DESCRIPTION SECTION.

11 DESCRIPTION. Posaconazole is an azole antifungal agent. Posaconazole is available as delayed-release tablet intended for oral administration. Posaconazole is designated chemically as 4-[4-[4-[4-[[(3 R, R)-5-(2, 4-difluoro phenyl) tetrahydro-5-(1 H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1 S,2 S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3 H-1,2,4-triazol-3-one with an empirical formula of 37H 42F 2N 8O and molecular weight of 700.79. The chemical structure is: Posaconazole is an off-white to white powder, slightly soluble in methanol and sparingly soluble in dimethyl sulfoxide. Posaconazole delayed-release tablet is light orange, oblong shape, film-coated tablet containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxy propyl cellulose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose and Opadry II Orange (consists of the following ingredients: polyvinyl alcohol-partially hydrolyzed, polyethylene glycol, talc, titanium dioxide, iron oxide yellow and iron oxide red). posaconazole-structure.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: Hypersensitivity [see Contraindications 4.1)] Arrhythmias and QT Prolongation [see Warnings and Precautions 5.2)] Hepatic Toxicity [see Warnings and Precautions 5.4)] o Common adverse reactions in studies with posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trial Experience in Adults Clinical Trial Experience with Posaconazole Delayed-Release Tablets for Prophylaxis The safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in non-comparative pharmacokinetic and safety trial of posaconazole delayed-release tablets when given as antifungal prophylaxis (Posaconazole Delayed-Release Tablet Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had mean age of 51 years (range 19 to 78 years, 17% of patients were >=65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy was given for median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day in each cohort). Table presents adverse reactions observed in patients treated with 300 mg daily dose at an incidence of >=10% in Posaconazole Delayed-Release Tablet Study. Table 9: Posaconazole Delayed-Release Tablet Study: Adverse Reactions in at Least 10% of Subjects Treated with 300 mg Daily Dose Body System Posaconazole delayed-release tablet (300 mg) n=210 (%)Subjects Reporting any Adverse Reaction 207 (99) Blood and Lymphatic System DisorderAnemia 22 (10) Thrombocytopenia 29 (14) Gastrointestinal DisordersAbdominal Pain 23 (11) Constipation 20 (10) Diarrhea 61 (29) Nausea 56 (27) Vomiting 28 (13) General Disorders and Administration Site ConditionsAsthenia 20 (10) Chills 22 (10) Mucosal Inflammation 29 (14) Edema Peripheral 33 (16) Pyrexia 59 (28) Metabolism and Nutrition DisordersHypokalemia 46 (22) Hypomagnesemia 20 (10) Nervous System DisordersHeadache 30 (14) Respiratory, Thoracic and Mediastinal DisordersCough 35 (17) Epistaxis 30 (14) Skin and Subcutaneous Tissue DisordersRash 34 (16) Vascular DisordersHypertension 23 (11) The most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea. The most common adverse reaction leading to discontinuation of posaconazole delayed-release tablets 300 mg once daily was nausea (2%). Additional Pediatric Use information is approved for Merck Sharp Dohme Corp.s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp Dohme Corp.s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 6.2 Postmarketing Experience. The following adverse reaction has been identified during the post-approval use of posaconazole. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency. Endocrine Disorders: Pseudoaldosteronism.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

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

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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

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: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), wide range of plasma exposures to posaconazole was noted following administration of Noxafil (R) oral suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy Table 17). lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections. Table 17: Noxafil (R) Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials Prophylaxis in AML/MDS Prophylaxis in GVHD Cavg Range (ng/mL) Treatment Failure (%) Cavg Range (ng/mL) Treatment Failure (%) Quartile 90 to 322 54.7 22 to 557 44.4 Quartile 322 to 490 37.0 557 to 915 20.6 Quartile 490 to 734 46.8 915 to 1563 17.5 Quartile 734 to 2200 27.8 1563 to 3650 17.5 Cavg the average posaconazole concentration when measured at steady state Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS HSCT recipients with GVHD Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections 12.3 Pharmacokinetics. General Pharmacokinetic Characteristics Posaconazole delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of posaconazole delayed-release tablets 300 mg twice daily on Day 1, then 300 mg once daily thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 20. Table 20: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg) NAUC - 24 hr (ng.hr/mL)Cav (ng/mL) max (ng/mL) min (ng/mL) max (hr) 1/2 (hr) CL/F (L/hr)Healthy Volunteers 12 51618 (25) 2151 (25) 2764 (21) 1785 (29) (3 to 6) 31 (40) 7.5 (26) Patients 50 37900 (42) 1580 (42) 2090 (38) 1310 (50) (1.3 to 8.3) 9.39 (45) CV coefficient of variation expressed as percentage (%CV); AUC 0-T Area under the plasma concentration-time curve from time zero to 24 hr; max maximum observed concentration; min minimum observed plasma concentration; max time of maximum observed