ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: oHypersensitivity [see Contraindications (4.1)]oArrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]oHepatic Toxicity [see Warnings and Precautions (5.4)]. oHypersensitivity [see Contraindications (4.1)]. oArrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]. oHepatic Toxicity [see Warnings and Precautions (5.4)]. oAdult Patients: Common adverse reactions in studies with posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oAdult Patients: Common adverse reactions in studies with posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. (6.1) 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trial Experience in Adults:Clinical Trial Safety Experience with Posaconazole Oral Suspension: The safety of posaconazole oral suspension has been assessed in 1,844 patients. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications. This represents heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection, as well as non-neutropenic patients. This patient population was 71% male, had mean age of 42 years (range to 84 years, 6% of patients were >=65 years of age and 1% was <18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 14% black). Posaconazole therapy was given to 171 patients for >=6 months, with 58 patients receiving posaconazole therapy for >=12 months. Table 10 presents adverse reactions observed at an incidence of >10% in posaconazole prophylaxis studies. Table 11 presents adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.Prophylaxis of Aspergillus and Candida: In the randomized, comparative prophylaxis studies (Posaconazole Oral Suspension Study and 2), the safety of posaconazole oral suspension 200 mg three times day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice day in severely immunocompromised patients.The most frequently reported adverse reactions (>30%) in the prophylaxis clinical trials were fever, diarrhea, and nausea.The most common adverse reactions leading to discontinuation of posaconazole in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).Table 10: Posaconazole Oral Suspension Study and Study 2. Adverse Reactions in at Least 10% of the Posaconazole Oral Suspension or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)Body SystemPosaconazole Oral Suspensionn=605 (%)Fluconazolen=539 (%)Itraconazolen=58 (%)Subjects Reporting any Adverse Reaction595(98)531(99)58(100)Body as Whole General DisordersFever274(45)254(47)32(55)Headache171(28)141(26)23(40)Rigors122(20)87(16)17(29)Fatigue101(17)98(18)5(9)Edema Legs93(15)67(12)11(19)Anorexia92(15)94(17)16(28)Dizziness64(11)56(10)5(9)Edema54(9)68(13)8(14)Weakness51(8)52(10)2(3)Cardiovascular Disorders, GeneralHypertension106(18)88(16)3(5)Hypotension83(14)79(15)10(17)Disorders of Blood and Lymphatic SystemAnemia149(25)124(23)16(28)Neutropenia141(23)122(23)23(40)Disorders of the Reproductive System and BreastVaginal HemorrhagePercentages of sex-specific adverse reactions are based on the number of males/females. 24(10)20(9)3(12)Gastrointestinal System DisordersDiarrhea256(42)212(39)35(60)Nausea232(38)198(37)30(52)Vomiting174(29)173(32)24(41)Abdominal Pain161(27)147(27)21(36)Constipation126(21)94(17)10(17)Dyspepsia61(10)50(9)6(10)Heart Rate and Rhythm DisordersTachycardia72(12)75(14)3(5)Infection and InfestationsPharyngitis71(12)60(11)12(21)Liver and Biliary System DisordersBilirubinemia59(10)51(9)11(19)Metabolic and Nutritional DisordersHypokalemia181(30)142(26)30(52)Hypomagnesemia110(18)84(16)11(19)Hyperglycemia68(11)76(14)2(3)Hypocalcemia56(9)55(10)5(9)Musculoskeletal System DisordersMusculoskeletal Pain95(16)82(15)9(16)Arthralgia69(11)67(12)5(9)Back Pain63(10)66(12)4(7)Platelet, Bleeding and Clotting DisordersThrombocytopenia175(29)146(27)20(34)Petechiae64(11)54(10)9(16)Psychiatric DisordersInsomnia103(17)92(17)11(19)Respiratory System DisordersCoughing146(24)130(24)14(24)Dyspnea121(20)116(22)15(26)Epistaxis82(14)73(14)12(21)Skin and Subcutaneous Tissue DisordersRash113(19)96(18)25(43)Pruritus69(11)62(12)11(19)HIV Infected Subjects with OPC: In randomized comparative studies in OPC, the safety of posaconazole oral suspension at dose of less than or equal to 400 mg once daily in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at dose of 100 mg once daily.An additional 239 HIV-infected patients with refractory OPC received posaconazole oral suspension in non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800 mg/day dose and the remainder received the less than or equal to 400 mg once daily dose.In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, vomiting, and coughing.The most common adverse reactions that led to treatment discontinuation of posaconazole in the Controlled OPC Pool included respiratory impairment (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of posaconazole were AIDS (7%) and respiratory impairment (3%).Table 11: Adverse Reactions in at Least 10% of the Treated Population in OPC Studies with Posaconazole Oral Suspension Body System Preferred TermNumber (%) of SubjectsControlled OPC PoolRefractory OPC PoolPosaconazole Oral SuspensionFluconazolePosaconazole Oral Suspensionn=557n=262n=239Subjects Reporting any Adverse ReactionNumber of subjects reporting adverse reactions at least once during the study, without regard to relationship to treatment. Subjects may have reported more than event. OPC=oropharyngeal candidiasis 356 (64)175 (67)221 (92)Body as Whole General Disorders Fever34 (6)22 (8)82 (34) Headache44 (8)23 (9)47 (20) Anorexia10 (2)4 (2)46 (19) Fatigue18 (3)12 (5)31 (13) Asthenia9 (2)5 (2)31 (13) Rigors2 (<1)4 (2)29 (12) Pain4 (1)2 (1)27 (11)Disorders of Blood and Lymphatic System Neutropenia21 (4)8 (3)39 (16) Anemia11 (2)5 (2)34 (14)Gastrointestinal System Disorders Diarrhea58 (10)34 (13)70 (29) Nausea48 (9)30 (11)70 (29) Vomiting37 (7)18 (7)67 (28) Abdominal Pain27 (5)17 (6)43 (18)Infection and Infestations Candidiasis, Oral3 (1)1 (<1)28 (12) Herpes Simplex16 (3)8 (3)26 (11) Pneumonia17 (3)6 (2)25 (10)Metabolic and Nutritional Disorders Weight Decrease4 (1)2 (1)33 (14) Dehydration4 (1)7 (3)27 (11)Psychiatric Disorders Insomnia8 (1)3 (1)39 (16)Respiratory System Disorders Coughing18 (3)11 (4)60 (25) Dyspnea8 (1)8 (3)28 (12)Skin and Subcutaneous Tissue Disorders Rash15 (3)10 (4)36 (15) Sweating Increased13 (2)5 (2)23 (10)Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%).Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of posaconazole are listed below:oBlood and Lymphatic System Disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravatedoEndocrine Disorders: adrenal insufficiencyoNervous System Disorders: paresthesiaoImmune System Disorders: allergic reaction [see Contraindications (4.1)] oCardiac Disorders: torsades de pointes [see Warnings and Precautions (5.2)] oVascular Disorders: pulmonary embolismoGastrointestinal Disorders: pancreatitisoLiver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice oRenal Urinary System Disorders: renal failure acuteClinical Laboratory Values: In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma concentrations of posaconazole.For the prophylaxis studies, the number of patients with changes in liver tests from Common Toxicity Criteria (CTC) Grade 0, 1, or at baseline to Grade or during the study is presented in Table 12. Table 12: Posaconazole Oral Suspension Study and Study 2. Changes in Liver Test Results from CTC Grade 0, 1, or at Baseline to Grade or 4Number (%) of Patients with ChangePosaconazole Oral Suspension Study 1Laboratory ParameterPosaconazole Oral Suspensionn=301Fluconazolen=299 AST11/266 (4)13/266 (5) ALT47/271 (17)39/272 (14) Bilirubin24/271 (9)20/275 (7) Alkaline Phosphatase9/271 (3)8/271 (3)Posaconazole Oral Suspension Study 2Laboratory ParameterPosaconazole Oral Suspension(n=304)Fluconazole/Itraconazole(n=298) AST9/286 (3)5/280 (2) ALT18/289 (6)13/284 (5) Bilirubin20/290 (7)25/285 (9) Alkaline Phosphatase4/281 (1)1/276 (<1)Change from Grade to at baseline to Grade or during the study. These data are presented in the form X/Y, where represents the number of patients who met the criterion as indicated, and represents the number of patients who had baseline observation and at least one post-baseline observation. CTC Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase.The number of patients treated for OPC with clinically significant liver test abnormalities at any time during the studies is provided in Table 13 (liver test abnormalities were present in some of these patients prior to initiation of the study drug).Table 13: Posaconazole Oral Suspension Studies: Clinically Significant Laboratory Test Abnormalities without Regard to Baseline ValueLaboratory TestControlledRefractoryPosaconazole Oral SuspensionFluconazolePosaconazole Oral Suspensionn=557(%)n=262(%)n=239(%)ALT 3.0 ULN16/537 (3)13/254 (5)25/226 (11)AST 3.0 ULN33/537 (6)26/254 (10)39/223 (17)Total Bilirubin 1.5 ULN15/536 (3)5/254 (2)9/197 (5)Alkaline Phosphatase 3.0 ULN17/535 (3)15/253 (6)24/190 (13)ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.The number of patients treated for invasive aspergillosis with clinically significant liver test abnormalities at any time during the Aspergillosis Treatment Study is provided in Table 14. Liver test abnormalities present prior to the initiation of study drug included ALT (22%), AST (13%), and bilirubin (13%). Table 14: Aspergillosis Treatment Study: Changes in Liver Test Results from CTC Grade 0, 1, or at Baseline to Grade or Number (%) of Patients with ChangeLaboratory ParameterPosaconazole n/N (%)Voriconazole n/N (%)AST22/281 (8)21/285 (7)ALT29/281(10)23/282 (8)Bilirubin26/280 (9)25/284 (9)Alkaline Phosphatase12/282 (4)20/284 (7)Change from Grade to at baseline to Grade or during the study. These data are presented in the form n/N, where represents the number of patients who met the criterion as indicated, and represents the number of patients who had baseline observation and at least one post-baseline observation. N=Number of subjects for given laboratory test with baseline value of CTC Grade 0, 1, or and at least one post-baseline value. CTC Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase.. oBlood and Lymphatic System Disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated. oEndocrine Disorders: adrenal insufficiency. oNervous System Disorders: paresthesia. oImmune System Disorders: allergic reaction [see Contraindications (4.1)] oCardiac Disorders: torsades de pointes [see Warnings and Precautions (5.2)] oVascular Disorders: pulmonary embolism. oGastrointestinal Disorders: pancreatitis. oLiver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice oRenal Urinary System Disorders: renal failure acute. 6.2 Postmarketing Experience The following adverse reaction has been identified during the post-approval use of posaconazole. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency.Endocrine Disorders: Pseudoaldosteronism.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

