ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. Common treatment-emergent adverse reactions in studies with posaconazole are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-844-834-0530 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Common treatment-emergent adverse reactions in studies with posaconazole are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. (6.1). 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)] Hypersensitivity [see Contraindications (4.1)] Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)] Hepatic Toxicity [see Warnings and Precautions (5.4)] 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. In clinical trials, the type of adverse reactions reported for posaconazole injection and posaconazole delayed-release tablets were generally similar to that reported in trials of posaconazole oral suspension.. 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 (Delayed-Release Tablet Study 1). 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 treatment-emergent adverse reactions observed in patients treated with 300 mg daily dose at an incidence of >=10% in posaconazole delayed-release tablet study.Table 7: Posaconazole Delayed-Release Tablet Study 1: Number (%) of Subjects Treated with 300 mg Daily Dose Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10%Body SystemPreferred TermPosaconazole delayed-release tablet (300 mg)(n=210)Subjects Reporting any Adverse Reaction201(99)Blood and Lymphatic System DisorderAnemia22(10)Thrombocytopenia29(14)Gastrointestinal DisordersAbdominal Pain23(11)Constipation20(10)Diarrhea61(29)Nausea56(27)Vomiting28(13)General Disorders and Administration Site ConditionsAsthenia20(10)Chills22(10)Mucosal Inflammation29(14)Edema Peripheral33(16)Pyrexia59(28)Metabolism and Nutrition DisordersHypokalemia46(22)Hypomagnesemia20(10)Nervous System DisordersHeadache30(14)Respiratory, Thoracic and Mediastinal DisordersCough35(17)Epistaxis30(14)Skin and Subcutaneous Tissue DisordersRash34(16)Vascular DisordersHypertension23(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%).. 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).The clinical significance of this finding is unknown; therefore, the use of posaconazole injection to patients under 18 years of age is not recommended.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 BID oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered high-fat meal (400-mg BID 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 BID oral suspension regimen.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.Posaconazole had no effect on fertility of male rats at dose up to 180 mg/kg (1.7 the 400-mg BID 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 BID oral suspension regimen).

