olized by cyp3a4 consider dosage adjustment and monitor for adverse effects and toxicity ( 7.1 , 7.10 , 7.11 ) digoxin monitor digoxin plasma concentrations ( 7.12 ) fosamprenavir monitor for breakthrough fungal infections ( 7.6 , 7.13 ) 7.1 immunosuppressants metabolized by cyp3a4 sirolimus: concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. therefore, posaconazole is contraindicated with sirolimus [see contraindications (4.2) and clinical pharmacology (12.3) ]. tacrolimus: posaconazole has been shown to significantly increase the c max and auc of tacrolimus. at initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see warnings and precautions (5.1) and clinical pharmacology (12.3) ]. cyclosporine: posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. it is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see warnings and precautions (5.1) and clinical pharmacology (12.3) ]. 7.2 cyp3a4 substrates concomitant administration of posaconazole with cyp3a4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to qtc prolongation and cases of torsades de pointes. therefore, posaconazole is contraindicated with these drugs [see contraindications (4.3) and warnings and precautions (5.2) ]. 7.3 hmg-coa reductase inhibitors (statins) primarily metabolized through cyp3a4 concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. therefore, posaconazole is contraindicated with hmg-coa reductase inhibitors primarily metabolized through cyp3a4 [see contraindications (4.4) and clinical pharmacology (12.3) ]. 7.4 ergot alkaloids most of the ergot alkaloids are substrates of cyp3a4. posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. therefore, posaconazole is contraindicated with ergot alkaloids [see contraindications (4.5) ]. 7.5 benzodiazepines metabolized by cyp3a4 concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. concomitant use of posaconazole and other benzodiazepines metabolized by cyp3a4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by cyp3a4 and benzodiazepine receptor antagonists must be available to reverse these effects [see warnings and precautions (5.6) and clinical pharmacology (12.3) ]. 7.6 anti-hiv drugs efavirenz: efavirenz induces udp-glucuronidase and significantly decreases posaconazole plasma concentrations [see clinical pharmacology (12.3) ]. it is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks. ritonavir and atazanavir: ritonavir and atazanavir are metabolized by cyp3a4 and posaconazole increases plasma concentrations of these drugs [see clinical pharmacology (12.3) ]. frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole. fosamprenavir: combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see clinical pharmacology (12.3) ]. 7.7 rifabutin rifabutin induces udp-glucuronidase and decreases posaconazole plasma concentrations. rifabutin is also metabolized by cyp3a4. therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations [see clinical pharmacology (12.3) ]. concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. however, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended. 7.8 phenytoin phenytoin induces udp-glucuronidase and decreases posaconazole plasma concentrations. phenytoin is also metabolized by cyp3a4. therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see clinical pharmacology (12.3) ]. concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. however, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered . 7.9 gastric acid suppressors/neutralizers no clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, h 2 -receptor antagonists and proton pump inhibitors [see clinical pharmacology (12.3) ]. no dosage adjustment of posaconazole delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used with antacids, h 2 -receptor antagonists and proton pump inhibitors. 7.10 vinca alkaloids most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of cyp3a4. concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions [see warnings and precautions (5.7) ]. posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. 7.11 calcium channel blockers metabolized by cyp3a4 posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by cyp3a4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. dose reduction of calcium channel blockers may be needed. 7.12 digoxin increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. therefore, monitoring of digoxin plasma concentrations is recommended during coadministration. 7.13 gastrointestinal motility agents concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole [see clinical pharmacology (12.3) ]. no dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide. 7.14 glipizide although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.

.6 , 7.5 ) vincristine toxicity: concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. ( 5.7 , 7.10 ) 5.1 calcineurin-inhibitor drug interactions concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see drug interactions (7.1) and clinical pharmacology (12.3) ]. nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly. 5.2 arrhythmias and qt prolongation some azoles, including posaconazole, have been associated with prolongation of the qt interval on the electrocardiogram. in addition, cases of torsades de pointes have been reported in patients taking posaconazole. results from a multiple time-matched ecg analysis in healthy volunteers did not show any increase in the mean of the qtc interval. multiple, time-matched ecgs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18 to 85 years of age) administered posaconazole oral suspension 400 mg bid with a high-fat meal. in this pooled analysis, the mean qtc (fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. a decrease in the qtc(f) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. the placebo-adjusted mean maximum qtc(f) interval change from baseline was <0 msec (–8 msec). no healthy subject administered posaconazole had a qtc(f) interval ≥500 msec or an increase ≥60 msec in their qtc(f) interval from baseline. posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. do not administer with drugs that are known to prolong the qtc interval and are metabolized through cyp3a4 [see contraindications (4.3) and drug interactions (7.2) ] . 5.3 electrolyte disturbances electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy. 5.4 hepatic toxicity hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (alt), aspartate aminotransferase (ast), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. the elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. these severe hepatic reactions were seen primarily in subjects receiving the posaconazole oral suspension 800 mg daily (400 mg bid or 200 mg qid) in clinical trials. liver function tests should be evaluated at the start of and during the course of posaconazole therapy. patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole. 5.5 renal impairment due to the variability in exposure with posaconazole delayed-release tablets, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see dosage and administration (2.6) and use in specific populations (8.6) ] . 5.6 use with midazolam concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see drug interactions (7.5) and clinical pharmacology (12.3) ]. 5.7 vincristine toxicity concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see drug interactions (7.10) ].