concentration; 1/2 terminal phase half-life; CL/F Apparent total body clearance 300 mg twice daily on Day 1, then 300 mg once daily thereafter Cav time-averaged concentrations (i.e., AUC 0-24 hr/24hr) Median (minimum-maximum) Absorption: When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with median max 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 max and AUC of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with high fat meal compared to fasted state (see Table 22). Table 22: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Posaconazole Delayed-Release Tablet to Healthy Subjects under Fasting and Fed Conditions Fasting ConditionsFed Conditions(High Fat Meal) Fed/FastingPharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)C max (ng/mL) 14 935 (34) 16 1060 (25) 1.16 (0.96, 1.41) AUC 0-72hr (hrng/mL) 14 26200 (28) 16 38400 (18) 1.51 (1.33, 1.72) max (hr) 14 5.00 (3.00, 8.00) 16 6.00 (5.00, 24.00) N/A GMR=Geometric least-squares mean ratio; CI=Confidence interval 48.5 fat Median (Min, Max) reported for max Concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 23). Table 23: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy Volunteers Coadministered Drug Administration Arms Change in max (ratio estimate 90% CI of the ratio estimate) Change in AUC 0-last (ratio estimate 90% CI of the ratio estimate) Mylanta (R) Ultimate strength liquid(Increase in gastric pH) 25.4 meq/5 mL, 20 mL 6% (1.06; 0.90 to 1.26) 4% (1.04; 0.90 to 1.20) Ranitidine (Zantac (R)) (Alteration in gastric pH) 150 mg (morning dose of 150 mg Ranitidine twice daily) 4% (1.04; 0.88 to 1.23) 3% (0.97; 0.84 to 1.12) Esomeprazole (Nexium (R)) (Increase in gastric pH) 40 mg (every morning for days, Day -4 to 1) 2% (1.02; 0.88 to 1.17) 5% (1.05; 0.89 to 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) Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for max or AUC 0-last. Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 and ranged from 226 to 295 between studies and dose levels. Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin. Metabolism: Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. Posaconazole is primarily metabolized via UDP glucuronidation (phase 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 an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27. Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in Mean max (ratio estimate; 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate; 90% CI of the ratio estimate) Efavirenz (UDP-G Induction) 400 mg once daily 10 and 20 days 400 mg (oral suspension) twice daily 10 and 20 days 45% (0.55; 0.47 to 0.66) 50% (0.50; 0.43 to 0.60) Fosamprenavir (unknown mechanism) 700 mg twice daily 10 days 200 mg once daily on the st day, 200 mg twice daily on the nd day, then 400 mg twice daily 8 Days 21% 0.79 (0.71 to 0.89) 23% 0.77 (0.68 to 0.87) Rifabutin (UDP-G Induction) 300 mg once daily 17 days 200 mg (tablets) once daily 10 days 43% (0.57; 0.43 to 0.75) 49% (0.51; 0.37 to 0.71) Phenytoin (UDP-G Induction) 200 mg once daily 10 days 200 mg (tablets) once daily 10 days 41% (0.59; 0.44 to 0.79) 50% (0.50; 0.36 to 0.71) Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for max or AUC. The tablet refers to non-commercial tablet formulation without polymer. In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. 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 28 [see Contraindications 4) and Drug Interactions 7.1) including recommendations]. Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and Patients Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Posaconazole Dose/ Schedule Effect on Bioavailability of Coadministered DrugsChange in Mean max (ratio estimate 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate 90% CI of the ratio estimate) Sirolimus mg single oral dose 400 mg (oral suspension) twice daily 16 days 572% (6.72; 5.62 to 8.03) 788% (8.88; 7.26 to 10.9) Cyclosporine Stable maintenance dose in heart transplant recipients 200 mg (tablets) once daily 10 days cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required Tacrolimus 0.05 mg/kg single oral dose 400 mg (oral suspension) twice daily 7 days 121% (2.21; 2.01 to 2.42) 358% (4.58; 4.03 to 5.19) Simvastatin 40 mg single oral dose 100 mg (oral suspension) once daily 13 days 200 mg (oral suspension) once daily 13 days Simvastatin 841% (9.41, 7.13 to 12.44) Simvastatin Acid 817% (9.17, 7.36 to 11.43) Simvastatin 1041% (11.41, 7.99 to 16.29) Simvastatin Acid 851% (9.51, 8.15 to 11.10) Simvastatin 931% (10.31, 8.40 to 12.67) Simvastatin Acid 634% (7.34, 5.82 to 9.25) Simvastatin 960% (10.60, 8.63 to 13.02) Simvastatin Acid 748% (8.48, 7.04 to 10.23) Midazolam 0.4 mg single intravenous dose 0.4 mg single intravenous dose mg single oral dose mg single oral dose 200 mg (oral suspension) twice daily 7 days 400 mg (oral suspension) twice daily 7 days 200 mg (oral suspension) once daily 7 days 400 mg (oral suspension) twice daily 7 days 30% (1.3; 1.13 to 1.48) 62% (1.62; 1.41 to 1.86) 169% (2.69; 2.46 to 2.93) 138% (2.38; 2.13 to 2.66) 362% (4.62; 4.02 to 5.3) 524% (6.24; 5.43 to 7.16) 470% (5.70; 4.82 to 6.74) 397% (4.97; 4.46 to 5.54) Rifabutin 300 mg once daily 17 days 200 mg (tablets) once daily 10 days 31% (1.31; 1.10 to 1.57) 72% (1.72;1.51 to 1.95) Phenytoin 200 mg once daily PO 10 days 200 mg (tablets) once daily 10 days 16% (1.16; 0.85 to 1.57) 16% (1.16; 0.84 to 1.59) Ritonavir 100 mg once daily 14 days 400 mg (oral suspension) twice daily 7 days 49% (1.49; 1.04 to 2.15) 80% (1.8;1.39 to 2.31) Atazanavir Atazanavir/ ritonavir boosted regimen 300 mg once daily 14 days 300 mg/100 mg once daily 14 days 400 mg (oral suspension) twice daily 7 days 400 mg (oral suspension) twice daily 7 days 155% (2.55; 1.89 to 3.45) 53% (1.53; 1.13 to 2.07) 268% (3.68; 2.89 to 4.70) 146% (2.46; 1.93 to 3.13) Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for max or AUC. The tablet refers to non-commercial tablet formulation without polymer. The mean terminal half-life of midazolam was increased from hours to to 11 hours during coadministration with posaconazole. Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg once daily. Excretion Following administration of Noxafil (R) 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. Specific Populations No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis). 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. 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 total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times day) of Noxafil oral suspension for prophylaxis of invasive fungal infections. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (>=18 years of age). In study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with Noxafil oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2,500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients. Additional Pediatric Use information is approved for Merck Sharp Dohme Corp.s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp Dohme Corp.s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 12.4 Microbiology. Mechanism of Action: Posaconazole 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. Resistance: Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known. Antimicrobial Activity: Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage 1)]. Microorganisms: Aspergillus spp. and Candida spp. Susceptibility Testing: For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.2 Prophylaxis of Aspergillus and Candida Infections with Noxafil(R) Oral Suspension. Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems. The first study (Noxafil (R) Oral Suspension Study 1) was randomized, double-blind trial that compared Noxafil (R) 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 (R) oral suspension; 77 days, fluconazole). Table 32 contains the results from Noxafil (R) Oral Suspension Study 1. Table 32: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Noxafil(R) Oral Suspension Study Posaconazolen=301Fluconazolen=299On therapy plus daysClinical Failure 50 (17%) 55 (18%) Failure due to: Proven/Probable IFI (2%) 22 (7%) (Aspergillus)3 (1%) 17 (6%) (Candida)1 (<1%) (1%) (Other) (1%) (1%) All Deaths Proven/probable fungal infection prior to death 22 (7%) (<1%) 24 (8%) (2%) SAF 27 (9%) 25 (8%) Through 16 weeksClinical Failure 99 (33%) 110 (37%) Failure due to: Proven/Probable IFI 16 (5%) 27 (9%) (Aspergillus)7 (2%) 21 (7%) (Candida)4 (1%) (1%) (Other) (2%) (1%) All Deaths Proven/probable fungal infection prior to death 58 (19%) 10 (3%) 59 (20%) 16 (5%) SAF 26 (9%) 30 (10%) Event free lost to follow-up 24 (8%) 30 (10%) Patients may have met more than one criterion defining failure. Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days). 95% confidence interval (posaconazole-fluconazole) (-11.5%, +3.7%). Patients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. These patients were considered failures. The second study (Noxafil (R) Oral Suspension Study 2) was randomized, open-label study that compared Noxafil (R) 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 (R) 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 33 contains the results from Noxafil (R) Oral Suspension Study 2. Table 33: Results from Open-Label Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Noxafil(R) Oral Suspension Study Posaconazolen=304Fluconazole/Itraconazolen=298On therapy plus daysClinical Failure ,+ 82 (27%) 126 (42%) Failure due to:Proven/Probable IFI (2%) 25 (8%) (Aspergillus)2 (1%) 20 (7%) (Candida)3 (1%) (1%) (Other) (1%) (1%) All Deaths Proven/probable fungal infection prior to death 17 (6%) (<1%) 25 (8%) (1%) SAF 67 (22%) 98 (33%) Through 100 days postrandomizationClinical Failure 158 (52%) 191 (64%) Failure due to:Proven/Probable IFI 14 (5%) 33 (11%) (Aspergillus)2 (1%) 26 (9%) (Candida)10 (3%) (1%) (Other) (1%) (1%) All Deaths Proven/probable fungal infection prior to death 44 (14%) (1%) 64 (21%) 16 (5%) SAF 98 (32%) 125 (42%) Event free lost to follow-up 34 (11%) 24 (8%) 95% confidence interval (posaconazole-fluconazole/itraconazole) (-22.9%, -7.8%). +Patients may have met more than one criterion defining failure. Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days). Patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures. In summary, clinical studies of prophylaxis were conducted with the Noxafil (R) oral suspension. As seen in the accompanying tables Tables 32 and 33), clinical failure represented composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Noxafil (R) Oral Suspension Study ( Table 32), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole-comparator -11.5% to 3.7%) while in Noxafil (R) Oral Suspension Study ( Table 33) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole-comparator -22.9% to -7.8%). All-cause mortality was similar at 16 weeks for both treatment arms in Noxafil (R) Oral Suspension Study [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in Noxafil (R) 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 posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Known hypersensitivity to posaconazole or other azole antifungal agents. 