-7.20)3.25 (34.6)12 to <18 yearsIV1360800(35.6)2530 (35.6)3510 (26.8)1740 (48.5)1.50 (1.30-1.63)4.41 (41.8)Tablet1047800(52.7)1990 (52.7)2250 (48.3)1580 (62.6)7.15 (6.70-7.30)6.27 (52.7)The population pharmacokinetic analysis of posaconazole in pediatric patients, including Pediatric Study 2, suggests that age, sex, ethnicity, and disease status have no clinically meaningful effect on the pharmacokinetics of posaconazole.Drug Interaction Studies:Posaconazole is primarily metabolized via UDP glucuronidation (phase enzymes) and is substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. summary of drugs studied clinically with the oral suspension or another tablet formulation, which affect posaconazole concentrations, is provided in Table 22.Table 23 and Table 24 include summary of the drug effects of concomitant medications that may impact the absorption of posaconazole when administered as either the oral suspension or delayed-release tablets.A clinical study in healthy volunteers also indicates that posaconazole is strong CYP3A4 inhibitor as evidenced by >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 25 [see Contraindications (4) and Drug Interactions (7.2) including recommendations]. Effects of Other Drugs on Posaconazole:Table 22: Summary of the Effects of Coadministered Drugs on Noxafil in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil 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 days400 mg (oral suspension) twice daily 10 and 20 days45%(0.55; 0.47-0.66)50%(0.50; 0.43-0.60)Fosamprenavir (unknown mechanism)700 mg twice daily 10 days200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily 8 Days21%0.79 (0.71-0.89)23%0.77 (0.68-0.87)Rifabutin(UDP-G Induction)300 mg once daily 17 days200 mg (tablets) once daily 10 daysThe tablet refers to 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 10 days200 mg (tablets) once daily 10 days 41%(0.59; 0.44-0.79)50%(0.50; 0.36-0.71)Posaconazole Oral Suspension: Concomitant administration of Noxafil oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (see Table 23.) Table 23: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Oral Suspension in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil 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)Cimetidine(Alteration of gastric pH)400 mg twice daily 10 days200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 39% (0.61; 0.53-0.70)39% (0.61; 0.54-0.69)Esomeprazole (Increase in gastric pH)The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide. 40 mg every morning 3 days400 mg (oral suspension) single dose46%(0.54; 0.43-0.69)32%(0.68; 0.57-0.81)Metoclopramide (Increase in gastric motility) 10 mg three times day 2 days400 mg (oral suspension) single dose21%(0.79; 0.72-0.87)19%(0.81; 0.72-0.91)Posaconazole Delayed-Release Tablets: Concomitant administration of Noxafil delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 24). Table 24: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Delayed-Release Tablets in Healthy VolunteersCoadministered DrugAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil 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(R) Ultimate strength liquid (Increase in gastric pH)25.4 mEq/5 mL, 20 mL6%(1.06; 0.90-1.26)4%(1.04; 0.90-1.20)Ranitidine (Zantac(R)) (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(R)) (Increase in gastric pH)40 mg (every morning for days, Day -4 to 1)2%(1.02; 0.88-1.17)5%(1.05; 0.89-1.24)Metoclopramide (Reglan(R)) (Increase in gastric motility)15 mg four times daily for days (Day -1 and 1)14%(0.86, 0.73,1.02)7%(0.93, 0.803,1.07)Effects of Posaconazole on Other Drugs:Table 25: Summary of the Effect of Noxafil on Coadministered Drugs in Healthy Volunteers and PatientsCoadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of Coadministered DrugsChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil 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)Sirolimus2-mg single oral dose400 mg (oral suspension) twice daily 16 days572%(6.72; 5.62-8.03)788%(8.88; 7.26-10.9)CyclosporineStable maintenance dose in heart transplant recipients200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. Cyclosporine whole blood trough concentrationsCyclosporine dose reductions of up to 29% were requiredTacrolimus0.05-mg/kg single oral dose400 mg (oral suspension) twice daily 7 days121%(2.21; 2.01-2.42)358%(4.58; 4.03-5.19)Simvastatin40-mg single oral dose100 mg (oral suspension) once daily 13 days Simvastatin841%(9.41, 7.13-12.44) Simvastatin Acid817% (9.17, 7.36-11.43)Simvastatin931%(10.31, 8.40-12.67)Simvastatin Acid634%(7.34, 5.82-9.25)200 mg (oral suspension) once daily 13 daysSimvastatin1041%(11.41, 7.99-16.29)Simvastatin Acid851%(9.51, 8.15-11.10)Simvastatin960%(10.60, 8.63-13.02)Simvastatin Acid748%(8.48, 7.04-10.23)Midazolam0.4-mg single intravenous doseThe mean terminal half-life of midazolam was increased from hours to to 11 hours during coadministration with Noxafil. 200 mg (oral suspension) twice daily 7 days30%(1.3; 1.13-1.48)362%(4.62; 4.02-5.3)0.4-mg single intravenous dose 400 mg (oral suspension) twice daily 7 days62%(1.62; 1.41-1.86)524%(6.24; 5.43-7.16)2-mg single oral dose 200 mg (oral suspension) once daily 7 days169%(2.69; 2.46-2.93)470%(5.70; 4.82-6.74)2-mg single oral dose 400 mg (oral suspension) twice daily 7 days138%(2.38; 2.13-2.66)397%(4.97; 4.46-5.54)Rifabutin300 mg once daily 17 days200 mg (tablets) once daily 10 days 31%(1.31; 1.10-1.57)72%(1.72;1.51-1.95)Phenytoin200 mg once daily PO 10 days200 mg (tablets) once daily 10 days 16%(1.16; 0.85-1.57)16%(1.16; 0.84-1.59)Ritonavir100 mg once daily 14 days400 mg (oral suspension)twice daily 7 days49%(1.49; 1.04-2.15)80%(1.8;1.39-2.31)Atazanavir300 mg once daily 14 days400 mg (oral suspension) twice daily 7 days155%(2.55; 1.89-3.45)268%(3.68; 2.89-4.70)Atazanavir/ritonavir boosted regimen300 mg/100 mg once daily 14 days 400 mg (oral suspension) twice daily 7 days53% (1.53; 1.13-2.07)146%(2.46; 1.93-3.13). 12.4 Microbiology. Mechanism of ActionPosaconazole blocks the synthesis of ergosterol, key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and 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.. ResistanceClinical 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 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)].. MicroorganismsAspergillus spp. and Candida spp. Susceptibility TestingFor 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 STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Treatment of Invasive Aspergillosis with Noxafil Injection and Noxafil Delayed-Release Tablets. Aspergillosis Treatment Study (NCT01782131) was randomized, double-blind, controlled trial which evaluated the safety and efficacy of Noxafil injection and Noxafil delayed-release tablets versus voriconazole for primary treatment of invasive fungal disease caused by Aspergillus species. Eligible patients had proven, probable, or possible invasive fungal infections per the European Organization for Research and Treatment of Cancer/Mycoses Study Group, EORTC/MSG criteria. Patients were stratified by risk for mortality or poor outcome where high risk included history of allogeneic bone marrow transplant, liver transplant, or relapsed leukemia undergoing salvage chemotherapy. The median age of patients was 57 years (range: 14-91 years), with 27.8% of patients aged >=65 years; patients were pediatric patients 14-16 years of age, of whom were treated with Noxafil and with voriconazole. The majority of patients were male (59.8%) and white (67.1%). With regard to risk factors for invasive aspergillosis, approximately two-thirds of the patients in the study had recent history of neutropenia, while approximately 20% with history of an allogeneic stem cell transplant. Over 80% of subjects in each treatment group had infection limited to the lower respiratory tract (primarily lung), while approximately 11% to 13% also had infection in another organ. Invasive aspergillosis was proven or probable in 58.1% of patients as classified by independent adjudicators blinded to study treatment assignment. At least one Aspergillus species was identified in 21% of the patients; A. fumigatus and A. flavus were the most common pathogens