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].. 12.2 Pharmacodynamics. Exposure Response Relationship: 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 posaconazole oral suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 12). 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 12: Posaconazole Oral Suspension Exposure Analysis (Cavg) in Prophylaxis TrialsProphylaxis in AML/MDSProphylaxis in GVHDCavg Range (ng/mL)Treatment Failure (%)Cavg Range (ng/mL)Treatment Failure (%)Quartile 190 to 32254.722 to 55744.4Quartile 2322 to 49037.0557 to 91520.6Quartile 3490 to 73446.8915 to 1,56317.5Quartile 4734 to 2,20027.81,563 to 3,65017.5Cavg 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 (BID) on Day 1, then 300 mg once daily (QD) 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 15.Table 15: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)NAUC0-24 hr (nghr/mL)Cav+ (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Tmax (hr)t1/2 (hr)CL/F(L/hr)Healthy Volunteers1251,618(25)2,151(25)2,764(21)1,785(29)4(3 to 6)31(40)7.5(26)Patients5037,900(42)1,580(42)2,090(38)1,310(50)4 (1.3 to 8.3)-9.39(45)CV coefficient of variation expressed as percentage (%CV); AUC0-T Area under the plasma concentration-time curve from time zero to 24 hr; max maximum observed concentration; min minimum observed plasma concentration; Tmax time of maximum observed concentration; 1/2 terminal phase half-life; CL /F Apparent total body clearance 300 mg BID on Day 1, then 300 mg QD thereafter+ Cav time-averaged concentrations (i.e., AUC0-24 hr/24hr) Median (minimum-maximum). Absorption: When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with median Tmax of to hours. Steady-state plasma concentrations are attained by Day at the 300 mg dose (QD after BID loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with high fat meal compared to fasted state (see Table 17). In order to enhance the oral absorption of posaconazole and optimize plasma concentrations, posaconazole delayed-release tablets should be administered with food.Table 17: 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 ConditionsFasting ConditionsFed Conditions (High Fat Meal)Fed/FastingPharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)Cmax (ng/mL)14935 (34)161,060 (25)1.16 (0.96, 1.41)AUC0-72hr (hrng/mL)1426,200 (28)1638,400 (18)1.51 (1.33, 1.72)Tmax +(hr)145.00 (3.00, 8.00)166.00 (5.00, 24.00)N/AGMR=Geometric least-squares mean ratio; CI=Confidence interval 48.5 fat+ Median (Min, Max) reported for Tmax 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 18).Table 18: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy VolunteersCoadministered DrugAdministration ArmsChange in Cmax (ratio estimate ;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 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 BID)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 (QAM 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 during 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 Cmax or AUC0-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 22. Table 22: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in MeanCmax (ratio estimate; 90%CI of the ratioestimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Efavirenz(UDP-G Induction)400 mg QD 10 and 20 days400 mg (oral suspension) BID 10 and 20 days45%(0.55; 0.47 to 0.66) 50%(0.50; 0.43 to 0.60)Fosamprenavir (unknown mechanism)700 mg BID 10 days200 mg QD on the 1st day, 200 mg BID on the 2nd day, then 400 mg BID 8 Days21%0.79 (0.71 to 0.89)23%0.77 (0.68 to 0.87)Rifabutin(UDP-G Induction)300 mg QD 17 days200 mg (tablets) QD 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 43%(0.57; 0.43 to 0.75) 49%(0.51; 0.37 to 0.71)Phenytoin(UDP-G Induction)200 mg QD 10 days200 mg (tablets) QD 10 days 41%(0.59; 0.44 to 0.79) 50%(0.50; 0.36 to 0.71)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 23 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].Table 23: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Volunteers and PatientsCoadministered Drug(Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of Coadministered DrugsChange in Mean Cmax (ratio estimate; 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) BID 16 days 572%(6.72; 5.62 to 8.03) 788%(8.88; 7.26 to 10.9)CyclosporineStable maintenance dose in heart transplant recipients200 mg (tablets) QD 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) BID 7 days 121%(2.21; 2.01 to 2.42) 358%(4.58; 4.03 to 5.19)Simvastatin40-mg single oral dose100 mg (oral suspension) QD 13 daysSimvastatin 841%(9.41, 7.13 to 12.44)Simvastatin Acid 817%(9.17, 7.36 to 11.43)Simvastatin 931%(10.31, 8.40 to 12.67)Simvastatin Acid634%(7.34, 5.82 to 9.25)200 mg (oral suspension) QD 13 daysSimvastatin 1,041%(11.41, 7.99 to 16.29)Simvastatin Acid851%(9.51, 8.15 to 11.10)Simvastatin 960%(10.60, 8.63 to 13.02)Simvastatin Acid748%(8.48, 7.04 to 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 posaconazole. 