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

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].. 12.2 Pharmacodynamics Exposure Response Relationship Prophylaxis: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), wide range of plasma exposures to posaconazole was noted following administration of posaconazole oral suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 17). lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.Table 17: Posaconazole Oral Suspension Exposure Analysis (Cavg) in Prophylaxis TrialsProphylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDSProphylaxis in GVHDHSCT recipients with GVHDCavg Range (ng/mL)Treatment FailureDefined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%)Cavg Range (ng/mL)Treatment Failure (%)Quartile 190 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 3,65017.5 Cavg the average posaconazole concentration when measured at steady state. 12.3 Pharmacokinetics General Pharmacokinetic Characteristics:Dose-proportional increases in plasma exposure (AUC) to posaconazole oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections.The mean (%CV) [min-max] posaconazole oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times day and 400 mg twice daily of the oral suspension are provided in Table 21. Table 21: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole Oral Suspension 200 mg Three Times Day and 400 mg Twice DailyDoseOral suspension administrationCavg (ng/mL)AUCAUC (0 to 24 hr) for 200 mg three times day and AUC (0 to 12 hr) for 400 mg twice daily (nghr/mL)CL/F (L/hr)V/F (L)t 1/2 (hr)200 mg three times dayHSCT recipients with GVHD (n=252)1,103 (67)[21.5 to 3650]NDNot done ND ND ND 200 mg three times dayNeutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215)583 (65)[89.7 to 2,200]15,900 (62)[4100 to 56,100]51.2 (54)[10.7 to 146]2425 (39)[828 to 5,702]37.2 (39)[19.1 to 148]400 mg twice dailyFebrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24 The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects. (n=23)723 (86)[6.70 to 2,256]9093 (80)[1,564 to 26,794]76.1 (78)[14.9 to 256]3088 (84)[407 to 13,140]31.7 (42)[12.4 to 67.3] Cavg the average posaconazole concentration when measured at steady stateAbsorption:Posaconazole oral suspension is absorbed with median Tmax of ~3 to hours. Steady-state plasma concentrations are attained at to 10 days following multiple-dose administration.Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when the oral suspension is administered with nonfat meal and approximately 4-times higher when administered with high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of posaconazole oral suspension 400 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when administered with liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 24). In addition, the effects of varying gastric administration conditions on the Cmax and AUC of posaconazole oral suspension in healthy volunteers have been investigated and are shown in Table 25.In order to assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole oral suspension during or immediately following full meal. In patients who cannot eat full meal, posaconazole oral suspension should be taken with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).Table 24: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted ConditionsDose (mg)Cmax (ng/mL)Tmax Median [min-max].(hr)AUC (I)(nghr/mL)CL/F(L/hr)t 1/2 (hr)200 mg fasted(n=20)n=15 for AUC (I), CL/F, and 1/2 132 (50)[45 to 267]3.50[1.5 to 36The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between hrs and 36 hrs).]4179 (31)[2,705 to 7,269]51 (25)[28 to 74]23.5 (25)[15.3 to 33.7]200 mg nonfat(n=20) 378 (43)[131 to 834]4 [3 to 5]10,753 (35)[4,579 to 17,092]21 (39)[12 to 44]22.2 (18)[17.4 to 28.7]200 mg high fat(54 gm fat)(n=20) 512 (34)[241 to 1,016]5 [4 to 5]15,059 (26)[10,341 to 24,476]14 (24)[8.2 to 19]23.0 (19)[17.2 to 33.4]400 mg fasted(n=23)n=10 for AUC (I), CL/F, and 1/2 121 (75)[27 to 366]4 [2 to 12]5258 (48)[2,834 to 9,567]91 (40)[42 to 141]27.3 (26)[16.8 to 38.9]400 mg with liquid nutritional supplement(14 gm fat)(n=23) 355 (43)[145 to 720]5 [4 to 8]11,295 (40)[3,865 to 20,592]43 (56)[19 to 103]26.0 (19)[18.2 to 35.0]Table 25: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Posaconazole Oral Suspension in Healthy VolunteersIn subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when posaconazole was administered via an NG tube compared to when posaconazole was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when posaconazole is administered via an NG tube because lower plasma exposure may be associated with an increased risk of treatment failure. Study DescriptionAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.;90% CI of the ratio estimate)Change in AUC(ratio estimate;90% CI of the ratio estimate)400 mg single dose with high-fat meal relative to fasted state (n=12) minutes before high-fat meal96%(1.96; 1.48 to 2.59)111%(2.11; 1.60 to 2.78)During high-fat meal339%(4.39; 3.32 to 5.80)382%(4.82; 3.66 to 6.35)20 minutes after high-fat meal333%(4.33; 3.28 to 5.73)387%(4.87; 3.70 to 6.42)400 mg twice daily and 200 mg four times daily for days in fasted state and with liquid nutritional supplement (BOOST(R)) (n=12)400 mg twice daily with BOOST65%(1.65; 1.29 to 2.11)66%(1.66; 1.30 to 2.13)200 mg four times daily with BOOSTNo EffectNo EffectDivided daily dose from 400 mg twice daily to 200 mg four times daily for days regardless of fasted conditions or with BOOST (n=12)Fasted state136%(2.36; 1.84 to 3.02)161%(2.61; 2.04 to 3.35)With BOOST137%(2.37; 1.86 to 3.04)157%(2.57; 2.00 to 3.30)400-mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)Ginger ale92%(1.92; 1.51 to 2.44)70%(1.70; 1.43 to 2.03)Esomeprazole32%(0.68; 0.53 to 0.86)30%(0.70; 0.59 to 0.83)400-mg single dose with prokinetic agent (metoclopramide 10 mg three times day for days) BOOST or an antikinetic agent (loperamide 4-mg single dose) BOOST (n=12)With metoclopramide BOOST21%(0.79; 0.72 to 0.87)19%(0.81; 0.72 to 0.91)With loperamide BOOST3%(0.97; 0.88 to 1.07)11%(1.11; 0.99 to 1.25)400-mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)Via NG tubeNG nasogastric 19%(0.81; 0.71 to 0.91)23%(0.77; 0.69 to 0.86)Concomitant administration of posaconazole oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (See Table 26). Table 26: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Oral Suspension in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in MeanCmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Cimetidine(Alteration of gastric pH)400 mg twice daily 10 days200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 39%(0.61; 0.53 to 0.70) 39%(0.61; 0.54 to 0.69)Esomeprazole (Increase in gastric pH)The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide. 40 mg every morning 3 days400 mg (oral suspension) single dose 46%(0.54; 0.43 to 0.69) 32%(0.68; 0.57 to 0.81)Metoclopramide (Increase in gastric motility) 10 mg three times day 2 days400 mg (oral suspension) single dose 21%(0.79; 0.72 to 0.87) 19%(0.81; 0.72 to 0.91)Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 and ranged from 226 to 295 between studies and dose levels.Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.Metabolism: Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.Posaconazole is primarily metabolized via UDP glucuronidation (phase enzymes) and is substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27. Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in MeanCmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Efavirenz(UDP-G Induction)400 mg once daily 10 and 20 days400 mg (oral suspension) twice daily 10 and 20 days45%(0.55; 0.47 to 0.66) 50%(0.50; 0.43 to 0.60)Fosamprenavir (unknown mechanism)700 mg twice daily 10 days200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily 8 Days21%0.79 (0.71 to 0.89)23%0.77 (0.68 to 0.87)Rifabutin(UDP-G Induction)300 mg once daily 17 days200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 43%(0.57; 0.43 to 0.75) 49%(0.51; 0.37 to 0.71)Phenytoin(UDP-G Induction)200 mg once daily 10 days200 mg (tablets) once daily 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 28 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and 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 estimateThe Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Sirolimus2 mg single oral dose400 mg (oral suspension) twice daily 16 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) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. cyclosporine whole blood trough concentrationsCyclosporine dose reductions of up to 29% were requiredTacrolimus0.05 mg/kg single oral dose400 mg (oral suspension) twice daily 7 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) once daily 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) once daily 13 daysSimvastatin 1041%(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) twice daily 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) twice daily 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) once daily 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) twice daily 7 days 138%(2.38; 2.13 to 2.66) 397%(4.97; 4.46 to 5.54)Rifabutin300 mg once daily 17 days200 mg (tablets) once daily 10 days 31%(1.31; 1.10 to 1.57) 72%(1.72;1.51 to 1.95)Phenytoin200 mg once daily PO 10 days200 mg (tablets) once daily 10 days 16%(1.16; 0.85 to 1.57) 16%(1.16; 0.84 to 1.59)Ritonavir100 mg once daily 14 days400 mg (oral suspension)twice daily 7 days 49%(1.49; 1.04 to 2.15) 80%(1.8;1.39 to 2.31)Atazanavir300 mg once daily 14 days400 mg (oral suspension) twice daily 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 once daily 14 days400 mg (oral suspension) twice daily 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 once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg once daily.