identified.Patients randomized to receive Noxafil were given dose of 300 mg once daily (twice daily on Day 1) IV or tablet. Patients randomized to receive voriconazole were given dose of mg/kg twice daily Day followed by mg/kg twice daily IV, or oral 300 mg twice daily Day followed by 200 mg twice daily. The recommended initial route of administration was IV; however, patients could begin oral therapy if clinically stable and able to tolerate oral dosing. The transition from IV to oral therapy occurred when the patient was clinically stable. The protocol recommended duration of therapy was 84 days with maximum allowed duration of 98 days. Median treatment duration was 67 days for Noxafil patients and 64 days for voriconazole patients. Overall, 55% to 60% of patients began treatment with the IV formulation with median duration of days for the initial IV dosing.The Intent to Treat (ITT) population included all patients randomized and receiving at least one dose of study treatment. All-cause mortality through Day 42 in the overall population (ITT) was 15.3% for Noxafil patients compared to 20.6% for voriconazole patients for an adjusted treatment difference of -5.3% with 95% confidence interval of -11.6 to 1.0%. Consistent results were seen in patients with proven or probable invasive aspergillosis per EORTC criteria (see Table 26).Table 26: Noxafil Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: All-Cause Mortality Through Day 42Noxafil Injection and Delayed-Release TabletsVoriconazolePopulationNn (%)Nn (%)DifferenceAdjusted treatment difference based on Miettinen and Nurminens method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme. (95% CI)Intent to Treat28844 (15.3)28759 (20.6)-5.3 (-11.6, 1.0)Proven/Probable Invasive Aspergillosis16331 (19.0)17132 (18.7)0.3 (-8.2, 8.8)Global clinical response at Week was assessed by blinded, independent adjudication committee based upon prespecified clinical, radiologic, and mycologic criteria. In the subgroup of patients with proven or probable invasive aspergillosis per EORTC criteria, the global clinical response of success (complete or partial response) at Week was seen in 44.8% for Noxafil-treated patients compared to 45.6% for voriconazole-treated patients (see Table 27). Table 27: Noxafil Injection and Noxafil Delayed-Release Tablets Invasive Aspergillosis Treatment Study: Successful Global Clinical ResponseSuccessful Global Clinical Response was defined as survival with partial or complete response. at Week 6PosaconazoleVoriconazolePopulationNSuccessNSuccessDifferenceAdjusted treatment difference based on Miettinen and Nurminens method stratified by randomization factor (risk for mortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme. (95% CI)Proven/Probable Invasive Aspergillosis 16373 (44.8)17178 (45.6)-0.6 (-11.2, 10.1). 14.2Prophylaxis of Aspergillus and Candida Infections with Noxafil Oral Suspension. Two randomized, controlled studies were conducted using Noxafil as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems.The first study (Noxafil Oral Suspension Study 1) was randomized, double-blind trial that compared Noxafil oral suspension (200 mg three times 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 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 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the treatment groups (80 days, Noxafil oral suspension; 77 days, fluconazole). Table 28 contains the results from Noxafil Oral Suspension Study 1.Table 28: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Noxafil Oral Suspension Study 1Posaconazolen=301Fluconazolen=299On therapy plus daysClinical 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 weeksClinical 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 death10 (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%)The second study (Noxafil Oral Suspension Study 2) was randomized, open-label study that compared Noxafil oral suspension (200 mg times day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice 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 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 days and 100 days postrandomization. The mean duration of therapy was comparable between the treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 29 contains the results from Noxafil Oral Suspension Study 2.Table 29: Results from Open-Label Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Noxafil Oral Suspension Study 2Posaconazolen=304Fluconazole/Itraconazolen=298On therapy plus daysClinical 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 postrandomizationClinical 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 death2 (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%)In summary, clinical studies of prophylaxis were conducted with the Noxafil oral suspension. As seen in the accompanying tables (Tables 23 and 24), clinical failure represented composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Noxafil Oral Suspension Study (Table 23), 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 (Table 24) 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 [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for Noxafil-treated patients in Noxafil Oral Suspension Study [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated fewer breakthrough infections caused by Aspergillus species in patients receiving Noxafil prophylaxis when compared to patients receiving fluconazole or itraconazole.. 14.3Treatment of Oropharyngeal Candidiasis with Noxafil Oral Suspension. Noxafil Oral Suspension Study was randomized, controlled, evaluator-blinded study in HIV-infected patients with oropharyngeal candidiasis. Patients were treated with Noxafil or fluconazole oral suspension (both Noxafil and fluconazole were given as follows: 100 mg twice day for day followed by 100 mg once day for 13 days).Clinical and mycological outcomes were assessed after 14 days of treatment and at weeks after the end of treatment. Patients who received at least dose of study medication and had positive oral swish culture of Candida species at baseline were included in the analyses (see Table 25). The majority of the subjects had C. albicans as the baseline pathogen.Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms) and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) weeks after the end of treatment were similar between the treatment arms (see Table 30).Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also similar between the treatment arms (see Table 30).Table 30: Noxafil Oral Suspension Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal CandidiasisNoxafilFluconazoleClinical Success at End of Therapy (Day 14)155/169 (91.7%)148/160 (92.5%)Clinical Relapse (4 Weeks after End of Therapy)45/155 (29.0%)52/148 (35.1%)Mycological Eradication (absence of CFU) at End of Therapy (Day 14)88/169 (52.1%)80/160 (50.0%)Mycological Relapse (4 Weeks after End of Treatment)49/88 (55.6%)51/80 (63.7%)Mycologic response rates, using criterion for success as posttreatment quantitative culture with <=20 colony forming units (CFU/mL) were also similar between the two groups (Noxafil 68.0%, fluconazole 68.1%). The clinical significance of this finding is unknown.. 14.4Noxafil Oral Suspension Treatment of Oropharyngeal Candidiasis Refractory to Treatment with Fluconazole or Itraconazole. Noxafil Oral Suspension Study was noncomparative study of Noxafil oral suspension in HIV-infected subjects with OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was considered refractory if there was failure to improve or worsening of OPC after standard course of therapy with fluconazole greater than or equal to 100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with Noxafil. Of the 199 subjects enrolled in this study, 89 subjects met these strict criteria for refractory infection.Forty-five subjects with refractory OPC were treated with Noxafil oral suspension 400 mg twice daily for days, followed by 400 mg once daily for 25 days with an option for further treatment during 3-month maintenance period. Following dosing amendment, further 44 subjects were treated with Noxafil 400 mg twice daily for 28 days. The efficacy of Noxafil was assessed by the clinical success (cure or improvement) rate after weeks of treatment. The clinical success rate was 74.2% (66/89). The clinical success rates for both the original and the amended dosing regimens were similar (73.3% and 75.0%, respectively).