200 mg (oral suspension) BID 7 days 30%(1.3; 1.13 to 1.48) 362%(4.62; 4.02 to 5.3)0.4-mg single intravenous dose 400 mg (oral suspension) BID 7 days62%(1.62; 1.41 to 1.86)524%(6.24; 5.43 to 7.16)2-mg single oral dose 200 mg (oral suspension) QD 7 days 169%(2.69; 2.46 to 2.93) 470%(5.70; 4.82 to 6.74)2-mg single oral dose 400 mg (oral suspension) BID 7 days 138%(2.38; 2.13 to 2.66) 397%(4.97; 4.46 to 5.54)Rifabutin300 mg QD 17 days200 mg (tablets) QD 10 days 31%(1.31; 1.10 to 1.57) 72%(1.72;1.51 to 1.95)Phenytoin200 mg QD PO 10 days200 mg (tablets) QD 10 days 16%(1.16; 0.85 to 1.57) 16%(1.16; 0.84 to 1.59)Ritonavir100 mg QD 14 days400 mg (oral suspension)BID 7 days 49%(1.49; 1.04 to 2.15) 80%(1.8;1.39 to 2.31)Atazanavir300 mg QD 14 days400 mg (oral suspension) BID 7 days 155%(2.55; 1.89 to 3.45) 268%(3.68; 2.89 to 4.70)Atazanavir/ ritonavir boosted regimen300 mg/100 mg QD 14 days400 mg (oral suspension) BID 7 days 53%(1.53; 1.13 to 2.07) 146%(2.46; 1.93 to 3.13)Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg QD.. Excretion:Following administration of posaconazole oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is 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.. 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 toposaconazole 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. 14.1 Prophylaxis of Aspergillus and Candida Infections with Posaconazole 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 (Oral Suspension Study 1) was randomized, double-blind trial that compared posaconazole 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, posaconazole; 77 days, fluconazole). Table 24 contains the results from Oral Suspension Study 1.Table 24: 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): 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 (Oral Suspension Study 2) was randomized, open-label study that compared posaconazole 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 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 25 contains the results from Oral Suspension Study 2.Table 25: Results from Open-Label Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: 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 posaconazole oral suspension. As seen in the accompanying tables (Tables 24 and 25), clinical failure represented composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Oral Suspension Study (Table 24), 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 Oral Suspension Study (Table 25) 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 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 Oral Suspension Study [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated substantially fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS. Do not administer to persons with known hypersensitivity to posaconazole or other azole antifungal agents. (4.1)Do not coadminister posaconazole with the following drugs; posaconazole increases concentrations of:Sirolimus: can result in sirolimus toxicity (4.2, 7.1)CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of TdP (4.3, 7.2)HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4: can lead to rhabdomyolysis (4.4, 7.3)Ergot alkaloids: can result in ergotism (4.5, 7.4) Do not administer to persons with known hypersensitivity to posaconazole or other azole antifungal agents. (4.1). Do not coadminister posaconazole with the following drugs; posaconazole increases concentrations of:Sirolimus: can result in sirolimus toxicity (4.2, 7.1)CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of TdP (4.3, 7.2)HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4: can lead to rhabdomyolysis (4.4, 7.3)Ergot alkaloids: can result in ergotism (4.5, 7.4) Sirolimus: can result in sirolimus toxicity (4.2, 7.1). CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of TdP (4.3, 7.2). HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4: can lead to rhabdomyolysis (4.4, 7.3). Ergot alkaloids: can result in ergotism (4.5, 7.4). 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)].