4.1) Coadministration of posaconazole with the following drugs is contraindicated; Posaconazole increases concentrations and toxicities of: Sirolimus 4.2, 5.1, 7.1) CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) 4.3, 5.2, 7.2) HMG-CoA Reductase Inhibitors Primarily Metabolized through CYP3A4 4.4, 7.3) Ergot alkaloids 4.5, 7.4) Venetoclax: in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp up phase 4.6, 5.10, 7.16) 4.1 Hypersensitivity. Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.. 4.2 Use with Sirolimus. Posaconazole is contraindicated with sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug Interactions 7.1) and Clinical Pharmacology 12.3)]. 4.3 QT Prolongation with Concomitant Use with CYP3A4 Substrates. Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see Warnings and Precautions 5.2) and Drug Interactions 7.2)]. 4.4 HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4. Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions 7.3) and Clinical Pharmacology 12.3)]. 4.5 Use with Ergot Alkaloids. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions 7.4)]. 4.6 Use with Venetoclax. Coadministration of posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Warnings and Precautions 5.10) and Drug Interactions 7.16)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Noxafil (R) oral suspension is not substitutable with posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to differences in the dosing of each formulation. Administer posaconazole delayed-release tablets with or without food. 2.1) Table 1: Recommended Dosage in Adult Patients and Pediatric Patients aged 13 years and older Indication Dose, and Duration of Therapy Prophylaxis of invasive Aspergillus and Candida infections Posaconazole Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tablets) twice day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression. 2.2, 2.3) 2.1 Important Administration Instructions. Non-substitutable Noxafil oral suspension is not substitutable with posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Posaconazole delayed-release tablets Swallow tablets whole. Do not divide, crush, or chew. Administer with or without food [see Dosage and Administration 2.5) and Clinical Pharmacology 12.3)] o For patients who cannot eat full meal, posaconazole delayed-release tablets should be used instead of Noxafil (R) oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Noxafil (R) oral suspension under both fed and fasted conditions. 2.2 Dosing Regimen in Adult Patients. Table 1: Dosing Regimens in Adult PatientsIndicationDose and Frequency Duration of TherapyProphylaxis of invasive Aspergillus and Candida infections 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 day Maintenance dose:Duration of therapy is based on recovery from neutropenia or immunosuppression. 2.3 Dosing Regimen in Pediatric Patients (ages 13 to less than 18 years of age). The recommended dosing regimen of posaconazole for pediatric patients 13 to less than 18 years of age is shown in Table [see Dosage and Administration 2.5) and Clinical Pharmacology 12.3)]. Table 2: Posaconazole Delayed-Release Tablet Dosing Regimens for Pediatric Patients (ages 13 to less than 18 years of age) Recommended PediatricDosage and Formulation IndicationDelayed-Release TabletDuration of therapyProphylaxis of invasive Aspergillus and Candida infections Loading dose: 300 mg twice daily on the first day Maintenance dose: 300 mg once daily Duration of therapy is based on recovery from neutropenia or immunosuppression. Additional Pediatric Use information is approved for Merck Sharp Dohme Corp.s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp Dohme Corp.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.. 2.5 Administration Instructions for Posaconazole Delayed-Release Tablets. Swallow tablets whole. Do not divide, crush, or chew. Administer posaconazole delayed-release tablets with or without food [see Clinical Pharmacology 12.3)]. 2.7 Non-substitutability between Noxafil(R) Oral Suspension and Other Formulations. Noxafil oral suspension is not substitutable with posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation.. 2.9 Dosage Adjustments in Patients with Renal Impairment. The pharmacokinetics of posaconazole delayed-release tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Posaconazole delayed-release tablets 100 mg are available as light orange, oblong shape, film-coated tablets debossed with on one side and P11 on the other side containing 100 mg of posaconazole.. Posaconazole delayed-release tablet: 100 mg 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 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. Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. Posaconazole is also strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole [see Clinical Pharmacology 12.3)]. The following information was derived from data with Noxafil oral suspension or early tablet formulation unless otherwise noted. All drug interactions with Noxafil (R) oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to posaconazole delayed-release tablet as well [see Drug Interactions 7.9) and 7.13)]. Interaction DrugInteractionRifabutin, phenytoin, efavirenz, cimetidine Avoid coadministration unless the benefit outweighs the risks 7.6, 7.7, 7.8, 7.9) Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity 7.1, 7.10, 7.11) Digoxin Monitor digoxin plasma concentrations 7.12) Fosamprenavir Monitor for breakthrough fungal infections 7.6, 7.13) 7.1 Immunosuppressants Metabolized by CYP3A4. Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications 4.2) and Clinical Pharmacology 12.3)]. Tacrolimus: Posaconazole has been shown to significantly increase the max and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions 5.1) and Clinical Pharmacology 12.3)]. Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions 5.1) and Clinical Pharmacology 12.3)]. 7.2 CYP3A4 Substrates. Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications 4.3) and Warnings and Precautions 5.2)]. 7.3 HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4. Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 [see Contraindications 4.4) and Clinical Pharmacology 12.3)]. 7.4 Ergot Alkaloids. Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids [see Contraindications 4.5)]. 7.5 Benzodiazepines Metabolized by CYP3A4. Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects [see Warnings and Precautions 5.6) and Clinical Pharmacology 12.3)]. 7.6 Anti-HIV Drugs. Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [see Clinical Pharmacology 12.3)]. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks. Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see Clinical Pharmacology 12.3)]. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole. Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see Clinical Pharmacology 12.3)]. 7.7 Rifabutin. Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations [see Clinical Pharmacology 12.3)]. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended. 7.8 Phenytoin. Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see Clinical Pharmacology 12.3)]. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered. 7.9 Gastric Acid Suppressors/Neutralizers. No clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, 2-receptor antagonists and proton pump inhibitors [see Clinical Pharmacology 12.3)]. No dosage adjustment of posaconazole delayed-release tablets is required when concomitantly used with antacids, 2-receptor antagonists and proton pump inhibitors. 7.10 Vinca Alkaloids. Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions [see Warnings and Precautions 5.7)]. Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole, for patients receiving vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. 7.11 Calcium Channel Blockers Metabolized by CYP3A4. Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.. 7.12 Digoxin. Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.. 7.13 Gastrointestinal Motility Agents. Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole [see Clinical Pharmacology 12.3)]. No dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide. 7.14 Glipizide. Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.. 7.16 Venetoclax. Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax max and AUC 0-INF, which may increase venetoclax toxicities [see Contraindications 4.6), Warnings and Precautions 5.10)]. Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

GERIATRIC USE SECTION.

8.5 Geriatric Use. No overall differences in the safety of posaconazole delayed-release tablets were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of posaconazole in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology 12.3)]. Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age. No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Posaconazole delayed-release tablets are available as light orange, oblong shape, film-coated tablets debossed with on one side and P11 on the other side containing 100 mg of posaconazole. Bottles with child-resistant closures of 60 delayed-release tablets (NDC 16714-535-01).. 16.2 Storage and Handling. Store at 20 to 25C (68 to 77F), excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Posaconazole is an azole antifungal indicated as follows: Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy as follows: 1.2) Posaconazole delayed-release tablets: adults and pediatric patients 13 years of age and older 1.2 Prophylaxis of Invasive Aspergillus and Candida Infections. Posaconazole delayed-release tablets are indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies 14.2)] as follows: Posaconazole delayed-release tablets: adults and pediatric patients 13 years of age and older Additional Pediatric Use information is approved for Merck Sharp Dohme Corp.s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp Dohme Corp.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information). Important Administration Instructions Posaconazole Delayed-Release Tablets Advise patients that posaconazole delayed-release tablets must be swallowed whole and not divided, crushed, or chewed. Instruct patients that if they miss dose, they should take it as soon as they remember. If they do not remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose. Drug Interactions Advise patients to inform their physician immediately if they: develop severe diarrhea or vomiting. are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4. are currently taking cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath. are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole. Serious and Potentially Serious Adverse Reactions Advise patients to inform their physician immediately if they: notice change in heart rate or heart rhythm or have heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions. are pregnant, plan to become pregnant, or are nursing. have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu. have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole. Manufactured for: Northstar Rx LLC Memphis, TN 38141. Manufactured by: Hetero Labs Limited Jeedimetla, Hyderabad 500 055, India The trademarks referenced herein are owned by their respective companies.Revised: 10/2022.