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Posaconazole formulations are supplied in different dose strengths of posaconazole, are approved for different indications, age groups, and weights, have different dosages and duration of therapy; and have different preparation and administration instructions. (2.1)Posaconazole oral suspension is not substitutable with Posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations. (2.1, 2.2, 2.3)Administer Posaconazole delayed-release tablets with or without food. (2.1)Administer Posaconazole oral suspension with full meal. (2.1)See the full prescribing information for important administration and preparation instructions for Posaconazole (delayed-release tablets and Posaconazole oral suspension (2.5, 2.6, 2.7)For adult and pediatric patients aged years of age and older, see the Full Prescribing Information for dosing recommendations for Posaconazole delayed-release tablets and Posaconazole oral suspension based on the indication, age, and weight associated with the dosage form. (1.1, 1.2, 1.3, 2.1, 2.2, 2.3, 2.4). Posaconazole formulations are supplied in different dose strengths of posaconazole, are approved for different indications, age groups, and weights, have different dosages and duration of therapy; and have different preparation and administration instructions. (2.1). Posaconazole oral suspension is not substitutable with Posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations. (2.1, 2.2, 2.3). Administer Posaconazole delayed-release tablets with or without food. (2.1). Administer Posaconazole oral suspension with full meal. (2.1). See the full prescribing information for important administration and preparation instructions for Posaconazole (delayed-release tablets and Posaconazole oral suspension (2.5, 2.6, 2.7). For adult and pediatric patients aged years of age and older, see the Full Prescribing Information for dosing recommendations for Posaconazole delayed-release tablets and Posaconazole oral suspension based on the indication, age, and weight associated with the dosage form. (1.1, 1.2, 1.3, 2.1, 2.2, 2.3, 2.4). 2.1 Important Administration Instructions. Posaconazole delayed-release tablets and Posaconazole oral suspension are approved for different indications, age groups and weights; have different dosages and duration of therapy; and have different preparation and administration instructions.Therefore, select the recommended dosage form based on the indication, age group, and weight and carefully follow the recommended dosage, preparation and administration instructions described for each product [see Dosage and Administration (2.2 to 2.8)], and the following important administration instructions described below.Non-substitutablePosaconazole oral suspension is not substitutable with Posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2, 2.3)]. Posaconazole delayed-release tabletsSwallow tablets whole. Do not divide, crush, or chew.Administer with or without food [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].For patients who cannot eat full meal, Posaconazole delayed-release tablets should be used instead of Posaconazole oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Posaconazole oral suspension under both fed and fasted conditions [see Dosage and Administration (2.6)].Posaconazole oral suspensionAdminister with full meal or with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat full meal [see Dosage and Administration (2.8)]. Swallow tablets whole. Do not divide, crush, or chew.. Administer with or without food [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].. For patients who cannot eat full meal, Posaconazole delayed-release tablets should be used instead of Posaconazole oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Posaconazole oral suspension under both fed and fasted conditions [see Dosage and Administration (2.6)].. Administer with full meal or with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat full meal [see Dosage and Administration (2.8)]. 2.2 Recommended Dosage of Posaconazole in Adult Patients. The recommended dosage of Posaconazole delayed-release tablets and Posaconazole oral suspension in adult patients for the treatment of invasive aspergillosis, prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, or for the treatment of oropharyngeal candidiasis (OPC) is shown in Table [see Dosage and Administration (2.5, 2.6, 2.7) and Clinical Pharmacology (12.3)]. Table 1: Recommended Dosage of Posaconazole Delayed-Release Tablets and Posaconazole Oral Suspension in Adult PatientsDosageDuration of TherapyTreatment of Invasive AspergillosisSwitching between the Noxafil injection and Posaconazole delayed-release tablets is acceptable. loading dose is not required when switching between dosage forms. Posaconazole Delayed-Release Tablets:Loading dose: 300 mg (three 100 mg delayed-release tablets) twice day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once day, starting on the second day.Loading dose:1 dayMaintenance dose:Recommended total duration of therapy is to 12 weeks.Prophylaxis of Invasive Aspergillus and Candida InfectionsPosaconazole Delayed-Release Tablets:Loading dose: 300 mg (three 100 mg delayed-release tablets) twice day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once day, starting on the second day.Posaconazole Oral Suspension: 200 mg (5 mL) three times day.Loading dose: dayMaintenance dose: Duration of therapy is based on recovery from neutropenia or immunosuppressionOropharyngeal Candidiasis (OPC)Posaconazole Oral Suspension: Loading dose: 100 mg (2.5 mL) twice day on the first day. Maintenance dose: 100 mg (2.5 mL) once day thereafter.Loading dose:1 dayMaintenance dose:13 daysOPC Refractory (rOPC) to Itraconazole and/or FluconazolePosaconazole Oral Suspension: 400 mg (10 mL) twice day. Duration of therapy is based on the severity of the patients underlying disease and clinical response.. 2.3 Recommended Dosage of Posaconazole for the Treatment of Invasive Aspergillosis and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients Years of Age and Older. Posaconazole delayed-release tabletsThe recommended dosage of Posaconazole delayed-release tablets in pediatric patients years of age and older who weigh greater than 40 kg for the treatment of invasive aspergillosis and prophylaxis of invasive Aspergillus and Candida infections is shown in Table [see Dosage and Administration (2.5, 2.6, 2.7) 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 Treatment of Invasive AspergillosisSwitching between the Noxafil injection and Posaconazole delayed-release tablets is acceptable. loading dose is not required when switching between formulations. and Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (2 Years of Age and Older)Recommended Pediatric Dosage of Posaconazole Delayed-Release TabletsDuration of TherapyPosaconazole Delayed-Release Tablets (patients weighing greater than 40 kg):Loading dose:300 mg (three 100 mg delayed-release tablets) twice day on the first day. Maintenance dose:300 mg (three 100 mg delayed-release tablets) once day, starting on the second day.Treatment of invasive aspergillosis:Recommended total duration of therapy is to 12 weeksProphylaxis of invasive Aspergillus and Candida infections:Duration of therapy is based on recovery from neutropenia or immunosuppression.Posaconazole Oral SuspensionThe recommended dosage of Posaconazole oral suspension in pediatric patients 13 years of age and older for the prophylaxis of invasive Aspergillus and Candida Infections is shown in Table 3.Table 3: Recommended Dosage of Posaconazole Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (13 Years of Age and Older)Recommended Pediatric Dosage of Posaconazole Oral SuspensionDuration of Therapy200 mg (5 mL) three times dayDuration of therapy is based on recovery from neutropenia or immunosuppression.. 