DESCRIPTION SECTION.

11 DESCRIPTION. Posaconazole is an azole antifungal agent available as delayed-release tablet for oral administration.Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and molecular weight of 700.8. The chemical structure is:Posaconazole is white powder with low aqueous solubility. Posaconazole delayed-release tablet is yellow, coated, oblong tablet, debossed with 100 on one side containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol partially hydrolyzed, titanium dioxide, macrogol/polyethylene glycol 3350, talc and iron oxide yellow.. 1.

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. Posaconazole delayed-release tablets and oral suspension are not interchangeable due to the differences in the dosing of each formulation.IndicationDose+ and Duration of TherapyProphylaxis of invasive Aspergillus and Candida InfectionsLoading 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. (2.3)+ Posaconazole delayed-release tablets should be taken with food. (2) 2.1 Important Administration Instructions for Posaconazole Delayed-Release Tablets. Posaconazole delayed-release tablets and oral suspension are not to be used interchangeably due to thedifferences in the dosing of each formulation [see Dosage and Administration (2.3), (2.5)].. Swallow tablets whole. Do not divide, crush, or chew.Administer with food [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole delayed-release tablets.. Swallow tablets whole. Do not divide, crush, or chew.. Administer with food [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].. Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole delayed-release tablets.. 2.3 Dosage and Administration Instructions for Posaconazole Delayed-Release Tablets. Dosage:Table 4: Dosage for Posaconazole Delayed-Release Tablets Indication Dose and Duration of TherapyProphylaxis of invasive Aspergillus andCandida infections 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.. Administration Instructions for Posaconazole Delayed-Release Tablets:Swallow tablets whole. Do not divide, crush, or chew.Administer posaconazole delayed-release tablets with food to enhance the oral absorption of posaconazole and optimize plasma concentrations [see Clinical Pharmacology (12.3)]. Posaconazole delayed-release tablets should be used only for the prophylaxis indication.Posaconazole delayed-release tablets generally provide higher plasma drug exposures than posaconazole oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.. Swallow tablets whole. Do not divide, crush, or chew.. Administer posaconazole delayed-release tablets with food to enhance the oral absorption of posaconazole and optimize plasma concentrations [see Clinical Pharmacology (12.3)]. Posaconazole delayed-release tablets should be used only for the prophylaxis indication.. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than posaconazole oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.. 2.5 Non-Interchangeability between posaconazole delayed-release tablets and posaconazole oral suspension. Posaconazole delayed-release tablets and oral suspension are not to be used interchangeably 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 (2.3)].. 2.6Dosage Adjustments in Patients with Renal Impairment. The pharmacokinetics of posaconazole delayed-release tablets is 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.

3DOSAGE FORMS AND STRENGTHS. Posaconazole delayed-release tablets are available as yellow, coated, oblong tablets, debossed with 100 on one side containing 100 mg of posaconazole.. Posaconazole delayed-release tablet 100 mg (3). Posaconazole delayed-release tablet 100 mg (3).

DRUG INTERACTIONS SECTION.

7DRUG 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 posaconazole oral suspension or early tablet formulation.. Interaction DrugInteractionRifabutin, phenytoin, efavirenz, cimetidineAvoid coadministration unless the benefit outweighs the risks (7.6, 7.7, 7.8, 7.9)Other drugs metabolized by CYP3A4Consider dosage adjustment and monitor for adverse effects and toxicity (7.1, 7.10, 7.11)DigoxinMonitor digoxin plasma concentrations (7.12)FosamprenavirMonitor 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 Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].. Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].. 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, H2-receptor antagonists and proton pump inhibitors [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.. 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age. The pharmacokinetics of posaconazole delayed-release tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.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.

16HOW SUPPLIED/STORAGE AND HANDLING. Posaconazole delayed-release tablets are available as yellow, coated, oblong tablets, debossed with 100 on one side containing 100 mg of posaconazole. Bottles with child-resistant closures of 60 delayed-release tablets (NDC 0527-2133-35). Bottles with screw cap closures of 1,000 delayed-release tablets (NDC 0527-2133-43). Cartons of 24 delayed-release tablets (12 units/blister, blisters/carton) (NDC 0527-2133-30).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.

1INDICATIONS AND USAGE. Posaconazole delayed-release tablets is an azole antifungal agent indicated for: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 HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy. (1.1) 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 HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy. (1.1) 1.1 Prophylaxis of Invasive Aspergillus and Candida Infections. Posaconazole delayed-release tablets are indicated for 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.Posaconazole delayed-release tablets 100 mg are indicated in patients 13 years of age and older.

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. 17.1 Administration. Advise patients to take posaconazole delayed-release tablets with food.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.. 17.2 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.. 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.. 17.3 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.. 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.

LACTATION SECTION.

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.

MECHANISM OF ACTION SECTION.

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

MICROBIOLOGY SECTION.

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 toposaconazole 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 BID oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered high-fat meal (400-mg BID 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 BID oral suspension regimen.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.Posaconazole had no effect on fertility of male rats at dose up to 180 mg/kg (1.7 the 400-mg BID 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 BID 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).The clinical significance of this finding is unknown; therefore, the use of posaconazole injection to patients under 18 years of age is not recommended.

OVERDOSAGE SECTION.