and administration (2.3) and clinical pharmacology (12.3) ]. patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole delayed-release tablets. 2.3 dosage and administration instructions for posaconazole delayed-release tablets dosage: table 4: dosage for posaconazole delayed-release tablets indication dose and duration of therapy prophylaxis of invasive aspergillus and candida infections loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. duration of therapy is based on recovery from neutropenia or immunosuppression. administration instructions for posaconazole delayed-release tablets: swallow tablets whole. do not divide, crush, or chew. administer posaconazole delayed-release tablets with food to enhance the oral absorption of posaconazole and optimize plasma concentrations [see clinical pharmacology (12.3) ]. posaconazole delayed-release tablets should be used only for the prophylaxis indication. posaconazole delayed-release tablets generally provide higher plasma drug exposures than posaconazole oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication. 2.5 non-interchangeability between posaconazole delayed-release tablets and posaconazole oral suspension posaconazole delayed-release tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation. therefore, follow the specific dosage recommendations for each of the formulations [see dosage and administration (2.3) ] . 2.6 dosage adjustments in patients with renal impairment the pharmacokinetics of posaconazole delayed-release tablets is not significantly affected by renal impairment. therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

osaconazole delayed-release tablets were generally similar to that reported in trials of posaconazole oral suspension. the safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical trials. patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole delayed-release tablets when given as antifungal prophylaxis (delayed-release tablet study 1). patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, gvhd, and post hsct. this patient population was 62% male, had a mean age of 51 years (range 19 to 78 years, 17% of patients were ≥65 years of age), and were 93% white and 16% hispanic. posaconazole therapy was given for a median duration of 28 days. twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on day 1 in each cohort). table 7 presents treatment-emergent adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in posaconazole delayed-release tablet study. table 7: posaconazole delayed-release tablet study 1: number (%) of subjects treated with 300 mg daily dose reporting treatment-emergent adverse reactions: frequency of at least 10% body system preferred term posaconazole delayed-release tablet (300 mg) (n=210) subjects reporting any adverse reaction 201 (99) blood and lymphatic system disorder anemia 22 (10) thrombocytopenia 29 (14) gastrointestinal disorders abdominal pain 23 (11) constipation 20 (10) diarrhea 61 (29) nausea 56 (27) vomiting 28 (13) general disorders and administration site conditions asthenia 20 (10) chills 22 (10) mucosal inflammation 29 (14) edema peripheral 33 (16) pyrexia 59 (28) metabolism and nutrition disorders hypokalemia 46 (22) hypomagnesemia 20 (10) nervous system disorders headache 30 (14) respiratory, thoracic and mediastinal disorders cough 35 (17) epistaxis 30 (14) skin and subcutaneous tissue disorders rash 34 (16) vascular disorders hypertension 23 (11) the most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea. the most common adverse reaction leading to discontinuation of posaconazole delayed-release tablets 300 mg once daily was nausea (2%). 6.2 postmarketing experience the following adverse reaction has been identified during the post-approval use of posaconazole. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. endocrine disorders: pseudoaldosteronism

olized by cyp3a4 consider dosage adjustment and monitor for adverse effects and toxicity ( 7.1 , 7.10 , 7.11 ) digoxin monitor digoxin plasma concentrations ( 7.12 ) fosamprenavir monitor for breakthrough fungal infections ( 7.6 , 7.13 ) 7.1 immunosuppressants metabolized by cyp3a4 sirolimus: concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. therefore, posaconazole is contraindicated with sirolimus [see contraindications (4.2) and clinical pharmacology (12.3) ]. tacrolimus: posaconazole has been shown to significantly increase the c max and auc of tacrolimus. at initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see warnings and precautions (5.1) and clinical pharmacology (12.3) ]. cyclosporine: posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. it is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see warnings and precautions (5.1) and clinical pharmacology (12.3) ]. 7.2 cyp3a4 substrates concomitant administration of posaconazole with cyp3a4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to qtc prolongation and cases of torsades de pointes. therefore, posaconazole is contraindicated with these drugs [see contraindications (4.3) and warnings and precautions (5.2) ]. 7.3 hmg-coa reductase inhibitors (statins) primarily metabolized through cyp3a4 concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. therefore, posaconazole is contraindicated with hmg-coa reductase inhibitors primarily metabolized through cyp3a4 [see contraindications (4.4) and clinical pharmacology (12.3) ]. 7.4 ergot alkaloids most of the ergot alkaloids are substrates of cyp3a4. posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. therefore, posaconazole is contraindicated with ergot alkaloids [see contraindications (4.5) ]. 7.5 benzodiazepines metabolized by cyp3a4 concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. concomitant use of posaconazole and other benzodiazepines metabolized by cyp3a4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by cyp3a4 and benzodiazepine receptor antagonists must be available to reverse these effects [see warnings and precautions (5.6) and clinical pharmacology (12.3) ]. 7.6 anti-hiv drugs efavirenz: efavirenz induces udp-glucuronidase and significantly decreases posaconazole plasma concentrations [see clinical pharmacology (12.3) ]. it is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks. ritonavir and atazanavir: ritonavir and atazanavir are metabolized by cyp3a4 and posaconazole increases plasma concentrations of these drugs [see clinical pharmacology (12.3) ]. frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole. fosamprenavir: combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see clinical pharmacology (12.3) ]. 