2.4 Recommended Dosage of Posaconazole Oral Suspension for the Treatment of Oropharyngeal Candidiasis in Pediatric Patients 13 Years of Age and Older. The recommended dosage of Posaconazole oral suspension for the treatment of oropharyngeal candidiasis (OPC) and OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients 13 years of age and older is shown in Table 4.The Posaconazole delayed-release tablets are not approved for the treatment of oropharyngeal candidiasis in pediatric patients.Table 4: Recommended Dosage of Posaconazole Oral Suspension for the Treatment of OPC and rOPC in Pediatric Patients (13 Years of Age and Older)Recommended Pediatric Dosage of Posaconazole Oral SuspensionDuration of TherapyOropharyngeal Candidiasis (OPC)Loading Dose:100 mg (2.5 mL) twice daily on the first dayMaintenance Dose:100 mg (2.5 mL) once dailyLoading dose:1 dayMaintenance dose:13 daysOPC Refractory (rOPC) to Itraconazole and/or Fluconazole400 mg (10 mL) twice dailyDuration of therapy is based on the severity of the patients underlying disease and clinical response.. 2.5 Administration Instructions for Posaconazole Delayed-Release Tablets. Swallow the Posaconazole delayed-release tablets whole. Do not divide, crush, or chew.Administer Posaconazole delayed-release orally tablets with or without food [see Clinical Pharmacology (12.3)]. Swallow the Posaconazole delayed-release tablets whole. Do not divide, crush, or chew.. Administer Posaconazole delayed-release orally tablets with or without food [see Clinical Pharmacology (12.3)]. 2.6 Administration Instructions for Posaconazole Oral Suspension. Administer Posaconazole oral suspension with full meal or with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat full meal. For patients who cannot eat full meal, use Posaconazole delayed-release tablets instead of the Posaconazole oral suspension for the prophylaxis of invasive Aspergillus and Candida infections in those who are at high risk of developing these infections due to being severely immunocompromised. This is because Posaconazole delayed-release tablets provide higher plasma drug exposures than Posaconazole oral suspension under fasted condition [see Dosage and Administration (2.1)].For those patients using the Posaconazole oral suspension:Shake Posaconazole oral suspension well before use. Administer with measured dosing spoon (see Figure 1) provided.Administer with measured dosing spoon provided in the package (see Figure 1).Figure 1: Measured dosing spoon provided in the package marked for doses of 2.5 mL and mL.Administer each dose of Posaconazole oral suspension during or immediately (i.e., within 20 minutes) following full meal [see Clinical Pharmacology (12.3)]. In patients who cannot eat full meal and for whom Posaconazole delayed-release tablets are not an option, administer each dose of Posaconazole oral suspension with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale). If these patients cannot tolerate an oral nutritional supplement or an acidic carbonated beverage either use:an alternative antifungal therapy, orPosaconazole oral suspension and closely monitor patients for breakthrough fungal infections.Rinse the spoon with water after each administration and before storage.. Shake Posaconazole oral suspension well before use. Administer with measured dosing spoon (see Figure 1) provided.. Administer with measured dosing spoon provided in the package (see Figure 1).. Administer each dose of Posaconazole oral suspension during or immediately (i.e., within 20 minutes) following full meal [see Clinical Pharmacology (12.3)]. In patients who cannot eat full meal and for whom Posaconazole delayed-release tablets are not an option, administer each dose of Posaconazole oral suspension with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale). If these patients cannot tolerate an oral nutritional supplement or an acidic carbonated beverage either use:an alternative antifungal therapy, orPosaconazole oral suspension and closely monitor patients for breakthrough fungal infections.. an alternative antifungal therapy, or. Posaconazole oral suspension and closely monitor patients for breakthrough fungal infections.. Rinse the spoon with water after each administration and before storage.. Figure 1. 2.7 Non-substitutability between Posaconazole Oral Suspension and Other Formulations. Posaconazole oral suspension is not substitutable with Posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2, 2.3)]. 2.8 Dosage Modifications in Patients with Renal Impairment. The recommended dosage of Posaconazole oral suspension and Posaconazole delayed-release tablets is the same in patients with renal impairment compared to those with normal renal function.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table 12 and Table 13 include drugs with clinically important drug interactions when administered concomitantly with posaconazole and instructions for preventing or managing them. Table 14 includes important drug interactions specific to the absorption of posaconazole administered as Posaconazole oral suspension.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 Posaconazole 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 [see Clinical Pharmacology (12.3)].Consult the labeling of concomitantly used drugs to obtain further information about interactions with posaconazole.. Interaction DrugInteractionRifabutin, phenytoin, efavirenz, cimetidine, esomeprazoleThe drug interactions with esomeprazole and metoclopramide do not apply to Posaconazole tablets (7.3, 12.3). 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)DigoxinMonitor digoxin plasma concentrations (7.2)Fosamprenavir, metoclopramide Monitor for breakthrough fungal infections (7.1). 7.1 Effects of Other Drugs on Posaconazole. Posaconazole is primarily metabolized via UDP-glucuronosyltransferase and is substrate of p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Concomitant use of posaconazole with drugs that can decrease the plasma posaconazole concentrations should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.Table 12: Drug Interactions Affecting Posaconazole When Administered Concomitantly with Other DrugsUDP-Glucuronidase InducersMechanism and Clinical Effect(s)Posaconazole is UDP-glucuronosyltransferase substrate. Concomitant use of posaconazole with UDP-glucuronidase inducers may decrease posaconazole exposure [see Clinical Pharmacology (12.3)], which may reduce the effectiveness of posaconazole.Prevention or ManagementEfavirenzAvoid concomitant use of posaconazole with efavirenz, unless the benefit outweighs the risks.RifabutinAvoid 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. PhenytoinAvoid 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. FosamprenavirMechanism and Clinical Effect(s)Concomitant use of posaconazole with fosamprenavir may lead to decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of posaconazole.Prevention or ManagementIf concomitant use of posaconazole with fosamprenavir is needed, monitor closely for breakthrough fungal infections.Table 13: Drug Interactions Affecting Posaconazole Oral Suspension Absorption When Administered Concomitantly with Other DrugsPosaconazole Oral SuspensionCimetidine and EsomeprazoleMechanism and Clinical Effect(s)Concomitant use of Noxafil oral suspension with cimetidine or esomeprazole resulted in decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of posaconazole.Prevention or ManagementAvoid concomitant use of posaconazole oral suspension with cimetidine or esomeprazole unless the benefit outweighs the risks. If concomitant use is needed, monitor closely for breakthrough fungal infections.MetoclopramideMechanism and Clinical Effect(s)Concomitant use of Noxafil oral suspension with metoclopramide decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of Posaconazole oral suspension.Prevention or ManagementIf Posaconazole oral suspension is concomitantly administered with metoclopramide, closely monitor for breakthrough fungal infections.. 