10OVERDOSAGE. There is no experience with overdosage of posaconazole delayed-release tablets.During the clinical trials, some patients received posaconazole oral suspension up to 1,600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1,200 mg BID posaconazole oral suspension for days. No related adverse reactions were noted by the investigator.Posaconazole is not removed by hemodialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 60 Tablet Bottle Label. NDC 0527-2133-35Posaconazole Delayed-Release Tablets100 mgAttention: Posaconazole Oral Suspension and Delayed-Release Tablets are NOT interchangeable due todifferences in the dosing of each formulation.Rx only 60 Tablets. 60-tab-label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of posaconazole delayed-release tablets has been established in the age groups 13 to 17 years of age. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adults. The safety and effectiveness of posaconazole in pediatric patients below the age of 13 years (birth to 12 years) have not been established.A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times day) of posaconazole oral suspension for prophylaxis of invasive fungal infections. The safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state average posaconazole concentration (Cavg) 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 posaconazole 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure Response Relationship: 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 posaconazole oral suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 12). 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 12: Posaconazole Oral Suspension Exposure Analysis (Cavg) in Prophylaxis TrialsProphylaxis in AML/MDSProphylaxis in GVHDCavg Range (ng/mL)Treatment Failure (%)Cavg Range (ng/mL)Treatment Failure (%)Quartile 190 to 32254.722 to 55744.4Quartile 2322 to 49037.0557 to 91520.6Quartile 3490 to 73446.8915 to 1,56317.5Quartile 4734 to 2,20027.81,563 to 3,65017.5Cavg 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 (BID) on Day 1, then 300 mg once daily (QD) 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 15.Table 15: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)NAUC0-24 hr (nghr/mL)Cav+ (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Tmax (hr)t1/2 (hr)CL/F(L/hr)Healthy Volunteers1251,618(25)2,151(25)2,764(21)1,785(29)4(3 to 6)31(40)7.5(26)Patients5037,900(42)1,580(42)2,090(38)1,310(50)4 (1.3 to 8.3)-9.39(45)CV coefficient of variation expressed as percentage (%CV); AUC0-T Area under the plasma concentration-time curve from time zero to 24 hr; max maximum observed concentration; min minimum observed plasma concentration; Tmax time of maximum observed concentration; 1/2 terminal phase half-life; CL /F Apparent total body clearance 300 mg BID on Day 1, then 300 mg QD thereafter+ Cav time-averaged concentrations (i.e., AUC0-24 hr/24hr) Median (minimum-maximum). Absorption: When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with median Tmax of to hours. Steady-state plasma concentrations are attained by Day at the 300 mg dose (QD after BID loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with high fat meal compared to fasted state (see Table 17). In order to enhance the oral absorption of posaconazole and optimize plasma concentrations, posaconazole delayed-release tablets should be administered with food.Table 17: 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 ConditionsFasting ConditionsFed Conditions (High Fat Meal)Fed/FastingPharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)Cmax (ng/mL)14935 (34)161,060 (25)1.16 (0.96, 1.41)AUC0-72hr (hrng/mL)1426,200 (28)1638,400 (18)1.51 (1.33, 1.72)Tmax +(hr)145.00 (3.00, 8.00)166.00 (5.00, 