7.7 rifabutin rifabutin induces udp-glucuronidase and decreases posaconazole plasma concentrations. rifabutin is also metabolized by cyp3a4. therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations [see clinical pharmacology (12.3) ]. concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. however, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended. 7.8 phenytoin phenytoin induces udp-glucuronidase and decreases posaconazole plasma concentrations. phenytoin is also metabolized by cyp3a4. therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see clinical pharmacology (12.3) ]. concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. however, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered . 7.9 gastric acid suppressors/neutralizers no clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, h 2 -receptor antagonists and proton pump inhibitors [see clinical pharmacology (12.3) ]. no dosage adjustment of posaconazole delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used with antacids, h 2 -receptor antagonists and proton pump inhibitors. 7.10 vinca alkaloids most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of cyp3a4. concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions [see warnings and precautions (5.7) ]. posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. 7.11 calcium channel blockers metabolized by cyp3a4 posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by cyp3a4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. dose reduction of calcium channel blockers may be needed. 7.12 digoxin increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. therefore, monitoring of digoxin plasma concentrations is recommended during coadministration. 7.13 gastrointestinal motility agents concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole [see clinical pharmacology (12.3) ]. no dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide. 7.14 glipizide although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.

litter size, and reduced body weight gain of females were seen at doses 5 times the exposure achieved with the 400 mg twice daily oral suspension regimen. doses of ≥ 3 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 a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data animal data posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (gestational days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). the no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. no malformations were seen in rabbits dosed during organogenesis (gestational days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). in the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5. times the clinical exposure) caused an increase in resorptions. in rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen. 8.2 lactation risk summary there are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. posaconazole is excreted in the milk of lactating rats. when a drug is present in animal milk, it is likely that the drug will be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of posaconazole delayed-release tablets has been established in the age groups 13 to 17 years of age. use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adults. the safety and effectiveness of posaconazole in pediatric patients below the age of 13 years (birth to 12 years) have not been established. a total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of posaconazole oral suspension for prophylaxis of invasive fungal infections. the safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state average posaconazole concentration (c avg ) was similar between these patients and adults (≥18 years of age). in a study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with posaconazole oral suspension, the exposure target of steady-state posaconazole c avg between 500 ng/ml and less than 2,500 ng/ml was attained in approximately 50% of patients instead of the pre-specified 90% of patients. 8.5 geriatric use of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age. the pharmacokinetics of posaconazole delayed-release tablets are comparable in young and elderly subjects. no overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients. no overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out. 8.6 renal impairment following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild (egfr: 50 to 80 ml/min/1.73 m 2 , n=6) or moderate (egfr: 20 to 49 ml/min/1.73 m 2 , n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. in subjects with severe renal impairment (egfr: <20 ml/min/1.73 m 2 ), the mean plasma exposure (auc) was similar to that in patients with normal renal function (egfr: >80 ml/min/1.73 m 2 ); however, the range of the auc estimates was highly variable (cv=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (cv<40%). due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see dosage and administration (2) ]. similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets. 8.7 hepatic impairment after a 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 c max was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. the mean apparent oral clearance (cl/f) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. the elimination half-life (t ½ ) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively. it is recommended that no dose adjustment of posaconazole is needed in patients with mild to severe hepatic impairment (child-pugh class a, b, or c) [see dosage and administration (2) and warnings and precautions (5.4) ]. similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets. 8.8 gender the pharmacokinetics of posaconazole are comparable in men and women. no adjustment in the dosage of posaconazole is necessary based on gender. 8.9 race the pharmacokinetic profile of posaconazole is not significantly affected by race. no adjustment in the dosage of posaconazole is necessary based on race. 8.10 weight pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. it is, therefore, suggested to closely monitor for breakthrough fungal infections.