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 oral suspension is eliminated with mean half-life (t 1/2 of 35 hours (range: 20 to 66 hours). Specific Populations:No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Race/Ethnicity: In population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure. Patients Weighing More Than 120 kg: Weight has clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)]. Pediatric Patients:The population pharmacokinetic analysis of posaconazole in pediatric patients suggests that age, sex, renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics of posaconazole.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. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (>=18 years of age). In study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with posaconazole oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.. 12.4 Microbiology Mechanism of Action: Posaconazole blocks the synthesis of ergosterol, key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole. Resistance: Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known. Antimicrobial Activity: Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Microorganisms:Aspergillus spp. and Candida spp. Susceptibility Testing: For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.2 Prophylaxis of Aspergillus and Candida Infections with 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 (Posaconazole 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 oral suspension; 77 days, fluconazole). Table 32 contains the results from Posaconazole Oral Suspension Study 1.Table 32: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Posaconazole 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 (Posaconazole 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 Posaconazole Oral Suspension Study 1, efficacy of prophylaxis was evaluated using composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). This study assessed patients while on treatment plus days and 100 days postrandomization. The mean duration of therapy was comparable between the treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 33 contains the results from Posaconazole Oral Suspension Study 2.Table 33: Results from Open-Label Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Posaconazole 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 Failure158 (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 32 and 33), clinical failure represented composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Posaconazole Oral Suspension Study (Table 32), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole-comparator -11.5% to 3.7%) while in Posaconazole Oral Suspension Study (Table 33) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole-comparator -22.9% to -7.8%).All-cause mortality was similar at 16 weeks for both treatment arms in Posaconazole 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 Posaconazole 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.. 14.3 Treatment of Oropharyngeal Candidiasis with Posaconazole Oral Suspension. Posaconazole Oral Suspension Study was randomized, controlled, evaluator-blinded study in HIV-infected patients with oropharyngeal candidiasis. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice day for day followed by 100 mg once day for 13 days).Clinical and mycological outcomes were assessed after 14 days of treatment and at weeks after the end of treatment. Patients who received at least dose of study medication and had positive oral swish culture of Candida species at baseline were included in the analyses (see Table 34). The majority of the subjects had C. albicans as the baseline pathogen.Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms) and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) weeks after the end of treatment were similar between the treatment arms (see Table 34).Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also similar between the treatment arms (see Table 34).Table 34: Posaconazole Oral Suspension Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal CandidiasisPosaconazoleFluconazoleClinical Success at End of Therapy (Day 14)155/169 (91.7%)148/160 (92.5%)Clinical Relapse (4 Weeks after End of Therapy)45/155 (29.0%)52/148 (35.1%)Mycological Eradication (Absence of CFU) at End of Therapy (Day 14)88/169 (52.1%)80/160 (50.0%)Mycological Relapse (4 Weeks after End of Treatment)49/88 (55.6%)51/80 (63.7%)Mycologic response rates, using criterion for success as posttreatment quantitative culture with <=20 colony forming units (CFU/mL) were also similar between the two groups (posaconazole 68.0%, fluconazole 68.1%). The clinical significance of this finding is unknown.. 14.4 Posaconazole Oral Suspension Treatment of Oropharyngeal Candidiasis Refractory to Treatment with Fluconazole or Itraconazole. Posaconazole Oral Suspension Study was noncomparative study of posaconazole oral suspension in HIV-infected subjects with OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was considered refractory if there was failure to improve or worsening of OPC after standard course of therapy with fluconazole greater than or equal to 100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with posaconazole. Of the 199 subjects enrolled in this study, 89 subjects met these strict criteria for refractory infection.Forty-five subjects with refractory OPC were treated with posaconazole oral suspension 400 mg twice daily for days, followed by 400 mg once daily for 25 days with an option for further treatment during 3-month maintenance period. Following dosing amendment, further 44 subjects were treated with posaconazole 400 mg twice daily for 28 days. The efficacy of posaconazole was assessed by the clinical success (cure or improvement) rate after weeks of treatment. The clinical success rate was 74.2% (66/89). The clinical success rates for both the original and the amended dosing regimens were similar (73.3% and 75.0%, respectively).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. oKnown hypersensitivity to posaconazole or other azole antifungal agents. (4.1) oCoadministration of posaconazole with the following drugs is contraindicated; posaconazole increases concentrations and toxicities of:oSirolimus: can result in sirolimus toxicity (4.2, 5.1, 7.1) oCYP3A4 Substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) (4.3, 5.2, 7.2) oHMG-CoA Reductase Inhibitors Primarily Metabolized through CYP3A4 (4.4, 7.3) oErgot alkaloids (4.5, 7.4) oVenetoclax: in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp up phase (4.6, 5.10, 7.16). oKnown hypersensitivity to posaconazole or other azole antifungal agents. (4.1) oCoadministration of posaconazole with the following drugs is contraindicated; posaconazole increases concentrations and toxicities of:oSirolimus: can result in sirolimus toxicity (4.2, 5.1, 7.1) oCYP3A4 Substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) (4.3, 5.2, 7.2) oHMG-CoA Reductase Inhibitors Primarily Metabolized through CYP3A4 (4.4, 7.3) oErgot alkaloids (4.5, 7.4) oVenetoclax: in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp up phase (4.6, 5.10, 7.16). oSirolimus: can result in sirolimus toxicity (4.2, 5.1, 7.1) oCYP3A4 Substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) (4.3, 5.2, 7.2) oHMG-CoA Reductase Inhibitors Primarily Metabolized through CYP3A4 (4.4, 7.3) oErgot alkaloids (4.5, 7.4) oVenetoclax: in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp up phase (4.6, 5.10, 7.16). 4.1 Hypersensitivity. Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.. 4.2 Use with Sirolimus. Posaconazole is contraindicated with sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].. 4.3 QT Prolongation with Concomitant Use with CYP3A4 Substrates. Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].. 4.4 HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4. Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].. 4.5 Use with Ergot Alkaloids. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].. 4.6 Use with Venetoclax Coadministration of posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Warnings and Precautions 5.10) and Drug Interactions (7.16)].