7.2 Effects of Posaconazole on Other Drugs. Posaconazole is strong CYP3A4 inhibitor. Therefore, concomitant use of posaconazole may increase plasma concentrations of drugs that are CYP3A4 substrates [see Clinical Pharmacology (12.3)].Table 14: Drug Interactions Affecting Drugs Administered Concomitantly with PosaconazoleDigoxinClinical Effect(s)Increased digoxin plasma concentrations have been reported in patients who received concomitant posaconazole and digoxin.Prevention or ManagementMonitor digoxin plasma concentrations during concomitant use of posaconazole.GlipizideClinical Effect(s)No dosage modification of glipizide is needed when used concomitantly with posaconazole. However, glucose concentrations decrease in some patients concomitantly administered posaconazole and glipizide.Prevention or ManagementIncrease monitoring of glucose concentrations when used concomitantly.CYP3A SubstratesImmunosuppressants that are CYP3A4 SubstratesMechanism and Clinical Effect(s)Posaconazole is strong CYP3A4 inhibitor. Therefore, plasma concentrations of CYP3A4 substrates may be increased by posaconazole use [see Clinical Pharmacology (12.3)]. Prevention or ManagementSirolimusPosaconazole is contraindicated with sirolimus [see Clinical Pharmacology (12.3)].TacrolimusAt 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)].CyclosporineAt 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 IntervalMechanism 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 ManagementPimozideConcomitant use with posaconazole is contraindicated.QuinidineHMG-CoA Reductase Inhibitors (Statins) that are CYP3A4 SubstratesMechanism 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 ManagementAtorvastatin, Lovastatin, SimvastatinConcomitant use with posaconazole is contraindicated.Benzodiazepines that are CYP3A4 SubstratesMechanism 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 ManagementMidazolam, Alprazolam, TriazolamClosely monitor for adverse reactions associated with high plasma concentrations of benzodiazepines that are CYP3A4 substrates during concomitant use, and benzodiazepine receptor antagonist should be available to reverse effects [see Warnings and Precautions (5.7)]. Calcium Channel Blockers that are CYP3A4 SubstratesMechanism and Clinical Effect(s)Posaconazole may increase the plasma concentrations of calcium channel blockers that are substrates of CYP3A4.Prevention or ManagementVerapamil, Diltiazem, Nifedipine, Nicardipine, FelodipineMonitor 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 SubstratesMechanism 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 ManagementRitonavir and AtazanavirMonitor frequently for adverse reactions and toxicity of ritonavir and atazanavir during concomitant use.Antineoplastic Drugs that are CYP3A4 SubstratesMechanism 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 ManagementVenetoclaxCLL/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 AlkaloidsMechanism 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 ManagementErgotamine, DihydroergotamineConcomitant use with posaconazole is contraindicated.PhenytoinMechanism and Clinical Effect(s)Phenytoin is CYP3A4 substrate. Concomitant use of posaconazole with phenytoin increased phenytoin plasma concentrations [see Clinical Pharmacology (12.3)]. Prevention or ManagementAvoid concomitant use of posaconazole with phenytoin unless the benefit outweighs the risk. frequently monitor phenytoin concentrations and consider dosage reduction of phenytoin. See Table 15 for additional monitoring considerations when phenytoin affects posaconazole via UDP-glucuronosyltransferase inhibition. RifabutinMechanism and Clinical Effect(s)Rifabutin is CYP3A4 substrate. Concomitant use of posaconazole with rifabutin increased rifabutin plasma concentrations [see Clinical Pharmacology (12.3)]. Prevention or ManagementAvoid 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. 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)].. 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)].. 7.3 Absence of Clinically Important Interaction with Posaconazole. 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 posaconazole 200 mg once daily.No clinically relevant effects on the pharmacokinetics of Noxafil delayed-release tablets were observed during concomitant use with antacids, H2-receptor antagonists and proton pump inhibitors, and metoclopramide [see Clinical Pharmacology (12.3)]. No dosage adjustment of Posaconazole delayed-release tablets is required during concomitant use with these drugs.No clinically relevant effects on the pharmacokinetics of Noxafil oral suspension were observed during concomitant use with antacids, H2-receptor antagonists (other than cimetidine), and loperamide [see Clinical Pharmacology (12.3)]. No dosage adjustment of Posaconazole oral suspension is required during concomitant use with these drugs (other than cimetidine).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. General Pharmacokinetic Characteristics. General Pharmacokinetic Characteristics of Posaconazole Delayed-Release TabletsNoxafil 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 Noxafil 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 16.Table 16: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Noxafil Delayed-Release Tablets (300 mg)300 mg twice daily on Day 1, then 300 mg once daily thereafter NAUC0-24 hr (nghr/mL)CavCav time-averaged concentrations (i.e., AUC0-24 hr/24 hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Tmax Median (minimum-maximum) (hr)t1/2 (hr)CL/F(L/hr)CV coefficient of variation expressed as 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; 1/2 terminal phase half-life; CL/F Apparent total body clearanceHealthy Volunteers1251618(25)2151(25)2764(21)1785(29)4(3-6)31(40)7.5(26)Patients5037900(42)1580(42)2090(38)1310(50)4 (1.3-8.3)-9.39(45). General Pharmacokinetic Characteristics of Posaconazole Oral SuspensionDose-proportional increases in plasma exposure (AUC) to Noxafil oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections.The mean (%CV) [min-max] Noxafil oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times day and 400 mg twice daily of the oral suspension are provided in Table 17.Table 17: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Noxafil Oral Suspension 200 mg Three Times Day and 400 mg Twice DailyDoseOral suspension administration Cavg (ng/mL)AUCAUC (0-24 hr) for 200 mg three times day and AUC (0-12 hr) for 400 mg twice daily (nghr/mL)CL/F (L/hr)V/F (L)t 1/2 (hr)Cavg the average posaconazole concentration when measured at steady state200 mg three times dayHSCT recipients with GVHD (n=252)1103 (67)[21.5-3650]NDNot done ND ND ND 200 mg three times dayNeutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215)583 (65)[89.7-2200]15,900 (62)[4100-56,100]51.2 (54)[10.7-146]2425 (39)[828-5702]37.2 (39)[19.1-148]400 mg twice dailyFebrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects. (n=23)723 (86)[6.70-2256]9093 (80)[1564-26,794]76.1 (78)[14.9-256]3088 (84)[407-13,140]31.7 (42)[12.4-67.3]. Absorption:. Absorption of Posaconazole Delayed-Release TabletsWhen given orally in healthy volunteers, Noxafil delayed-release tablets are absorbed with median Tmax of to hours. Steady-state plasma concentrations are attained by Day at the 300 mg dose (once daily after twice daily loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of Noxafil delayed-release tablets are increased 16% and 51%, respectively, when given with high fat meal compared to fasted state (see Table 18).Table 18: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Noxafil Delayed-Release Tablet to Healthy Subjects under Fasting and Fed ConditionsFasting ConditionsFed Conditions(High Fat Meal)48.5 fat Fed/FastingPharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)GMR=Geometric least-squares mean ratio; CI=Confidence intervalCmax (ng/mL)14935 (34)161060 (25)1.16 (0.96, 1.41)AUC0-72hr (hrng/mL)1426200 (28)1638400 (18)1.51 (1.33, 1.72)Tmax Median (Min, Max) reported for Tmax (hr)145.00 (3.00, 8.00)166.00 (5.00, 24.00)N/A. Absorption of Posaconazole Oral SuspensionNoxafil oral suspension is absorbed with median Tmax of ~3 to hours. Steady-state plasma concentrations are attained at to 10 days following multiple-dose administration.Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when the oral suspension is administered with nonfat meal and approximately 4-times higher when administered with high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of Noxafil oral suspension 400 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when administered with liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 19). In addition, the effects of varying gastric administration conditions on the Cmax and AUC of Noxafil oral suspension in healthy volunteers have been investigated and are shown in Table 20.To assure attainment of adequate plasma concentrations, it is recommended to administer Posaconazole oral suspension during or immediately following full meal. In patients who cannot eat full meal, Posaconazole oral suspension should be taken with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).Table 19: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Noxafil Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted ConditionsDose (mg)Cmax (ng/mL)Tmax Median [min-max]. (hr)AUC (I)(nghr/mL)CL/F(L/hr)t 1/2 (hr)200 mg fasted(n=20)n=15 for AUC (I), CL/F, and 1/2 132 (50)[45-267]3.50[1.5-36The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between hrs and 36 hrs).]4179 (31)[2705-7269]51 (25)[28-74]23.5 (25)[15.3-33.7]200 mg nonfat(n=20) 378 (43)[131-834]4 [3-5]10,753 (35)[4579-17,092]21 (39)[12-44]22.2 (18)[17.4-28.7]200 mg high fat(54 gm fat)(n=20) 512 (34)[241-1016]5 [4-5]15,059 (26)[10,341-24,476]14 (24)[8.2-19]23.0 (19)[17.2-33.4]400 mg fasted(n=23)n=10 for AUC (I), CL/F, and 1/2 121 (75)[27-366]4 [2-12]5258 (48)[2834-9567]91 (40) [42-141]27.3 (26)[16.8-38.9]400 mg with liquid nutritional supplement(14 gm fat)(n=23) 355 (43)[145-720]5 [4-8]11,295 (40)[3865-20,592]43 (56)[19-103]26.0 (19)[18.2-35.0]Table 20: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Noxafil Oral Suspension in Healthy VolunteersIn subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when Noxafil was administered via an NG tube compared to when Noxafil was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when posaconazole is administered via an NG tube because lower plasma exposure may be associated with an increased risk of treatment failure. Study DescriptionAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in AUC(ratio estimate; 90% CI of the ratio estimate)400-mg single dose with high-fat meal relative to fasted state (n=12)5 minutes before high-fat meal96%(1.96; 1.48-2.59)111%(2.11; 1.60-2.78)During high-fat meal339%(4.39; 3.32-5.80)382%(4.82; 3.66-6.35)20 minutes after high-fat meal333%(4.33; 3.28-5.73)387%(4.87; 3.70-6.42)400 mg twice daily and 200 mg four times daily for days in fasted state and with liquid nutritional supplement (BOOST(R)) (n=12)400 mg twice daily with BOOST65%(1.65; 1.29-2.11)66%(1.66; 1.30-2.13)200 mg four times daily with BOOSTNo EffectNo EffectDivided daily dose from 400 mg twice daily to 200 mg four times daily for days regardless of fasted conditions or with BOOST (n=12)Fasted state136%(2.36; 1.84-3.02)161%(2.61; 2.04-3.35)With BOOST137%(2.37; 1.86-3.04)157%(2.57; 2.00-3.30)400-mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)Ginger ale92%(1.92; 1.51-2.44)70%(1.70; 1.43-2.03)Esomeprazole32%(0.68; 0.53-0.86)30%(0.70; 0.59-0.83)400-mg single dose with prokinetic agent (metoclopramide 10 mg three times day for days) BOOST or an antikinetic agent (loperamide 4-mg single dose) BOOST (n=12)With metoclopramide BOOST21%(0.79; 0.72-0.87)19%(0.81; 0.72-0.91)With loperamide BOOST3%(0.97; 0.88-1.07)11%(1.11; 0.99-1.25)400-mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)Via NG tubeNG nasogastric 19%(0.81; 0.71-0.91)23%(0.77; 0.69-0.86). Distribution: Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.. Metabolism:Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 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 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 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 mean half-life (t 1/2 ranging between 26 to 31 hours. Posaconazole oral suspension is eliminated with mean half-life (t 1/2 of 35 hours (range: 20-66 hours).Specific PopulationsNo clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Patients with Renal Impairment:After Noxafil oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m2 or higher compared to those with eGFR >80 mL/minute/1.73 m2. Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m2 treated with Noxafil oral suspension to those with eGFR >80 mL/minute/1.73 m2 treated with Noxafil oral suspension, the range of the AUC estimates was highly variable (CV=96%) in patients with eGFR less than 20 mL/minute/1.73 m2 compared to those with eGFR >80 mL/minute/1.73 m2 (CV <40%).Similar posaconazole pharmacokinetic results are expected after administration of Posaconazole delayed-release tablets [see Use in Specific Populations (8.6)]. Patients with Hepatic Impairment:After single oral dose of Noxafil oral suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively [see Use in Specific Populations (8.7)]. Race/Ethnicity:In 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 clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)].Pediatric Patients:Treatment of invasive aspergillosis in pediatric patients years of age and older: total of 31 patients to less than 18 years of age (body weight of >=12 kg) received pediatric dosing based on body weight of Noxafil delayed-release tablets, Noxafil Injection, and Noxafil PowderMix for delayed-release oral suspension [see Dosage and Administration (2.3]. The mean population pharmacokinetic model parameters after multiple dose administration of Noxafil delayed-release tablets, Noxafil Injection, and Noxafil PowderMix for delayed-release oral suspension in pediatric patients to less than 18 years of age for the treatment of invasive aspergillosis (Pediatric Study 2) are shown in Table 21. [see Adverse Reactions (6.1)].Table 21: Summary of Steady-State Geometric Mean Pharmacokinetic ParametersParameter estimates reported only for N>2 (excludes single patient >=2 to <12 receiving tablet and patients >=12 to <18 years receiving PFS) (% Geometric CV) After Multiple Dosing with Noxafil Injection, Noxafil PowderMix for Delayed-Release Oral Suspension, and Noxafil Delayed-Release Tablets in Pediatric Patients being Treated for Invasive AspergillosisAge GroupDose TypeNSome patients had values (1 for IV dosing and for oral dosing) AUC0-24 hours (ng.hr/mL)Cav Cav time-averaged concentrations (i.e., AUC0-24 hours/24hr) (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Tmax Median (minimum-maximum) (hr)CL/FClearance (CL for IV and CL/F for PFS or Tablet) (L/hr)IV Noxafil injection; PFS Noxafil PowderMix for delayed-release oral suspension; Tablet= Noxafil delayed-release tablets; AUC0-24 hours 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; CL/F apparent total body clearance2 to <12 yearsIV961900(49.8)2580 (49.8)3630 (30.8)1710 (82.2)1.50 (1.25-1.77)2.56 (47.8)PFS645200(30.2)1880 (30.2)2220 (26.5)1370 (41.8)7.00 (6.40-7.20)3.25 (34.6)12 to <18 yearsIV1360800(35.6)2530 (35.6)3510 (26.8)1740 (48.5)1.50 (1.30-1.63)4.41 (41.8)Tablet1047800(52.7)1990 (52.7)2250 (48.3)1580 (62.6)7.15 (6.70-7.30)6.27 (52.7)The population pharmacokinetic analysis of posaconazole in pediatric patients, including Pediatric Study 2, suggests that age, sex, ethnicity, and disease status have no clinically meaningful effect on the pharmacokinetics of posaconazole.Drug Interaction Studies:Posaconazole is primarily metabolized via UDP glucuronidation (phase enzymes) and is substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. summary of drugs studied clinically with the oral suspension or another tablet formulation, which affect posaconazole concentrations, is provided in Table 22.Table 23 and Table 24 include summary of the drug effects of concomitant medications that may impact the absorption of posaconazole when administered as either the oral suspension or delayed-release tablets.A clinical study in healthy volunteers also indicates that posaconazole is strong CYP3A4 inhibitor as evidenced by >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 25 [see Contraindications (4) and Drug Interactions (7.2) including recommendations]. Effects of Other Drugs on Posaconazole:Table 22: Summary of the Effects of Coadministered