24.00)N/AGMR=Geometric least-squares mean ratio; CI=Confidence interval 48.5 fat+ Median (Min, Max) reported for Tmax 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 18).Table 18: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy VolunteersCoadministered DrugAdministration ArmsChange in Cmax (ratio estimate ;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 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 BID)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 (QAM 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 during 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 Cmax or AUC0-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 22. Table 22: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in MeanCmax (ratio estimate; 90%CI of the ratioestimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Efavirenz(UDP-G Induction)400 mg QD 10 and 20 days400 mg (oral suspension) BID 10 and 20 days45%(0.55; 0.47 to 0.66) 50%(0.50; 0.43 to 0.60)Fosamprenavir (unknown mechanism)700 mg BID 10 days200 mg QD on the 1st day, 200 mg BID on the 2nd day, then 400 mg BID 8 Days21%0.79 (0.71 to 0.89)23%0.77 (0.68 to 0.87)Rifabutin(UDP-G Induction)300 mg QD 17 days200 mg (tablets) QD 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 43%(0.57; 0.43 to 0.75) 49%(0.51; 0.37 to 0.71)Phenytoin(UDP-G Induction)200 mg QD 10 days200 mg (tablets) QD 10 days 41%(0.59; 0.44 to 0.79) 50%(0.50; 0.36 to 0.71)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 23 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].Table 23: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Volunteers and PatientsCoadministered Drug(Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of Coadministered DrugsChange in Mean Cmax (ratio estimate; 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) BID 16 days 572%(6.72; 5.62 to 8.03) 788%(8.88; 7.26 to 10.9)CyclosporineStable maintenance dose in heart transplant recipients200 mg (tablets) QD 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) BID 7 days 121%(2.21; 2.01 to 2.42) 358%(4.58; 4.03 to 5.19)Simvastatin40-mg single oral dose100 mg (oral suspension) QD 13 daysSimvastatin 841%(9.41, 7.13 to 12.44)Simvastatin Acid 817%(9.17, 7.36 to 11.43)Simvastatin 931%(10.31, 8.40 to 12.67)Simvastatin Acid634%(7.34, 5.82 to 9.25)200 mg (oral suspension) QD 13 daysSimvastatin 1,041%(11.41, 7.99 to 16.29)Simvastatin Acid851%(9.51, 8.15 to 11.10)Simvastatin 960%(10.60, 8.63 to 13.02)Simvastatin Acid748%(8.48, 7.04 to 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 posaconazole. 200 mg (oral suspension) BID 7 days 30%(1.3; 1.13 to 1.48) 362%(4.62; 4.02 to 5.3)0.4-mg single intravenous dose 400 mg (oral suspension) BID 7 days62%(1.62; 1.41 to 1.86)524%(6.24; 5.43 to 7.16)2-mg single oral dose 200 mg (oral suspension) QD 7 days 169%(2.69; 2.46 to 2.93) 470%(5.70; 4.82 to 6.74)2-mg single oral dose 400 mg (oral suspension) BID 7 days 138%(2.38; 2.13 to 2.66) 397%(4.97; 4.46 to 5.54)Rifabutin300 mg QD 17 days200 mg (tablets) QD 10 days 31%(1.31; 1.10 to 1.57) 72%(1.72;1.51 to 1.95)Phenytoin200 mg QD PO 10 days200 mg (tablets) QD 10 days 16%(1.16; 0.85 to 1.57) 16%(1.16; 0.84 to 1.59)Ritonavir100 mg QD 14 days400 mg (oral suspension)BID 7 days 49%(1.49; 1.04 to 2.15) 80%(1.8;1.39 to 2.31)Atazanavir300 mg QD 14 days400 mg (oral suspension) BID 7 days 155%(2.55; 1.89 to 3.45) 268%(3.68; 2.89 to 4.70)Atazanavir/ ritonavir boosted regimen300 mg/100 mg QD 14 days400 mg (oral suspension) BID 7 days 53%(1.53; 1.13 to 2.07) 146%(2.46; 1.93 to 3.13)Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg QD.. Excretion:Following administration of posaconazole oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is 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.