DESCRIPTION SECTION.

11 DESCRIPTION Posaconazole is an azole antifungal agent available as an injection solution to be diluted before intravenous administration, delayed-release tablet, oral suspension, and powder for delayed-release oral suspension intended 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 to off-white powder that is practically insoluble in water.Posaconazole oral suspension is white to off-white, cherry-brandy flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: cherry-brandy flavor, citric acid monohydrate, hydroxyethyl cellulose, glycerin, polyoxyl 35 castor oil, simethicone emulsion, sodium benzoate, sodium citrate, sorbitol solution, titanium dioxide, and water.. chemical-structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oPosaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for the formulation. (2.1 2.2, 2.3) oAdminister posaconazole oral suspension with full meal (2.1)Table 1: Recommended Dosage in Adult PatientsIndicationDosage Form, Dose, and Duration of TherapyProphylaxis of invasive Aspergillus and Candida infectionsPosaconazole Oral Suspension: 200 mg (5 mL) three times day. Duration of therapy is based on recovery from neutropenia or immunosuppression. (2.2, 2.3)Oropharyngeal Candidiasis (OPC)Posaconazole Oral Suspension: Loading Dose: 100 mg (2.5 mL) twice day on the first day. Maintenance Dose: 100 mg (2.5 mL) once day for 13 days. (2.2, 2.3)OPC Refractory (rOPC) to Itraconazole and/or FluconazolePosaconazole Oral Suspension: 400 mg (10 mL) twice day. Duration of therapy is based on the severity of the patients underlying disease and clinical response. (2.2, 2.3)oFor pediatric patients, see the Full Prescribing Information for dosing recommendations for posaconazole oral suspension based on the age and indication associated with the dosage form. (1.2, 1.3, 2.1, 2.3). oPosaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for the formulation. (2.1 2.2, 2.3) oAdminister posaconazole oral suspension with full meal (2.1). oFor pediatric patients, see the Full Prescribing Information for dosing recommendations for posaconazole oral suspension based on the age and indication associated with the dosage form. (1.2, 1.3, 2.1, 2.3). 2.1 Important Administration Instructions. Non-substitutable:Posaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for the formulation [see Dosage and Administration 2.2, 2.3)].Posaconazole oral suspension:oAdminister with full meal or with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat full meal [see Dosage and Administration (2.6)].oCo-administration 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 [see Drug Interactions (7.6, 7.7, 7.8, 7.9, 7.13)].. oAdminister with full meal or with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat full meal [see Dosage and Administration (2.6)].. oCo-administration 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 [see Drug Interactions (7.6, 7.7, 7.8, 7.9, 7.13)].. 2.2 Dosing Regimen in Adult Patients Table 1: Dosing Regimens in Adult Patients IndicationDose and FrequencyDuration of TherapyProphylaxis of invasive Aspergillus and Candida infectionsPosaconazole Oral Suspension: 200 mg (5 mL) three times day.Duration of therapy is based on recovery from neutropenia or immunosuppression.Oropharyngeal Candidiasis (OPC)Posaconazole Oral Suspension:Loading dose: 100 mg (2.5 mL) twice day on the first day.Maintenance dose: 100 mg (2.5 mL) once day thereafter. Loading dose: day Maintenance dose: 13 daysOPC Refractory (rOPC) to Itraconazole and/or FluconazolePosaconazole Oral Suspension: 400 mg (10 mL) twice day.Duration of therapy is based on the severity of the patients underlying disease and clinical response.. 2.3 Dosing Regimen in Pediatric Patients (ages 13 to less than 18 years of age) The recommended dosing regimen of posaconazole oral suspension for pediatric patients ages 13 to less than 18 years of age is shown in Table [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)]. Table 3: Posaconazole Oral Suspension Dosing Regimens for Pediatric Patients (ages 13 to less than 18 years of age)IndicationLoading Dose (volume) and frequencyMaintenance Dose (volume) and frequencyDuration of TherapyProphylaxis of invasive Aspergillus and Candida infections200 mg (5 mL) three times day200 mg (5 mL) three times dayDuration of therapy is based on recovery from neutropenia or immunosuppression.Oropharyngeal Candidiasis (OPC)100 mg (2.5 mL) twice daily on the first day.100 mg (2.5 mL) once daily13 daysOPC Refractory (rOPC) to Itraconazole and/or Fluconazole400 mg (10 mL) twice daily 400 mg (10 mL) twice dailyDuration of therapy is based on the severity of the patients underlying disease and clinical response.. 2.6 Administration Instructions for Posaconazole Oral Suspension. oShake posaconazole oral suspension well before use. Administer with measured dosing spoon (see Figure 1) provided.Figure 1: measured dosing spoon is provided, marked for doses of 2.5 mL and mL. oRinse the spoon with water after each administration and before storage.oAdminister each dose of posaconazole oral suspension during or immediately (i.e., within 20 minutes) following full meal [see Clinical Pharmacology 12.3)].oFor patients who cannot eat full meal, posaconazole delayed-release tablets should be used instead of posaconazole oral suspension for the prophylaxis indication. Posaconzole delayed-release tablets provide higher plasma drug exposures than posaconazole oral suspension under fasted conditions [see Dosage and Administration 2.1)].oIn patients who cannot eat full meal and for whom posaconazole delayed-release tablets or posaconazole injection are not options, administer each dose of posaconazole oral suspension with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).oFor patients who cannot eat full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking posaconazole delayed-release tablets or posaconazole injection, an alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.. oShake posaconazole oral suspension well before use. Administer with measured dosing spoon (see Figure 1) provided.. oRinse the spoon with water after each administration and before storage.. oAdminister each dose of posaconazole oral suspension during or immediately (i.e., within 20 minutes) following full meal [see Clinical Pharmacology 12.3)].. oFor patients who cannot eat full meal, posaconazole delayed-release tablets should be used instead of posaconazole oral suspension for the prophylaxis indication. Posaconzole delayed-release tablets provide higher plasma drug exposures than posaconazole oral suspension under fasted conditions [see Dosage and Administration 2.1)].. oIn patients who cannot eat full meal and for whom posaconazole delayed-release tablets or posaconazole injection are not options, administer each dose of posaconazole oral suspension with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).. oFor patients who cannot eat full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking posaconazole delayed-release tablets or posaconazole injection, an alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.. Figure - Measured dosing spoon. 2.7 Non-substitutability between Posaconazole Oral Suspension and Other Formulations. Posaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration 2.2, 2.3)].. 2.9 Dosage Adjustments in Patients with Renal Impairment. The pharmacokinetics of posaconazole oral suspension are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Posaconazole oral suspension is available as white to off-white, cherry brandy flavored suspension in 4-ounce (120 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL).. Posaconazole oral suspension: 40 mg per mL (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is substrate of p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.Posaconazole is also strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole [see Clinical Pharmacology (12.3)].The following information was derived from data with posaconazole oral suspension or early tablet formulation unless otherwise noted [see Drug Interactions (7.9) and (7.13)].. Interaction DrugInteractionRifabutin, phenytoin, efavirenz, cimetidine, esomeprazoleAvoid 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)Fosamprenavir, metoclopramideMonitor 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. Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with posaconazole oral suspension results in decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. It is recommended to avoid concomitant use of cimetidine and esomeprazole with posaconazole oral suspension unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.No clinically relevant effects were observed when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. No dosage adjustment of posaconazole oral suspension is required when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine.. 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. Metoclopramide, when given with posaconazole oral suspension, decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. If metoclopramide is concomitantly administered with posaconazole oral suspension, it is recommended to closely monitor for breakthrough fungal infections.Loperamide does not affect posaconazole plasma concentrations after posaconazole oral suspension administration [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole oral suspension is required when loperamide and posaconazole oral suspension are used concomitantly.. 7.14 Glipizide. Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.. 7.16 Venetoclax Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities [see Contraindications (4.6), Warnings and Precautions (5.10)]. Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