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 a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data animal data posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (gestational days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). the no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. no malformations were seen in rabbits dosed during organogenesis (gestational days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). in the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5. times the clinical exposure) caused an increase in resorptions. in rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.

h posaconazole oral suspension, the exposure target of steady-state posaconazole c avg between 500 ng/ml and less than 2,500 ng/ml was attained in approximately 50% of patients instead of the pre-specified 90% of patients.

xposure analysis (c avg ) in prophylaxis trials prophylaxis in aml/mds neutropenic patients who were receiving cytotoxic chemotherapy for aml or mds prophylaxis in gvhd hsct recipients with gvhd c avg range (ng/ml) treatment failure defined as treatment discontinuation, use of empiric systemic antifungal therapy (saf), or occurrence of breakthrough invasive fungal infections (%) c avg range (ng/ml) treatment failure (%) quartile 1 90 to 322 54.7 22 to 557 44.4 quartile 2 322 to 490 37.0 557 to 915 20.6 quartile 3 490 to 734 46.8 915 to 1,563 17.5 quartile 4 734 to 2,200 27.8 1,563 to 3,650 17.5 c avg = the average posaconazole concentration when measured at steady state 12.3 pharmacokinetics general pharmacokinetic characteristics posaconazole delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. the mean pharmacokinetic parameters of posaconazole at steady state following administration of posaconazole delayed-release tablets 300 mg twice daily (bid) on day 1, then 300 mg once daily (qd) thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for aml or mds or hsct recipients with gvhd are shown in table 15. table 15: arithmetic mean (%cv) of steady state pk parameters in healthy volunteers and patients following administration of posaconazole delayed-release tablets (300 mg) 300 mg bid on day 1, then 300 mg qd thereafter n auc 0-24 hr (ng∙hr/ml) c av c av = time-averaged concentrations (i.e., auc0-24 hr/24hr) (ng/ml) c max (ng/ml) c min (ng/ml) t max median (minimum-maximum) (hr) t 1/2 (hr) cl/f (l/hr) healthy volunteers 12 51,618 (25) 2,151 (25) 2,764 (21) 1,785 (29) 4 (3 to 6) 31 (40) 7.5 (26) patients 50 37,900 (42) 1,580 (42) 2,090 (38) 1,310 (50) 4 (1.3 to 8.3) - 9.39 (45) cv = coefficient of variation expressed as a percentage (%cv); auc 0-t = area under the plasma concentration-time curve from time zero to 24 hr; c max = maximum observed concentration; c min = minimum observed plasma concentration; t max = time of maximum observed concentration; t ½ = terminal phase half-life; cl /f = apparent total body clearance absorption: when given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with a median t max of 4 to 5 hours. steady-state plasma concentrations are attained by day 6 at the 300 mg dose (qd after bid loading dose at day 1). the absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. the c max and auc of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see table 17 ). in order to enhance the oral absorption of posaconazole and optimize plasma concentrations, posaconazole delayed-release tablets should be administered with food. table 17: statistical comparison of plasma pharmacokinetics of posaconazole following single oral dose administration of 300 mg posaconazole delayed-release tablet to healthy subjects under fasting and fed conditions fasting conditions fed conditions (high fat meal) 48.5 g fat fed/fasting pharmacokinetic parameter n mean (%cv) n mean (%cv) gmr (90% ci) c max (ng/ml) 14 935 (34) 16 1,060 (25) 1.16 (0.96, 1.41) auc 0-72hr (hr∙ng/ml) 14 26,200 (28) 16 38,400 (18) 1.51 (1.33, 1.72) t max median (min, max) reported for tmax (hr) 14 5.00 (3.00, 8.00) 16 6.00 (5.00, 24.00) n/a gmr=geometric least-squares mean ratio; ci=confidence interval concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric ph or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see table 