PREGNANCY SECTION.

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 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 5. 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.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.L7048A Rev. 10/2020Patient InformationPosaconazole (po-sa-kon-a-zole)Delayed-Release TabletsWhat is posaconazole delayed-release tabletsPosaconazole delayed-release tablets are prescription medicines used to help prevent fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Posaconazole 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 diseasea low white blood cell count due to chemotherapy for blood cancers (hematologic malignancy)Posaconazole delayed-release tablets are for adults and children over 13 years of age.It is not known if posaconazole delayed-release tablets are safe and effective in children under 13 years of age.Who should not take posaconazole delayed-release tabletsDo not take posaconazole delayed-release tablets if you:are allergic to posaconazole, any of the ingredients in posaconazole delayed-release tablets, or other azole antifungal medicines. See the end of this leaflet for complete list of ingredients in posaconazole delayed-release tablets..are taking any of the following medicines:sirolimuspimozidequinidinecertain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)ergot alkaloids (ergotamine, dihydroergotamine) 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.What should tell my healthcare provider before taking posaconazole delayed-release tabletsBefore you take posaconazole delayed-release tablets, tell your healthcare provider if you:are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole delayed-release tablets.are taking midazolam, hypnotic and sedative medicine.are taking vincristine, vinblastine and other vinca alkaloids (medicines used to treat cancer).have or had liver problems.have or had kidney problems.have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.are pregnant or plan to become pregnant. It is not known if posaconazole delayed-release tablets will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole delayed-release tablets or breastfeed. You should not do both.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Posaconazole 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.Ask yourhealthcare 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 will take posaconazole delayed-release tabletsDo not switch between taking posaconazole delayed-release tablets and posaconazole oral suspension without talking to your healthcare provider.Take posaconazole delayed-release tablets exactly as your healthcare provider tells you to take it.Your healthcare provider will tell you how much posaconazole delayed-release tablets to take and when to take it.Take posaconazole delayed-release tablets for as long as your healthcare provider tells you to take it.If you take too much posaconazole delayed-release tablets, call your healthcare provider or go to the nearest hospital emergency room right away.Take posaconazole delayed-release tablets with 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.Follow the instructions from your healthcare provider on how much posaconazole delayed-release tablets you should take and when to take it.What are the possible side effects of posaconazole delayed-release tabletsPosaconazole delayed-release tablets may cause serious side effects, including:drug interactions with cyclosporine or tacrolimus. If you take posaconazole delayed-release tablets with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole delayed-release tablets. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole delayed-release tablets, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.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 delayed-release tablets. Call your healthcare provider right away if you have any of the following symptoms of liver problems:itchy skinnausea or vomitingyellowing of your eyesfeeling very tiredflu-like symptomsincreased amounts of midazolam in your blood. If you take posaconazole delayed-release tablets 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 delayed-release tablets.The most common side effects of posaconazole delayed-release tablets include:diarrheanauseafevervomitingheadachecoughinglow potassium levels in the bloodIf you take posaconazole delayed-release tablets, tell your healthcare provider right away if you have diarrhea or vomiting.Tell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of posaconazole delayed-release tablets. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store posaconazole delayed-release tabletsStore posaconazole delayed-release tablets at room temperature between 68F to 77F (20C to 25C).Safely throw away medicine that is out of date or no longer needed.Keep posaconazole delayed-release tablets and all medicines out of the reach of children.General information about the safe and effective use of posaconazole delayed-release tablets.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use posaconazole delayed-release tablets for condition for which it was not prescribed. Do not give posaconazole delayed-release tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about posaconazole delayed-release tablets that is written for health professionals.What are the ingredients in posaconazole delayed-release tabletsActive ingredient: posaconazole Inactive ingredients: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol partially hydrolyzed, titanium dioxide, macrogol/polyethylene glycol 3350, talc and iron oxide yellowDistributed by:Lannett Company, Inc.Philadelphia, PA 19136Manufactured by:Haimen Pharma Inc.,No. 163, Zhuhai Rd., Binjiang Street,Haimen, Jiangsu 226100,ChinaThe trademarks depicted in this piece are owned by their respective companies.For more information, call 1-844-834-0530.. had hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease. low white blood cell count due to chemotherapy for blood cancers (hematologic malignancy). are allergic to posaconazole, any of the ingredients in posaconazole delayed-release tablets, or other azole antifungal medicines. See the end of this leaflet for complete list of ingredients in posaconazole delayed-release tablets... are taking any of the following medicines:sirolimuspimozidequinidinecertain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)ergot alkaloids (ergotamine, dihydroergotamine) sirolimus. pimozide. quinidine. certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin). ergot alkaloids (ergotamine, dihydroergotamine). 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 delayed-release tablets.. are taking midazolam, hypnotic and sedative medicine.. are taking vincristine, vinblastine and other vinca alkaloids (medicines used to treat cancer).. have or had liver problems.. have or had kidney problems.. have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.. are pregnant or plan to become pregnant. It is not known if posaconazole delayed-release tablets will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole delayed-release tablets or breastfeed. You should not do both.. rifabutin or phenytoin. If you are taking these medicines, you should not take posaconazole delayed-release tablets.. Do not switch between taking posaconazole delayed-release tablets and posaconazole oral suspension without talking to your healthcare provider.. Take posaconazole delayed-release tablets exactly as your healthcare provider tells you to take it.. Your healthcare provider will tell you how much posaconazole delayed-release tablets to take and when to take it.. Take posaconazole delayed-release tablets for as long as your healthcare provider tells you to take it.. If you take too much posaconazole delayed-release tablets, call your healthcare provider or go to the nearest hospital emergency room right away.. Take posaconazole delayed-release tablets with 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.. drug interactions with cyclosporine or tacrolimus. If you take posaconazole delayed-release tablets with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole delayed-release tablets. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.. problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole delayed-release tablets, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.. 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 delayed-release tablets. Call your healthcare provider right away if you have any of the following symptoms of liver problems:itchy skinnausea or vomitingyellowing of your eyesfeeling very tiredflu-like symptoms. itchy skin. nausea or vomiting. yellowing of your eyes. feeling very tired. flu-like symptoms. increased amounts of midazolam in your blood. If you take posaconazole delayed-release tablets 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 delayed-release tablets.. 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).. Safely throw away medicine that is out of date or no longer needed.