GERIATRIC USE SECTION.

8.5 Geriatric Use. No overall differences in the safety of posaconazole oral suspension were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for posaconazole oral suspension in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].Of the 605 patients randomized to posaconazole oral suspension in the Posaconazole Oral Suspension Study and Study 2, 63 (10%) were >=65 years of age. In addition, 48 patients treated with greater than or equal to 800-mg/day posaconazole oral suspension in another indication were >=65 years of age. No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied Posaconazole Oral SuspensionPosaconazole oral suspension is available as white to off-white, cherry brandy flavored suspension in 4-ounce (120 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL).NDC 0054-0449-49: Bottle of 105 mLSupplied with each oral suspension bottle is plastic dosing spoon calibrated for measuring 2.5-mL and 5-mL doses. 16.2 Storage and Handling Store at 20 to 25C (68 to 77F); [See USP Controlled Room Temperature.] DO NOT FREEZE.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Posaconazole is an azole antifungal indicated as follows: oPosaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy as follows: (1.2) oPosaconazole oral suspension: adults and pediatric patients 13 years of age and older oPosaconazole oral suspension is indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in adult and pediatric patients aged 13 years and older. (1.3). oPosaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy as follows: (1.2) oPosaconazole oral suspension: adults and pediatric patients 13 years of age and older oPosaconazole oral suspension: adults and pediatric patients 13 years of age and older oPosaconazole oral suspension is indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in adult and pediatric patients aged 13 years and older. (1.3). 1.2 Prophylaxis of Invasive Aspergillus and Candida Infections. Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies 14.2)] as follows: oPosaconazole oral suspension: adults and pediatric patients 13 years of age and older. oPosaconazole oral suspension: adults and pediatric patients 13 years of age and older. 1.3 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole. Posaconazole oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information). Important Administration Instructions Advise patients to take each dose of posaconazole oral suspension during or immediately (i.e., within 20 minutes) following full meal. In patients who cannot eat full meal, each dose of posaconazole oral suspension should be administered with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in order to enhance absorption.Instruct patients that if they miss dose, they should take it as soon as they remember. However, if it is almost time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose. Drug InteractionsAdvise patients to inform their physician immediately if they:odevelop severe diarrhea or vomiting.oare currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.oare currently taking cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.oare taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole.Serious and Potentially Serious Adverse ReactionsAdvise patients to inform their physician immediately if they:onotice 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.oare pregnant, plan to become pregnant, or are nursing.ohave 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.ohave ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.The trademarks referenced herein are owned by their respective companies.Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50000256/05 Revised March 2022 odevelop severe diarrhea or vomiting.. oare currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.. oare currently taking cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.. oare taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole.. onotice 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.. oare pregnant, plan to become pregnant, or are nursing.. ohave 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.. ohave ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.

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 to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known. Antimicrobial Activity: Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Microorganisms:Aspergillus spp. and Candida spp. Susceptibility Testing: For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

NONCLINICAL TOXICOLOGY SECTION.

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

NURSING MOTHERS SECTION.

8.2 Lactation. Risk Summary:There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition.

OVERDOSAGE SECTION.