Drugs on Noxafil in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil 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 days400 mg (oral suspension) twice daily 10 and 20 days45%(0.55; 0.47-0.66)50%(0.50; 0.43-0.60)Fosamprenavir (unknown mechanism)700 mg twice daily 10 days200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily 8 Days21%0.79 (0.71-0.89)23%0.77 (0.68-0.87)Rifabutin(UDP-G Induction)300 mg once daily 17 days200 mg (tablets) once daily 10 daysThe tablet refers to 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 10 days200 mg (tablets) once daily 10 days 41%(0.59; 0.44-0.79)50%(0.50; 0.36-0.71)Posaconazole Oral Suspension: Concomitant administration of Noxafil oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (see Table 23.) Table 23: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Oral Suspension in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil 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)Cimetidine(Alteration of gastric pH)400 mg twice daily 10 days200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 39% (0.61; 0.53-0.70)39% (0.61; 0.54-0.69)Esomeprazole (Increase in gastric pH)The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide. 40 mg every morning 3 days400 mg (oral suspension) single dose46%(0.54; 0.43-0.69)32%(0.68; 0.57-0.81)Metoclopramide (Increase in gastric motility) 10 mg three times day 2 days400 mg (oral suspension) single dose21%(0.79; 0.72-0.87)19%(0.81; 0.72-0.91)Posaconazole Delayed-Release Tablets: Concomitant administration of Noxafil delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 24). Table 24: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Noxafil Delayed-Release Tablets in Healthy VolunteersCoadministered DrugAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil to Noxafil 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(R) Ultimate strength liquid (Increase in gastric pH)25.4 mEq/5 mL, 20 mL6%(1.06; 0.90-1.26)4%(1.04; 0.90-1.20)Ranitidine (Zantac(R)) (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(R)) (Increase in gastric pH)40 mg (every morning for days, Day -4 to 1)2%(1.02; 0.88-1.17)5%(1.05; 0.89-1.24)Metoclopramide (Reglan(R)) (Increase in gastric motility)15 mg four times daily for days (Day -1 and 1)14%(0.86, 0.73,1.02)7%(0.93, 0.803,1.07)Effects of Posaconazole on Other Drugs:Table 25: Summary of the Effect of Noxafil on Coadministered Drugs in Healthy Volunteers and PatientsCoadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/ScheduleNoxafil Dose/ScheduleEffect on Bioavailability of Coadministered DrugsChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus Noxafil 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)Sirolimus2-mg single oral dose400 mg (oral suspension) twice daily 16 days572%(6.72; 5.62-8.03)788%(8.88; 7.26-10.9)CyclosporineStable maintenance dose in heart transplant recipients200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. Cyclosporine whole blood trough concentrationsCyclosporine dose reductions of up to 29% were requiredTacrolimus0.05-mg/kg single oral dose400 mg (oral suspension) twice daily 7 days121%(2.21; 2.01-2.42)358%(4.58; 4.03-5.19)Simvastatin40-mg single oral dose100 mg (oral suspension) once daily 13 days Simvastatin841%(9.41, 7.13-12.44) Simvastatin Acid817% (9.17, 7.36-11.43)Simvastatin931%(10.31, 8.40-12.67)Simvastatin Acid634%(7.34, 5.82-9.25)200 mg (oral suspension) once daily 13 daysSimvastatin1041%(11.41, 7.99-16.29)Simvastatin Acid851%(9.51, 8.15-11.10)Simvastatin960%(10.60, 8.63-13.02)Simvastatin Acid748%(8.48, 7.04-10.23)Midazolam0.4-mg single intravenous doseThe mean terminal half-life of midazolam was increased from hours to to 11 hours during coadministration with Noxafil. 200 mg (oral suspension) twice daily 7 days30%(1.3; 1.13-1.48)362%(4.62; 4.02-5.3)0.4-mg single intravenous dose 400 mg (oral suspension) twice daily 7 days62%(1.62; 1.41-1.86)524%(6.24; 5.43-7.16)2-mg single oral dose 200 mg (oral suspension) once daily 7 days169%(2.69; 2.46-2.93)470%(5.70; 4.82-6.74)2-mg single oral dose 400 mg (oral suspension) twice daily 7 days138%(2.38; 2.13-2.66)397%(4.97; 4.46-5.54)Rifabutin300 mg once daily 17 days200 mg (tablets) once daily 10 days 31%(1.31; 1.10-1.57)72%(1.72;1.51-1.95)Phenytoin200 mg once daily PO 10 days200 mg (tablets) once daily 10 days 16%(1.16; 0.85-1.57)16%(1.16; 0.84-1.59)Ritonavir100 mg once daily 14 days400 mg (oral suspension)twice daily 7 days49%(1.49; 1.04-2.15)80%(1.8;1.39-2.31)Atazanavir300 mg once daily 14 days400 mg (oral suspension) twice daily 7 days155%(2.55; 1.89-3.45)268%(3.68; 2.89-4.70)Atazanavir/ritonavir boosted regimen300 mg/100 mg once daily 14 days 400 mg (oral suspension) twice daily 7 days53% (1.53; 1.13-2.07)146%(2.46; 1.93-3.13).

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 1/2026Patient InformationPosaconazole delayed-release tabletsPosaconazole oral suspensionWhat is posaconazolePosaconazole (which refers to delayed-release tablets and oral suspension) is prescription medicine used in adults and children to help prevent or treat fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Posaconazole is used in people who have an increased chance of getting these infections due to weak immune system. These include people who have had hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with 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 years of age and older who weigh greater than 88 lbs (40 kg).treatment of fungal infections in adults and children years of age and older who weigh greater than 88 lbs (40 kg). Posaconazole oral suspension is used for: prevention of fungal infections in adults and children 13 years of age and older. Posaconazole oral suspension is also used to treat fungal infection called thrush caused by Candida in your mouth or throat area. Posaconazole oral suspension can be used as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked. Posaconazole oral suspension is for adults and children 13 years of age and older.It is not known if Posaconazole oral suspension is safe and effective in children under 13 years of age for the treatment of thrush as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked. It is not known if posaconazole is safe and effective in children under years of age.Do not take posaconazole if you:are allergic to posaconazole, any of the ingredients in posaconazole, or other azole antifungal medicines. See the end of this Patient Information leaflet for complete list of ingredients in posaconazole.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 new medicine without talking to your healthcare provider or pharmacist.Before you take posaconazole, 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 decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole.are taking midazolam, hypnotic and sedative medicine.are taking vincristine, vinblastine and other vinca alkaloids (medicines used to treat cancer).are taking venetoclax, 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 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 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 can affect the way other medicines work, and other medicines can affect the way posaconazole works, 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 or Posaconazole oral suspension.cimetidine or esomeprazole. If you are taking these medicines, you should not take Posaconazole oral suspension.Ask your healthcare provider or pharmacist for list of these medicines if you are not sure.Know the medicines you take. Keep list of them with you to show your healthcare provider or pharmacist when you get new medicine.How should take posaconazoleDo not switch between Posaconazole oral suspension and Posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension.Take posaconazole exactly as your healthcare provider tells you to take it.Your healthcare provider will tell you how much posaconazole to take and when to take it.Take posaconazole for as long as your healthcare provider tells you to take it.If you take too much posaconazole, call your healthcare provider or go to the nearest hospital emergency room right away.Posaconazole 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 different medicine.If you miss 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.Posaconazole oral suspension:Shake Posaconazole oral suspension well before use.Take each dose of Posaconazole oral suspension during or within 20 minutes after full meal. If you cannot eat full meal, take each dose of Posaconazole oral suspension with liquid nutritional supplement or an acidic carbonated beverage, like ginger ale.A measured dosing spoon comes with your Posaconazole oral suspension and is marked for doses of 2.5 mL and mL. See Figure A. Rinse the spoon with water after each dose of Posaconazole oral suspension and before you store it away.If you miss dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take double dose to make up for the missed dose or take more than your prescribed dose. Follow the instructions from your healthcare provider on how much posaconazole you should take and when to take it. What are the possible side effects of posaconazolePosaconazole may cause serious side effects, including:drug interactions with cyclosporine or tacrolimus. If you take posaconazole with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have 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. 