SPL UNCLASSIFIED SECTION.

1.1 Prophylaxis of Invasive Aspergillus and Candida Infections. Posaconazole delayed-release tablets are indicated for 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.Posaconazole delayed-release tablets 100 mg are indicated in patients 13 years of age and older.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1)Severe renal impairment: Monitor closely for breakthrough fungal infections. (8.6). Pregnancy: Based on animal data, may cause fetal harm. (8.1). 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 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 5. 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 safety and effectiveness of posaconazole delayed-release tablets has been established in the age groups 13 to 17 years of age. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adults. The safety and effectiveness of posaconazole in pediatric patients below the age of 13 years (birth to 12 years) have not been established.A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times day) of posaconazole oral suspension for prophylaxis of invasive fungal infections. The safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state average posaconazole concentration (Cavg) 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 posaconazole 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.. 8.5 Geriatric Use. Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age. The pharmacokinetics of posaconazole delayed-release tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.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 oral suspension, there was no significant effect of mild (eGFR: 50 to 80 mL/min/1.73 m2, n=6) or moderate (eGFR: 20 to 49 mL/min/1.73 m2, n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2)]. Similar recommendations apply to posaconazole delayed-release tablets; however, specific study has not been conducted with the delayed-release tablets.. 8.7 Hepatic Impairment. After single oral dose of posaconazole oral suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (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 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)]. Similar recommendations apply to posaconazole delayed-release tablets; however, specific study has not been conducted with the delayed-release tablets.. 8.8 Gender. The pharmacokinetics of posaconazole are comparable in men and women. 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.

5WARNINGS 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 LFTs may occur. Discontinuation should be considered in patients who develop abnormal LFTs or monitor LFTs during treatment. (5.4)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). 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 LFTs may occur. Discontinuation should be considered in patients who develop abnormal LFTs or monitor LFTs during treatment. (5.4). 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). 5.1 Calcineurin-Inhibitor Drug Interactions. 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 posaconazole oral suspension 400 mg BID 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 aQTc(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 function 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 BID or 200 mg QID) in clinical trials.Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function 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 function 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, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].. 5.6 Use with Midazolam. 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)].

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1) 6/2021Dosage and Administration (2) 6/2021Contraindications (4) 1/2022Warnings and Precautions (5) 1/2022.