18 ). table 18: the effect of concomitant medications that affect the gastric ph and gastric motility on the pharmacokinetics of posaconazole delayed-release tablets in healthy volunteers coadministered drug administration arms change in c max (ratio estimate ratio estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for cmax or auc0-last. ; 90% ci of the ratio estimate) change in auc 0-last (ratio estimate ; 90% ci of the ratio estimate) mylanta ® ultimate strength liquid (increase in gastric ph) 25.4 meq/5 ml, 20 ml ↑6% (1.06; 0.90 to 1.26)↑ ↑4% (1.04; 0.90 to 1.20) ranitidine (zantac ® ) (alteration in gastric ph) 150 mg (morning dose of 150 mg ranitidine bid) ↑4% (1.04; 0.88 to 1.23)↑ ↓3% (0.97; 0.84 to 1.12) esomeprazole (nexium ® ) (increase in gastric ph) 40 mg (qam 5 days, day -4 to 1) ↑2% (1.02; 0.88 to 1.17)↑ ↑5% (1.05; 0.89 to 1.24) metoclopramide (reglan ® ) (increase in gastric motility) 15 mg four times daily during 2 days (day -1 and 1) ↓14% (0.86, 0.73,1.02) ↓7% (0.93, 0.803,1.07) distribution: the mean volume of distribution of posaconazole after intravenous solution administration was 261 l and ranged from 226 to 295 l between studies and dose levels. posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin. metabolism: posaconazole primarily circulates as the parent compound in plasma. of the circulating metabolites, the majority are glucuronide conjugates formed via udp glucuronidation (phase 2 enzymes). posaconazole does not have any major circulating oxidative (cyp450 mediated) metabolites. the excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. posaconazole is primarily metabolized via udp glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (p-gp) efflux. therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. a summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in table 22. table 22: summary of the effect of coadministered drugs on posaconazole in healthy volunteers coadministered drug (postulated mechanism of interaction) coadministered drug dose/schedule posaconazole dose/schedule effect on bioavailability of posaconazole change in mean c max (ratio estimate ratio 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 qd × 10 and 20 days 400 mg (oral suspension) bid × 10 and 20 days ↓45% (0.55; 0.47 to 0.66) ↓ 50% (0.50; 0.43 to 0.60) fosamprenavir (unknown mechanism) 700 mg bid × 10 days 200 mg qd on the 1 st day, 200 mg bid on the 2 nd day, then 400 mg bid × 8 days ↓21% 0.79 (0.71 to 0.89) ↓23% 0.77 (0.68 to 0.87) rifabutin (udp-g induction) 300 mg qd × 17 days 200 mg (tablets) qd × 10 days the tablet refers to a non-commercial tablet formulation without polymer. ↓ 43% (0.57; 0.43 to 0.75) ↓ 49% (0.51; 0.37 to 0.71) phenytoin (udp-g induction) 200 mg qd × 10 days 200 mg (tablets) qd × 10 days ↓ 41% (0.59; 0.44 to 0.79) ↓ 50% (0.50; 0.36 to 0.71) in vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of cyp3a4. a clinical study in healthy volunteers also indicates that posaconazole is a strong cyp3a4 inhibitor as evidenced by a >5-fold increase in midazolam auc. therefore, plasma concentrations of drugs predominantly metabolized by cyp3a4 may be increased by posaconazole. a summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in table 23 [see contraindications (4) and drug interactions (7.1) including recommendations]. table 23: summary of the effect of posaconazole on coadministered drugs in healthy volunteers and patients coadministered drug (postulated mechanism of interaction is inhibition of cyp3a4 by posaconazole) coadministered drug dose/schedule posaconazole dose/schedule effect on bioavailability of coadministered drugs change in mean c max (ratio estimate 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) sirolimus 2-mg single oral dose 400 mg (oral suspension) bid × 16 days ↑ 572% (6.72; 5.62 to 8.03) ↑ 788% (8.88; 7.26 to 10.9) cyclosporine stable maintenance dose in heart transplant recipients 200 mg (tablets) qd × 10 days the tablet refers to a non-commercial tablet formulation without polymer. ↑ cyclosporine whole blood trough concentrations cyclosporine dose reductions of up to 29% were required tacrolimus 0.05-mg/kg single oral dose 400 mg (oral suspension) bid × 7 days ↑ 121% (2.21; 