10 OVERDOSAGE. 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 twice daily 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.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 105 mL Bottle Carton NDC 0054-0449-49105 mL Posaconazole Oral Suspension 200 mg/5 mL Each mL contains 40 mg posaconazole. Rx Only 105 mL Bottle Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of posaconazole oral suspension for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 13 and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy.The safety and effectiveness of posaconazole oral suspension have been established for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients aged 13 years and older.Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. The safety and effectiveness of posaconazole oral suspension have not been established in pediatric patients younger than 13 years of age.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Exposure Response Relationship Prophylaxis: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), wide range of plasma exposures to posaconazole was noted following administration of posaconazole oral suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 17). lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.Table 17: Posaconazole Oral Suspension Exposure Analysis (Cavg) in Prophylaxis TrialsProphylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDSProphylaxis in GVHDHSCT recipients with GVHDCavg Range (ng/mL)Treatment FailureDefined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%)Cavg Range (ng/mL)Treatment Failure (%)Quartile 190 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 3,65017.5 Cavg the average posaconazole concentration when measured at steady state.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics General Pharmacokinetic Characteristics:Dose-proportional increases in plasma exposure (AUC) to posaconazole oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections.The mean (%CV) [min-max] posaconazole oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times day and 400 mg twice daily of the oral suspension are provided in Table 21. Table 21: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole Oral Suspension 200 mg Three Times Day and 400 mg Twice DailyDoseOral suspension administrationCavg (ng/mL)AUCAUC (0 to 24 hr) for 200 mg three times day and AUC (0 to 12 hr) for 400 mg twice daily (nghr/mL)CL/F (L/hr)V/F (L)t 1/2 (hr)200 mg three times dayHSCT recipients with GVHD (n=252)1,103 (67)[21.5 to 3650]NDNot done ND ND ND 200 mg three times dayNeutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215)583 (65)[89.7 to 2,200]15,900 (62)[4100 to 56,100]51.2 (54)[10.7 to 146]2425 (39)[828 to 5,702]37.2 (39)[19.1 to 148]400 mg twice dailyFebrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24 The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects. (n=23)723 (86)[6.70 to 2,256]9093 (80)[1,564 to 26,794]76.1 (78)[14.9 to 256]3088 (84)[407 to 13,140]31.7 (42)[12.4 to 67.3] Cavg the average posaconazole concentration when measured at steady stateAbsorption:Posaconazole oral suspension is absorbed with median Tmax of ~3 to hours. Steady-state plasma concentrations are attained at to 10 days following multiple-dose administration.Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when the oral suspension is administered with nonfat meal and approximately 4-times higher when administered with high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of posaconazole oral suspension 400 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when administered with liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 24). In addition, the effects of varying gastric administration conditions on the Cmax and AUC of posaconazole oral suspension in healthy volunteers have been investigated and are shown in Table 25.In order to assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole oral suspension during or immediately following full meal. In patients who cannot eat full meal, posaconazole oral suspension should be taken with liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).Table 24: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted ConditionsDose (mg)Cmax (ng/mL)Tmax Median [min-max].(hr)AUC (I)(nghr/mL)CL/F(L/hr)t 1/2 (hr)200 mg fasted(n=20)n=15 for AUC (I), CL/F, and 1/2 132 (50)[45 to 267]3.50[1.5 to 36The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between hrs and 36 hrs).]4179 (31)[2,705 to 7,269]51 (25)[28 to 74]23.5 (25)[15.3 to 33.7]200 mg nonfat(n=20) 378 (43)[131 to 834]4 [3 to 5]10,753 (35)[4,579 to 17,092]21 (39)[12 to 44]22.2 (18)[17.4 to 28.7]200 mg high fat(54 gm fat)(n=20) 512 (34)[241 to 1,016]5 [4 to 5]15,059 (26)[10,341 to 24,476]14 (24)[8.2 to 19]23.0 (19)[17.2 to 33.4]400 mg fasted(n=23)n=10 for AUC (I), CL/F, and 1/2 121 (75)[27 to 366]4 [2 to 12]5258 (48)[2,834 to 9,567]91 (40)[42 to 141]27.3 (26)[16.8 to 38.9]400 mg with liquid nutritional supplement(14 gm fat)(n=23) 355 (43)[145 to 720]5 [4 to 8]11,295 (40)[3,865 to 20,592]43 (56)[19 to 103]26.0 (19)[18.2 to 35.0]Table 25: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Posaconazole Oral Suspension in Healthy VolunteersIn subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when posaconazole was administered via an NG tube compared to when posaconazole was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when posaconazole is administered via an NG tube because lower plasma exposure may be associated with an increased risk of treatment failure. Study DescriptionAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.;90% CI of the ratio estimate)Change in AUC(ratio estimate;90% CI of the ratio estimate)400 mg single dose with high-fat meal relative to fasted state (n=12) minutes before high-fat meal96%(1.96; 1.48 to 2.59)111%(2.11; 1.60 to 2.78)During high-fat meal339%(4.39; 3.32 to 5.80)382%(4.82; 3.66 to 6.35)20 minutes after high-fat meal333%(4.33; 3.28 to 5.73)387%(4.87; 3.70 to 6.42)400 mg twice daily and 200 mg four times daily for days in fasted state and with liquid nutritional supplement (BOOST(R)) (n=12)400 mg twice daily with BOOST65%(1.65; 1.29 to 2.11)66%(1.66; 1.30 to 2.13)200 mg four times daily with BOOSTNo EffectNo EffectDivided daily dose from 400 mg twice daily to 200 mg four times daily for days regardless of fasted conditions or with BOOST (n=12)Fasted state136%(2.36; 1.84 to 3.02)161%(2.61; 2.04 to 3.35)With BOOST137%(2.37; 1.86 to 3.04)157%(2.57; 2.00 to 3.30)400-mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)Ginger ale92%(1.92; 1.51 to 2.44)70%(1.70; 1.43 to 2.03)Esomeprazole32%(0.68; 0.53 to 0.86)30%(0.70; 0.59 to 0.83)400-mg single dose with prokinetic agent (metoclopramide 10 mg three times day for days) BOOST or an antikinetic agent (loperamide 4-mg single dose) BOOST (n=12)With metoclopramide BOOST21%(0.79; 0.72 to 0.87)19%(0.81; 0.72 to 0.91)With loperamide BOOST3%(0.97; 0.88 to 1.07)11%(1.11; 0.99 to 1.25)400-mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)Via NG tubeNG nasogastric 19%(0.81; 0.71 to 0.91)23%(0.77; 0.69 to 0.86)Concomitant administration of posaconazole oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (See Table 26). Table 26: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Oral Suspension in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in MeanCmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Cimetidine(Alteration of gastric pH)400 mg twice daily 10 days200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 39%(0.61; 0.53 to 0.70) 39%(0.61; 0.54 to 0.69)Esomeprazole (Increase in gastric pH)The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide. 40 mg every morning 3 days400 mg (oral suspension) single dose 46%(0.54; 0.43 to 0.69) 32%(0.68; 0.57 to 0.81)Metoclopramide (Increase in gastric motility) 10 mg three times day 2 days400 mg (oral suspension) single dose 21%(0.79; 0.72 to 0.87) 19%(0.81; 0.72 to 0.91)Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 and ranged from 226 to 295 between studies and dose levels.Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.Metabolism: Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.Posaconazole is primarily metabolized via UDP glucuronidation (phase enzymes) and is substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27. Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in MeanCmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Efavirenz(UDP-G Induction)400 mg once daily 10 and 20 days400 mg (oral suspension) twice daily 10 and 20 days45%(0.55; 0.47 to 0.66) 50%(0.50; 0.43 to 0.60)Fosamprenavir (unknown mechanism)700 mg twice daily 10 days200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily 8 Days21%0.79 (0.71 to 0.89)23%0.77 (0.68 to 0.87)Rifabutin(UDP-G Induction)300 mg once daily 17 days200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 43%(0.57; 0.43 to 0.75) 49%(0.51; 0.37 to 0.71)Phenytoin(UDP-G Induction)200 mg once daily 10 days200 mg (tablets) once daily 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 28 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and 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 estimateThe Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Sirolimus2 mg single oral dose400 mg (oral suspension) twice daily 16 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) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. cyclosporine whole blood trough concentrationsCyclosporine dose reductions of up to 29% were requiredTacrolimus0.05 mg/kg single oral dose400 mg (oral suspension) twice daily 7 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) once daily 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) once daily 13 daysSimvastatin 1041%(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) twice daily 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) twice daily 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) once daily 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) twice daily 7 days 138%(2.38; 2.13 to 2.66) 397%(4.97; 4.46 to 5.54)Rifabutin300 mg once daily 17 days200 mg (tablets) once daily 10 days 31%(1.31; 1.10 to 1.57) 72%(1.72;1.51 to 1.95)Phenytoin200 mg once daily PO 10 days200 mg (tablets) once daily 10 days 16%(1.16; 0.85 to 1.57) 16%(1.16; 0.84 to 1.59)Ritonavir100 mg once daily 14 days400 mg (oral suspension)twice daily 7 days 49%(1.49; 1.04 to 2.15) 80%(1.8;1.39 to 2.31)Atazanavir300 mg once daily 14 days400 mg (oral suspension) twice daily 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 once daily 14 days400 mg (oral suspension) twice daily 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 once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg once daily.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 oral suspension is eliminated with mean half-life (t 1/2 of 35 hours (range: 20 to 66 hours). Specific Populations:No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Race/Ethnicity: In population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure. Patients Weighing More Than 120 kg: Weight has clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)]. Pediatric Patients:The population pharmacokinetic analysis of posaconazole in pediatric patients suggests that age, sex, renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics of posaconazole.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. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (>=18 years of age). In study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with posaconazole oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary:Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses >=1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of >= times the clinical exposure caused an increase in resorptions in these rabbits (see Data ). Based on animal data, advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. Data:Animal Data: Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days through 15) at doses >=27 mg/kg (>=1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, reduction in body weight gain of females and reduction in litter size were seen.