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Posaconazole is an azole antifungal agent [see Clinical Pharmacology 12.4)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis No drug-related neoplasms were recorded in rats or mice treated with posaconazole for years at doses higher than the clinical dose. In 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times the exposure achieved with 400 mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered high-fat meal (400 mg twice daily oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with 400 mg twice daily oral suspension regimen. Mutagenesis Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), chromosome aberration study in human peripheral blood lymphocytes, Chinese hamster ovary cell mutagenicity study, and mouse bone marrow micronucleus study. Impairment of Fertility Posaconazole had no effect on fertility of male rats at dose up to 180 mg/kg (1.7 the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at dose up to 45 mg/kg (2.2 the 400 mg twice daily oral suspension regimen). 13.2 Animal Toxicology and/or Pharmacology. In nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from to weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in separate study of 10-week old dogs dosed with intravenous posaconazole for 13 weeks with 9-week recovery period or follow-up study of 31-week old dogs dosed for months.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no experience with overdosage of posaconazole delayed-release tablets. During the clinical trials, some patients received Noxafil (R)oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg twice daily Noxafil (R) oral suspension for days. No related adverse reactions were noted by the investigator. Posaconazole is not removed by hemodialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Posaconazole Delayed-Release Tablets 100 mg container label posaconazole-container-label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of posaconazole delayed-release tablets for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 13 years and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 13 years of age and older [see Adverse Reactions 6.1), Clinical Pharmacology 12.3) and Clinical Studies 14)]. The safety and effectiveness of posaconazole have not been established in pediatric patients younger than years of age. Additional Pediatric Use information is approved for Merck Sharp Dohme Corp.s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp Dohme Corp.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure Response Relationship Prophylaxis: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), wide range of plasma exposures to posaconazole was noted following administration of Noxafil (R) oral suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy Table 17). lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections. Table 17: Noxafil (R) Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials Prophylaxis in AML/MDS Prophylaxis in GVHD Cavg Range (ng/mL) Treatment Failure (%) Cavg Range (ng/mL) Treatment Failure (%) Quartile 90 to 322 54.7 22 to 557 44.4 Quartile 322 to 490 37.0 557 to 915 20.6 Quartile 490 to 734 46.8 915 to 1563 17.5 Quartile 734 to 2200 27.8 1563 to 3650 17.5 Cavg the average posaconazole concentration when measured at steady state Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS HSCT recipients with GVHD Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. General Pharmacokinetic Characteristics Posaconazole delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of posaconazole delayed-release tablets 300 mg twice daily on Day 1, then 300 mg once daily thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 20. Table 20: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg) NAUC - 24 hr (ng.hr/mL)Cav (ng/mL) max (ng/mL) min (ng/mL) max (hr) 1/2 (hr) CL/F (L/hr)Healthy Volunteers 12 51618 (25) 2151 (25) 2764 (21) 1785 (29) (3 to 6) 31 (40) 7.5 (26) Patients 50 37900 (42) 1580 (42) 2090 (38) 1310 (50) (1.3 to 8.3) 9.39 (45) CV coefficient of variation expressed as percentage (%CV); AUC 0-T Area under the plasma concentration-time curve from time zero to 24 hr; max maximum observed concentration; min minimum observed plasma concentration; max time of maximum observed concentration; 1/2 terminal phase half-life; CL/F Apparent total body clearance 300 mg twice daily on Day 1, then 300 mg once daily thereafter Cav time-averaged concentrations (i.e., AUC 0-24 hr/24hr) Median (minimum-maximum) Absorption: When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with median max 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 max and AUC of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with high fat meal compared to fasted state (see Table 22). Table 22: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Posaconazole Delayed-Release Tablet to Healthy Subjects under Fasting and Fed Conditions Fasting ConditionsFed Conditions(High Fat Meal) Fed/FastingPharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)C max (ng/mL) 14 935 (34) 16 1060 (25) 1.16 (0.96, 1.41) AUC 0-72hr (hrng/mL) 14 26200 (28) 16 38400 (18) 1.51 (1.33, 1.72) max (hr) 14 5.00 (3.00, 8.00) 16 6.00 (5.00, 24.00) N/A GMR=Geometric least-squares mean ratio; CI=Confidence interval 48.5 fat Median (Min, Max) reported for max Concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 23). Table 23: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy Volunteers Coadministered Drug Administration Arms Change in max (ratio estimate 90% CI of the ratio estimate) Change in AUC 0-last (ratio estimate 90% CI of the ratio estimate) Mylanta (R) Ultimate strength liquid(Increase in gastric pH) 25.4 meq/5 mL, 20 mL 6% (1.06; 0.90 to 1.26) 4% (1.04; 0.90 to 1.20) Ranitidine (Zantac (R)) (Alteration in gastric pH) 150 mg (morning dose of 150 mg Ranitidine twice daily) 4% (1.04; 0.88 to 1.23) 3% (0.97; 0.84 to 1.12) Esomeprazole (Nexium (R)) (Increase in gastric pH) 40 mg (every morning for days, Day -4 to 1) 2% (1.02; 0.88 to 1.17) 5% (1.05; 0.89 to 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) Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for max or AUC 0-last. Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 and ranged from 226 to 295 between studies and dose levels. Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin. Metabolism: Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. Posaconazole is primarily metabolized via UDP glucuronidation (phase 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 an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27. Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in Mean max (ratio estimate; 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate; 90% CI of the ratio estimate) Efavirenz (UDP-G Induction) 400 mg once daily 10 and 20 days 400 mg (oral suspension) twice daily 10 and 20 days 45% (0.55; 0.47 to 0.66) 50% (0.50; 0.43 to 0.60) Fosamprenavir (unknown mechanism) 700 mg twice daily 10 days 200 mg once daily on the st day, 200 mg twice daily on the nd day, then 400 mg twice daily 8 Days 21% 0.79 (0.71 to 0.89) 23% 0.77 (0.68 to 0.87) Rifabutin (UDP-G Induction) 300 mg once daily 17 days 200 mg (tablets) once daily 10 days 43% (0.57; 0.43 to 0.75) 49% (0.51; 0.37 to 0.71) Phenytoin (UDP-G Induction) 200 mg once daily 10 days 200 mg (tablets) once daily 10 days 41% (0.59; 0.44 to 0.79) 50% (0.50; 0.36 to 0.71) Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for max or AUC. The tablet refers to non-commercial tablet formulation without polymer. In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. 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 28 [see Contraindications 4) and Drug Interactions 7.1) including recommendations]. Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and Patients Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Posaconazole Dose/ Schedule Effect on Bioavailability of Coadministered DrugsChange in Mean max (ratio estimate 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate 90% CI of the ratio estimate) Sirolimus mg single oral dose 400 mg (oral suspension) twice daily 16 days 572% (6.72; 5.62 to 8.03) 788% (8.88; 7.26 to 10.9) Cyclosporine Stable maintenance dose in heart transplant recipients 200 mg (tablets) once daily 10 days cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required Tacrolimus 0.05 mg/kg single oral dose 400 mg (oral suspension) twice daily 7 days 121% (2.21; 2.01 to 2.42) 358% (4.58; 4.03 to 5.19) Simvastatin 40 mg single oral dose 100 mg (oral suspension) once daily 13 days 200 mg (oral suspension) once daily 13 days Simvastatin 841% (9.41, 7.13 to 12.44) Simvastatin Acid 817% (9.17, 7.36 to 11.43) Simvastatin 1041% (11.41, 7.99 to 16.29) Simvastatin Acid 851% (9.51, 8.15 to 11.10) Simvastatin 931% (10.31, 8.40 to 12.67) Simvastatin Acid 634% (7.34, 5.82 to 9.25) Simvastatin 960% (10.60, 8.63 to 13.02) Simvastatin Acid 748% (8.48, 7.04 to 10.23) Midazolam 0.4 mg single intravenous dose 0.4 mg single intravenous dose mg single oral dose mg single oral dose 200 mg (oral suspension) twice daily 7 days 400 mg (oral suspension) twice daily 7 days 200 mg (oral suspension) once daily 7 days 400 mg (oral suspension) twice daily 7 days 30% (1.3; 1.13 to 1.48) 62% (1.62; 1.41 to 1.86) 169% (2.69; 2.46 to 2.93) 138% (2.38; 2.13 to 2.66) 362% (4.62; 4.02 to 5.3) 524% (6.24; 5.43 to 7.16) 470% (5.70; 4.82 to 6.74) 397% (4.97; 4.46 to 5.54) Rifabutin 300 mg once daily 17 days 200 mg (tablets) once daily 10 days 31% (1.31; 1.10 to 1.57) 72% (1.72;1.51 to 1.95) Phenytoin 200 mg once daily PO 10 days 200 mg (tablets) once daily 10 days 16% (1.16; 0.85 to 1.57) 16% (1.16; 0.84 to 1.59) Ritonavir 100 mg once daily 14 days 400 mg (oral suspension) twice daily 7 days 49% (1.49; 1.04 to 2.15) 80% (1.8;1.39 to 2.31) Atazanavir Atazanavir/ ritonavir boosted regimen 300 mg once daily 14 days 300 mg/100 mg once daily 14 days 400 mg (oral suspension) twice daily 7 days 400 mg (oral suspension) twice daily 7 days 155% (2.55; 1.89 to 3.45) 53% (1.53; 1.13 to 2.07) 268% (3.68; 2.89 to 4.70) 146% (2.46; 1.93 to 3.13) Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for max or AUC. The tablet refers to non-commercial tablet formulation without polymer. The mean terminal half-life of midazolam was increased from hours to to 11 hours during coadministration with posaconazole. Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg once daily. Excretion Following administration of Noxafil (R) 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. Specific Populations No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis). 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. 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 total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times day) of Noxafil oral suspension for prophylaxis of invasive fungal infections. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (>=18 years of age). In study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with Noxafil oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2,500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients. Additional Pediatric Use information is approved for Merck Sharp Dohme Corp.s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp Dohme Corp.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

PREGNANCY SECTION.