2.01 to 2.42) ↑ 358% (4.58; 4.03 to 5.19) simvastatin 40-mg single oral dose 100 mg (oral suspension) qd × 13 days simvastatin ↑ 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 acid ↑634% (7.34, 5.82 to 9.25) 200 mg (oral suspension) qd × 13 days simvastatin ↑ 1,041% (11.41, 7.99 to 16.29) simvastatin acid ↑851% (9.51, 8.15 to 11.10) simvastatin ↑ 960% (10.60, 8.63 to 13.02) simvastatin acid ↑748% (8.48, 7.04 to 10.23) midazolam 0.4-mg single intravenous dose the mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole. 200 mg (oral suspension) bid × 7 days ↑ 30% (1.3; 1.13 to 1.48) ↑ 362% (4.62; 4.02 to 5.3) 0.4-mg single intravenous dose 400 mg (oral suspension) bid × 7 days ↑62% (1.62; 1.41 to 1.86) ↑524% (6.24; 5.43 to 7.16) 2-mg single oral dose 200 mg (oral suspension) qd × 7 days ↑ 169% (2.69; 2.46 to 2.93) ↑ 470% (5.70; 4.82 to 6.74) 2-mg single oral dose 400 mg (oral suspension) bid × 7 days ↑ 138% (2.38; 2.13 to 2.66) ↑ 397% (4.97; 4.46 to 5.54) rifabutin 300 mg qd × 17 days 200 mg (tablets) qd × 10 days ↑ 31% (1.31; 1.10 to 1.57) ↑ 72% (1.72;1.51 to 1.95) phenytoin 200 mg qd po × 10 days 200 mg (tablets) qd × 10 days ↑ 16% (1.16; 0.85 to 1.57) ↑ 16% (1.16; 0.84 to 1.59) ritonavir 100 mg qd × 14 days 400 mg (oral suspension) bid × 7 days ↑ 49% (1.49; 1.04 to 2.15) ↑ 80% (1.8;1.39 to 2.31) atazanavir 300 mg qd × 14 days 400 mg (oral suspension) bid × 7 days ↑ 155% (2.55; 1.89 to 3.45) ↑ 268% (3.68; 2.89 to 4.70) atazanavir/ ritonavir boosted regimen 300 mg/100 mg qd × 14 days 400 mg (oral suspension) bid × 7 days ↑ 53% (1.53; 1.13 to 2.07) ↑ 146% (2.46; 1.93 to 3.13) additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg qd; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg qd. excretion: following administration of posaconazole oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug). posaconazole delayed-release tablet is eliminated with a mean half-life (t ½ ) ranging between 26 to 31 hours. 12.4 microbiology mechanism of action: posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome p-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. this results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. this may be responsible for the antifungal activity of posaconazole. resistance: clinical isolates of candida albicans and candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. these isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. the clinical significance of this finding is not known. antimicrobial activity: posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see indications and usage (1) ]. microorganisms: aspergillus spp. and candida spp. susceptibility testing for specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by fda for this drug, please see: https://www.fda.gov/stic .

1 (25) 2,764 (21) 1,785 (29) 4 (3 to 6) 31 (40) 7.5 (26) patients 50 37,900 (42) 1,580 (42) 2,090 (38) 1,310 (50) 4 (1.3 to 8.3) - 9.39 (45) cv = coefficient of variation expressed as a percentage (%cv); auc 0-t = area under the plasma concentration-time curve from time zero to 24 hr; c max = maximum observed concentration; c min = minimum observed plasma concentration; t max = time of maximum observed concentration; t ½ = terminal phase half-life; cl /f = apparent total body clearance absorption: when given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with a median t max of 4 to 5 hours. steady-state plasma concentrations are attained by day 6 at the 300 mg dose (qd after bid loading dose at day 1). the absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. the c max and auc of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see table 17 ). in order to enhance the oral absorption of posaconazole and optimize plasma concentrations, posaconazole delayed-release tablets should be administered with food. table 17: statistical comparison of plasma pharmacokinetics of posaconazole following single oral dose administration of 300 mg posaconazole delayed-release tablet to healthy subjects under fasting and fed conditions fasting conditions fed conditions (high fat meal) 48.5 g fat fed/fasting pharmacokinetic parameter n mean (%cv) n mean (%cv) gmr (90% ci) c max (ng/ml) 14 935 (34) 16 1,060 (25) 1.16 (0.96, 1.41) auc 