RECENT MAJOR CHANGES SECTION.

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

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information. Posaconazole Oral Suspension(poe sa kon zole)Rx onlyWhat is posaconazole oral suspensionPosaconazole oral suspension is prescription medicine used in adults and children to help prevent or treat fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Posaconazole is used in people who have an increased chance of getting these infections due to weak immune system. These include people who have had hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with low white blood cell count due to chemotherapy for blood cancers (hematologic malignancies).Posaconazole oral suspension is used for: oprevention of fungal infections in adults and children 13 years of age and older.Posaconazole oral suspension is also used to treat fungal infection called thrush caused by Candida in your mouth or throat area. Posaconazole oral suspension can be used as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked.Posaconazole oral suspension is for adults and children over 13 years of age and older. Who should not take posaconazole oral suspensionDo not take posaconazole if you:oare allergic to posaconazole, any of the ingredients in posaconazole, or other azole antifungal medicines. See the end of this leaflet for complete list of ingredients in posaconazole.oare taking any of the following medicines: osirolimusopimozideoquinidineocertain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)oergot alkaloids (ergotamine, dihydroergotamine)ohave chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. Do not start taking new medicine without talking to your healthcare provider or pharmacist.What should tell my healthcare provider before taking posaconazole oral suspensionBefore you take posaconazole, tell your healthcare provider if you:oare taking certain medicines that lower your immune system like cyclosporine or tacrolimus.oare 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.oare taking midazolam, hypnotic and sedative medicine.oare taking vincristine, vinblastine and other vinca alkaloids (medicines used to treat cancer).oare taking venetoclax, medicine used to treat cancer.ohave or had liver problems.ohave or had kidney problems.ohave or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.oare pregnant or plan to become pregnant. It is not known if posaconazole will harm your unborn baby.oare breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole or breastfeed. You should not do both.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Posaconazole can affect the way other medicines work, and other medicines can affect the way posaconazole works, and can cause serious side effects. Especially tell your healthcare provider if you take:orifabutin or phenytoin. If you are taking these medicines, you should not take posaconazole oral suspension.ocimetidine or esomeprazole. If you are taking these medicines, you should not take posaconazole oral suspension.Ask your healthcare provider or pharmacist for list of these medicines if you are not sure.Know the medicines you take. Keep list of them with you to show your healthcare provider or pharmacist when you get new medicine.How will take posaconazole oral suspensionoDo not switch between posaconazole oral suspension and posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension.oTake posaconazole exactly as your healthcare provider tells you to take it.oYour healthcare provider will tell you how much posaconazole to take and when to take it.oTake posaconazole for as long as your healthcare provider tells you to take it.oIf you take too much posaconazole, call your healthcare provider or go to the nearest hospital emergency room right away.oPosaconazole oral suspension:oShake posaconazole oral suspension well before use.oTake each dose of posaconazole oral suspension during or within 20 minutes after full meal. If you cannot eat full meal, take each dose of posaconazole oral suspension with liquid nutritional supplement or an acidic carbonated beverage, like ginger ale.oA measured dosing spoon comes with your posaconazole oral suspension and is marked for doses of 2.5 mL and mL. See Figure and B.Figure AFigure BoRinse the spoon with water after each dose of posaconazole oral suspension and before you store it away.oIf you miss dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take double dose to make up for the missed dose.Follow the instructions from your healthcare provider on how much posaconazole you should take and when to take it.What are the possible side effects of posaconazole oral suspensionPosaconazole may cause serious side effects, including:odrug interactions with cyclosporine or tacrolimus. If you take posaconazole with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.oproblems 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 oral suspension, 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. ochanges in body salt (electrolytes) levels in your blood. Your healthcare provider should check your electrolytes while you are taking posaconazole.oliver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of posaconazole. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole. Call your healthcare provider right away if you have any of the following symptoms of liver problems:oitchy skinonausea or vomitingoyellowing of your eyes or skinofeeling very tiredoflu-like symptomsoincreased amounts of midazolam in your blood. If you take posaconazole with midazolam, posaconazole increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole.The most common side effects of posaconazole include:odiarrheaonauseaofeverovomitingoheadacheocoughingolow potassium levels in the bloodIf you take posaconazole oral suspension, tell your healthcare provider right away if you have diarrhea or vomiting.Tell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of posaconazole. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store posaconazole oral suspensionoStore posaconazole oral suspension at room temperature between 68F to 77F (20C to 25C).oDo not freeze posaconazole oral suspension.Safely throw away medicine that is out of date or no longer needed.Keep posaconazole and all medicines out of the reach of children.General information about the safe and effective use of posaconazole.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use posaconazole for condition for which it was not prescribed. Do not give posaconazole to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about posaconazole that is written for health professionals. What are the ingredients in posaconazole oral suspensionActive ingredient: posaconazole Inactive ingredients: cherry-brandy flavor, citric acid monohydrate, hydroxyethyl cellulose, glycerin, polyoxyl 35 castor oil, simethicone emulsion, sodium benzoate, sodium citrate, sorbitol solution, titanium dioxide, and water.The trademarks depicted in this piece are owned by their respective companies.This Patient Information has been approved by the U.S. Food and Drug Administration.Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50000256/05 Revised March 2022 oprevention of fungal infections in adults and children 13 years of age and older.. oare allergic to posaconazole, any of the ingredients in posaconazole, or other azole antifungal medicines. See the end of this leaflet for complete list of ingredients in posaconazole.. oare taking any of the following medicines: osirolimus. opimozide. oquinidine. ocertain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin). oergot alkaloids (ergotamine, dihydroergotamine). ohave chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.. oare taking certain medicines that lower your immune system like cyclosporine or tacrolimus.. oare 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.. oare taking midazolam, hypnotic and sedative medicine.. oare taking vincristine, vinblastine and other vinca alkaloids (medicines used to treat cancer).. oare taking venetoclax, medicine used to treat cancer.. ohave or had liver problems.. ohave or had kidney problems.. ohave or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.. oare pregnant or plan to become pregnant. It is not known if posaconazole will harm your unborn baby.. oare breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole or breastfeed. You should not do both.. orifabutin or phenytoin. If you are taking these medicines, you should not take posaconazole oral suspension.. ocimetidine or esomeprazole. If you are taking these medicines, you should not take posaconazole oral suspension.. oDo not switch between posaconazole oral suspension and posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension.. oTake posaconazole exactly as your healthcare provider tells you to take it.. oYour healthcare provider will tell you how much posaconazole to take and when to take it.. oTake posaconazole for as long as your healthcare provider tells you to take it.. oIf you take too much posaconazole, call your healthcare provider or go to the nearest hospital emergency room right away.. oPosaconazole oral suspension:. oShake posaconazole oral suspension well before use.. oTake each dose of posaconazole oral suspension during or within 20 minutes after full meal. If you cannot eat full meal, take each dose of posaconazole oral suspension with liquid nutritional supplement or an acidic carbonated beverage, like ginger ale.. oA measured dosing spoon comes with your posaconazole oral suspension and is marked for doses of 2.5 mL and mL. See Figure and B.. oRinse the spoon with water after each dose of posaconazole oral suspension and before you store it away.. oIf you miss dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take double dose to make up for the missed dose.. odrug interactions with cyclosporine or tacrolimus. If you take posaconazole with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.. oproblems 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 oral suspension, 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. ochanges in body salt (electrolytes) levels in your blood. Your healthcare provider should check your electrolytes while you are taking posaconazole.. oliver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of posaconazole. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole. Call your healthcare provider right away if you have any of the following symptoms of liver problems:. oitchy skin. onausea or vomiting. oyellowing of your eyes or skin. ofeeling very tired. oflu-like symptoms. oincreased amounts of midazolam in your blood. If you take posaconazole with midazolam, posaconazole increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole.. odiarrhea. onausea. ofever. ovomiting. oheadache. ocoughing. olow potassium levels in the blood. oStore posaconazole oral suspension at room temperature between 68F to 77F (20C to 25C).. oDo not freeze posaconazole oral suspension.. Figure - Dosing spoon. Figure - Dosing Spoon.