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. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole. Call your healthcare provider right away if you have any of the following symptoms of liver problems: itchy skinnausea or vomitingyellowing of your eyes or skinfeeling very tiredflu-like symptomsincreased amounts of midazolam in your blood. If you take posaconazole with midazolam, posaconazole increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole.The most common side effects of posaconazole include:diarrheanauseafevervomitingheadachecoughinglow potassium levels in the bloodIf you take Posaconazole delayed-release tablets or Posaconazole oral suspension, 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. 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 store posaconazolePosaconazole delayed-release tabletsStore Posaconazole delayed-release tablets at room temperature between 68F to 77F (20C to 25C).Posaconazole oral suspensionStore Posaconazole oral suspension at room temperature between 68F to 77F (20C to 25C).Do not freeze Posaconazole oral suspension. Safely throw away medicine that is out of date or no longer needed. Keep posaconazole and all medicines out of the reach of children. General information about the safe and effective use of posaconazole.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use posaconazole for condition for which it was not prescribed. Do not give posaconazole to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about posaconazole that is written for health professionals.What are the ingredients in posaconazoleActive ingredient: posaconazole Inactive ingredients:Posaconazole delayed-release tablets: croscarmellose sodium, hydroxypropylcellulose, hypromellose acetate succinate, iron oxide yellow, Macrogol/PEG 3350, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol partially hydrolyzed, silicon dioxide, talc, and titanium dioxide. Posaconazole oral suspension: artificial cherry flavor, citric acid monohydrate, glycerin, liquid glucose, polysorbate 80, purified water, simethicone, sodium benzoate, sodium citrate dihydrate, titanium dioxide, and xanthan gum. Manufactured for: Endo USA, Malvern, PA 19355Delayed-Release Tablets: Manuf. by: N. V. Organon, Kloosterstraat 6, 5349 AB Oss, NetherlandsOral Suspension: Manuf. by: Patheon Inc., Whitby, Ontario, Canada L1N5Z5usppi-gmk5592-mf-2602r007PI1016-01-78-04. prevention of fungal infections in adults and children years of age and older who weigh greater than 88 lbs (40 kg).. treatment of fungal infections in adults and children years of age and older who weigh greater than 88 lbs (40 kg).. prevention of fungal infections in adults and children 13 years of age and older.. are allergic to posaconazole, any of the ingredients in posaconazole, or other azole antifungal medicines. See the end of this Patient Information leaflet for complete list of ingredients in posaconazole.. are taking any of the following medicines:sirolimuspimozidequinidinecertain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)ergot alkaloids (ergotamine, dihydroergotamine) 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.. 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 decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole.. are taking midazolam, hypnotic and sedative medicine.. are taking vincristine, vinblastine and other vinca alkaloids (medicines used to treat cancer).. are taking venetoclax, 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 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 or breastfeed. You should not do both.. rifabutin or phenytoin. If you are taking these medicines, you should not take Posaconazole delayed-release tablets or Posaconazole oral suspension.. cimetidine or esomeprazole. If you are taking these medicines, you should not take Posaconazole oral suspension.. Do not switch between Posaconazole oral suspension and Posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension.. Take posaconazole exactly as your healthcare provider tells you to take it.. Your healthcare provider will tell you how much posaconazole to take and when to take it.. Take posaconazole for as long as your healthcare provider tells you to take it.. If you take too much posaconazole, call your healthcare provider or go to the nearest hospital emergency room right away.. Posaconazole 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 different medicine.If you miss 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.. 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 different medicine.. If you miss 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.. Posaconazole oral suspension:Shake Posaconazole oral suspension well before use.Take each dose of Posaconazole oral suspension during or within 20 minutes after full meal. If you cannot eat full meal, take each dose of Posaconazole oral suspension with liquid nutritional supplement or an acidic carbonated beverage, like ginger ale.A measured dosing spoon comes with your Posaconazole oral suspension and is marked for doses of 2.5 mL and mL. See Figure A. Rinse the spoon with water after each dose of Posaconazole oral suspension and before you store it away.If you miss dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take double dose to make up for the missed dose or take more than your prescribed dose.. Shake Posaconazole oral suspension well before use.. Take each dose of Posaconazole oral suspension during or within 20 minutes after full meal. If you cannot eat full meal, take each dose of Posaconazole oral suspension with liquid nutritional supplement or an acidic carbonated beverage, like ginger ale.. measured dosing spoon comes with your Posaconazole oral suspension and is marked for doses of 2.5 mL and mL. See Figure A. Rinse the spoon with water after each dose of Posaconazole oral suspension and before you store it away.. If you miss dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take double dose to make up for the missed dose or take more than your prescribed dose.. drug interactions with cyclosporine or tacrolimus. If you take posaconazole with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.. problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have 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. 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. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole. Call your healthcare provider right away if you have any of the following symptoms of liver problems: 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 with midazolam, posaconazole increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole.. diarrhea. nausea. fever. vomiting. headache. coughing. low potassium levels in the blood. Store Posaconazole delayed-release tablets at room temperature between 68F to 77F (20C to 25C).. Store Posaconazole oral suspension at room temperature between 68F to 77F (20C to 25C).. Do not freeze Posaconazole oral suspension.. Figure1 USPPI.