0-72hr (hr∙ng/ml) 14 26,200 (28) 16 38,400 (18) 1.51 (1.33, 1.72) t max median (min, max) reported for tmax (hr) 14 5.00 (3.00, 8.00) 16 6.00 (5.00, 24.00) n/a gmr=geometric least-squares mean ratio; ci=confidence interval concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric ph or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see table 18 ). table 18: the effect of concomitant medications that affect the gastric ph and gastric motility on the pharmacokinetics of posaconazole delayed-release tablets in healthy volunteers coadministered drug administration arms change in c max (ratio estimate ratio estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for cmax or auc0-last. ; 90% ci of the ratio estimate) change in auc 0-last (ratio estimate ; 90% ci of the ratio estimate) mylanta ® ultimate strength liquid (increase in gastric ph) 25.4 meq/5 ml, 20 ml ↑6% (1.06; 0.90 to 1.26)↑ ↑4% (1.04; 0.90 to 1.20) ranitidine (zantac ® ) (alteration in gastric ph) 150 mg (morning dose of 150 mg ranitidine bid) ↑4% (1.04; 0.88 to 1.23)↑ ↓3% (0.97; 0.84 to 1.12) esomeprazole (nexium ® ) (increase in gastric ph) 40 mg (qam 5 days, day -4 to 1) ↑2% (1.02; 0.88 to 1.17)↑ ↑5% (1.05; 0.89 to 1.24) metoclopramide (reglan ® ) (increase in gastric motility) 15 mg four times daily during 2 days (day -1 and 1) ↓14% (0.86, 0.73,1.02) ↓7% (0.93, 0.803,1.07) distribution: the mean volume of distribution of posaconazole after intravenous solution administration was 261 l and ranged from 226 to 295 l between studies and dose levels. posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin. metabolism: posaconazole primarily circulates as the parent compound in plasma. of the circulating metabolites, the majority are glucuronide conjugates formed via udp glucuronidation (phase 2 enzymes). posaconazole does not have any major circulating oxidative (cyp450 mediated) metabolites. the excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. posaconazole is primarily metabolized via udp glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (p-gp) efflux. therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. a summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in table 22. table 22: summary of the effect of coadministered drugs on posaconazole in healthy volunteers coadministered drug (postulated mechanism of interaction) coadministered drug dose/schedule posaconazole dose/schedule effect on bioavailability of posaconazole change in mean c max (ratio estimate ratio 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 qd × 10 and 20 days 400 mg (oral suspension) bid × 10 and 20 days ↓45% (0.55; 0.47 to 0.66) ↓ 50% (0.50; 0.43 to 0.60) fosamprenavir (unknown mechanism) 700 mg bid × 10 days 200 mg qd on the 1 st day, 200 mg bid on the 2 nd day, then 400 mg bid × 8 days ↓21% 0.79 (0.71 to 0.89) ↓23% 0.77 (0.68 to 0.87) rifabutin (udp-g induction) 300 mg qd × 17 days 200 mg (tablets) qd × 10 days the tablet refers to a non-commercial tablet formulation without polymer. ↓ 43% (0.57; 0.43 to 0.75) ↓ 49% (0.51; 0.37 to 0.71) phenytoin (udp-g induction) 200 mg qd × 10 days 200 mg (tablets) qd × 10 days ↓ 41% (0.59; 0.44 to 0.79) ↓ 50% (0.50; 0.36 to 0.71) in vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of cyp3a4. a clinical study in healthy volunteers also indicates that posaconazole is a strong cyp3a4 inhibitor as evidenced by a >5-fold increase in midazolam auc. therefore, plasma concentrations of drugs predominantly metabolized by cyp3a4 may be increased by posaconazole. a summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in table 23 [see contraindications (4) and drug interactions (7.1) including recommendations]. table 23: summary of the effect of posaconazole on coadministered drugs in healthy volunteers and patients coadministered drug (postulated mechanism of interaction is inhibition of cyp3a4 by posaconazole) coadministered drug dose/schedule posaconazole dose/schedule effect on bioavailability of coadministered drugs change in mean c max (ratio estimate 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) sirolimus 2-mg single oral dose 400 mg (oral suspension) bid × 16 days ↑ 572% (6.72; 5.62 to 8.03) ↑ 788% (8.88; 7.26 to 10.9) cyclosporine