SPL UNCLASSIFIED SECTION.

1.2 Prophylaxis of Invasive Aspergillus and Candida Infections. Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies 14.2)] as follows: oPosaconazole oral suspension: adults and pediatric patients 13 years of age and older. oPosaconazole oral suspension: adults and pediatric patients 13 years of age and older.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling Store at 20 to 25C (68 to 77F); [See USP Controlled Room Temperature.] DO NOT FREEZE.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oPregnancy: Based on animal data, may cause fetal harm. (8.1 oPediatrics: Safety and effectiveness in patients younger than 13 years of age have not been established. (8.4)oSevere Renal Impairment: Monitor closely for breakthrough fungal infections. (8.6 . oPregnancy: Based on animal data, may cause fetal harm. (8.1 . oPediatrics: Safety and effectiveness in patients younger than 13 years of age have not been established. (8.4). oSevere Renal Impairment: Monitor closely for breakthrough fungal infections. (8.6 . 8.1 Pregnancy. Risk Summary:Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses >=1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of >= times the clinical exposure caused an increase in resorptions in these rabbits (see Data ). Based on animal data, advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. Data:Animal Data: Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days through 15) at doses >=27 mg/kg (>=1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, reduction in body weight gain of females and reduction in litter size were seen. 8.2 Lactation. Risk Summary:There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of posaconazole oral suspension for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 13 and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy.The safety and effectiveness of posaconazole oral suspension have been established for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients aged 13 years and older.Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. The safety and effectiveness of posaconazole oral suspension have not been established in pediatric patients younger than 13 years of age.. 8.5 Geriatric Use. No overall differences in the safety of posaconazole oral suspension were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for posaconazole oral suspension in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].Of the 605 patients randomized to posaconazole oral suspension in the Posaconazole Oral Suspension Study and Study 2, 63 (10%) were >=65 years of age. In addition, 48 patients treated with greater than or equal to 800-mg/day posaconazole oral suspension in another indication were >=65 years of age. No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.. 8.6 Renal Impairment. Following single-dose administration of 400 mg of the posaconazole 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)]. 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 oral suspension 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)].. 8.8 Gender. The pharmacokinetics of posaconazole are comparable in males and females. No adjustment in the dosage of posaconazole is necessary based on gender.. 8.9 Race. The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of posaconazole is necessary based on race.. 8.10 Weight. Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oCalcineurin-Inhibitor Toxicity: Posaconazole increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. (5.1)oArrhythmias 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)oElectrolyte Disturbances: Monitor and correct, especially those involving potassium (K+), magnesium (Mg++), and calcium (Ca++), before and during posaconazole therapy. (5.3)oHepatic Toxicity: Elevations in liver tests may occur. Discontinuation should be considered in patients who develop abnormal liver tests or monitor liver tests during treatment. (5.4)oConcomitant Use with Midazolam: Posaconazole can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. (5.6, 7.5)oVincristine 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) oBreakthrough Fungal Infections: Monitor patients with severe diarrhea or vomiting when receiving posaconazole oral suspension. (5.9) oVenetoclax Toxicity: Concomitant administration of posaconazole with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. (4.6, 5.10, 7.16) oCalcineurin-Inhibitor Toxicity: Posaconazole increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. (5.1). oArrhythmias 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). oElectrolyte Disturbances: Monitor and correct, especially those involving potassium (K+), magnesium (Mg++), and calcium (Ca++), before and during posaconazole therapy. (5.3). oHepatic Toxicity: Elevations in liver tests may occur. Discontinuation should be considered in patients who develop abnormal liver tests or monitor liver tests during treatment. (5.4). oConcomitant Use with Midazolam: Posaconazole can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. (5.6, 7.5). oVincristine 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) oBreakthrough Fungal Infections: Monitor patients with severe diarrhea or vomiting when receiving posaconazole oral suspension. (5.9) oVenetoclax Toxicity: Concomitant administration of posaconazole with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. (4.6, 5.10, 7.16) 5.1 Calcineurin-Inhibitor Toxicity. Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.. 5.2 Arrhythmias and QT Prolongation. Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole.Results from multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18 to 85 years of age) administered posaconazole oral suspension 400 mg twice daily with high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was -5 msec following administration of the recommended clinical dose. decrease in the QTc(F) interval (-3 msec) was also observed in small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (-8 msec). No healthy subject administered posaconazole had QTc(F) interval >=500 msec or an increase >=60 msec in their QTc(F) interval from baseline.Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)]. 5.3 Electrolyte Disturbances Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.. 5.4 Hepatic Toxicity. Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the posaconazole oral suspension 800 mg daily (400 mg twice daily or 200 mg four times day) in clinical trials.Liver tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.. 5.5 Renal Impairment. Due to the variability in exposure with posaconazole oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration 2.9 and Use in Specific Populations (8.6)]. 5.6 Midazolam Toxicity. Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].. 5.7 Vincristine Toxicity Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.10)].. 5.9 Breakthrough Fungal Infections Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole.. 5.10 Venetoclax Toxicity Concomitant administration of posaconazole, strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of posaconazole during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications 4.6)]. Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax [see Drug Interactions 7.16)]. Refer to the venetoclax prescribing information for dosing instructions.