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

RECENT MAJOR CHANGES SECTION.

Contraindications 4) 1/2022 Warnings and Precautions 5) 1/2022.

SPL UNCLASSIFIED SECTION.

1.2 Prophylaxis of Invasive Aspergillus and Candida Infections. Posaconazole delayed-release tablets are indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies 14.2)] as follows: Posaconazole delayed-release tablets: adults and pediatric patients 13 years of age and older Additional Pediatric Use information is approved for Merck Sharp Dohme Corp.s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp Dohme Corp.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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) 8.1 Pregnancy. Risk Summary Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses >=1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of >= times the clinical exposure caused an increase in resorptions in these rabbits (see Data). Based on animal data, advise pregnant women of the potential risk to 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 Summary There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When 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 safety and effectiveness of posaconazole delayed-release tablets for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 13 years and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 13 years of age and older [see Adverse Reactions 6.1), Clinical Pharmacology 12.3) and Clinical Studies 14)]. The safety and effectiveness of posaconazole have not been established in pediatric patients younger than years of age. Additional Pediatric Use information is approved for Merck Sharp Dohme Corp.s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp Dohme Corp.s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 8.5 Geriatric Use. No overall differences in the safety of posaconazole delayed-release tablets were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of posaconazole in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology 12.3)]. Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age. No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment. Following single-dose administration of 400 mg of the Noxafil (R) oral suspension, there was no significant effect of mild (eGFR: 50 to 80 mL/min/1.73 2, n=6) or moderate (eGFR: 20 to 49 mL/min/1.73 2, n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration 2)] Similar recommendations apply to posaconazole delayed-release tablets; however, specific study has not been conducted with the posaconazole delayed-release tablets. 8.7 Hepatic Impairment. After single oral dose of Noxafil (R) 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 max was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t 1/2 was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively. It is recommended that no dose adjustment of posaconazole delayed-release tablets is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration 2) and Warnings and Precautions 5.4)]. However, specific study has not been conducted with posaconazole delayed-release tablets. 8.8 Gender. The pharmacokinetics of posaconazole are comparable in males and females. No adjustment in the dosage of posaconazole is necessary based on gender.. 8.9 Race. The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of posaconazole is necessary based on race.. 8.10 Weight. Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections.

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) Electrolyte Disturbances: Monitor and correct, especially those involving potassium (K +), magnesium (Mg ++), and calcium (Ca ++), before and during posaconazole therapy. 5.3) 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. 5.4) Concomitant Use with Midazolam: Posaconazole can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. 5.6, 7.5) 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. 5.7, 7.10) Breakthrough Fungal Infections: Monitor patients with severe diarrhea or vomiting when receiving posaconazole delayed-release tablets. 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, 7.16) 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 7.1) and Clinical Pharmacology 12.3)]. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly. 5.2 Arrhythmias and QT Prolongation. Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole. Results from 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 to 85 years of age) administered Noxafil (R) 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 posaconazole 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 Hepatic Toxicity. Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the Noxafil (R) 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. 5.5 Renal Impairment. Due to the variability in exposure with posaconazole delayed-release tablets, Noxafil oral suspension, and Noxafil PowderMix for delayed-release oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration 2.9) and Use in Specific Populations 8.6)]. 5.6 Midazolam Toxicity. Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions 7.5) and Clinical Pharmacology 12.3)]. 5.7 Vincristine Toxicity. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions 7.10)]. 5.9 Breakthrough Fungal Infections. Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole delayed-release tablets.. 5.10 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 7.16)]. Refer to the venetoclax prescribing information for dosing instructions.