stable maintenance dose in heart transplant recipients 200 mg (tablets) qd × 10 days the tablet refers to a non-commercial tablet formulation without polymer. ↑ cyclosporine whole blood trough concentrations cyclosporine dose reductions of up to 29% were required tacrolimus 0.05-mg/kg single oral dose 400 mg (oral suspension) bid × 7 days ↑ 121% (2.21; 2.01 to 2.42) ↑ 358% (4.58; 4.03 to 5.19) simvastatin 40-mg single oral dose 100 mg (oral suspension) qd × 13 days simvastatin ↑ 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 acid ↑634% (7.34, 5.82 to 9.25) 200 mg (oral suspension) qd × 13 days simvastatin ↑ 1,041% (11.41, 7.99 to 16.29) simvastatin acid ↑851% (9.51, 8.15 to 11.10) simvastatin ↑ 960% (10.60, 8.63 to 13.02) simvastatin acid ↑748% (8.48, 7.04 to 10.23) midazolam 0.4-mg single intravenous dose the mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole. 200 mg (oral suspension) bid × 7 days ↑ 30% (1.3; 1.13 to 1.48) ↑ 362% (4.62; 4.02 to 5.3) 0.4-mg single intravenous dose 400 mg (oral suspension) bid × 7 days ↑62% (1.62; 1.41 to 1.86) ↑524% (6.24; 5.43 to 7.16) 2-mg single oral dose 200 mg (oral suspension) qd × 7 days ↑ 169% (2.69; 2.46 to 2.93) ↑ 470% (5.70; 4.82 to 6.74) 2-mg single oral dose 400 mg (oral suspension) bid × 7 days ↑ 138% (2.38; 2.13 to 2.66) ↑ 397% (4.97; 4.46 to 5.54) rifabutin 300 mg qd × 17 days 200 mg (tablets) qd × 10 days ↑ 31% (1.31; 1.10 to 1.57) ↑ 72% (1.72;1.51 to 1.95) phenytoin 200 mg qd po × 10 days 200 mg (tablets) qd × 10 days ↑ 16% (1.16; 0.85 to 1.57) ↑ 16% (1.16; 0.84 to 1.59) ritonavir 100 mg qd × 14 days 400 mg (oral suspension) bid × 7 days ↑ 49% (1.49; 1.04 to 2.15) ↑ 80% (1.8;1.39 to 2.31) atazanavir 300 mg qd × 14 days 400 mg (oral suspension) bid × 7 days ↑ 155% (2.55; 1.89 to 3.45) ↑ 268% (3.68; 2.89 to 4.70) atazanavir/ ritonavir boosted regimen 300 mg/100 mg qd × 14 days 400 mg (oral suspension) bid × 7 days ↑ 53% (1.53; 1.13 to 2.07) ↑ 146% (2.46; 1.93 to 3.13) additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg qd; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg qd. excretion: following administration of posaconazole oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug). posaconazole delayed-release tablet is eliminated with a mean half-life (t ½ ) ranging between 26 to 31 hours.

azole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400-mg bid oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400-mg bid oral suspension regimen). 13.2 animal toxicology and/or pharmacology in a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 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 a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age). the clinical significance of this finding is unknown; therefore, the use of posaconazole injection to patients under 18 years of age is not recommended.

tility of male rats at a dose up to 180 mg/kg (1.7 × the 400-mg bid oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400-mg bid oral suspension regimen).

as comparable between the 2 treatment groups (80 days, posaconazole; 77 days, fluconazole). table 24 contains the results from oral suspension study 1. table 24: results from blinded clinical study in prophylaxis of ifi in all randomized patients with hematopoietic stem cell transplant (hsct) and graft-vs.-host disease (gvhd): oral suspension study 1 posaconazole n=301 fluconazole n=299 on therapy plus 7 days clinical failure patients may have met more than one criterion defining failure. 50 (17%) 55 (18%) failure due to: proven/probable ifi 7 (2%) 22 (7%) (aspergillus) 3 (1%) 17 (6%) (candida) 1 (<1%) 3 (1%) (other) 3 (1%) 2 (1%) all deaths 22 (7%) 24 (8%) proven/probable fungal infection prior to death 2 (<1%) 6 (2%) saf use of systemic antifungal therapy (saf) criterion is based on protocol definitions (empiric/ifi usage >4 consecutive days). 27 (9%) 25 (8%) through 16 weeks clinical failure , 95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%). 99 (33%) 110 (37%) failure due to: proven/probable ifi 16 (5%) 27 (9%) (aspergillus) 7 (2%) 21 (7%) (candida) 4 (1%) 4 (1%) (other) 5 (2%) 2 (1%) all deaths 58 (19%) 59 (20%) proven/probable fungal infection prior to death 10 (3%) 16 (5%) saf 26 (9%) 30 (10%) event free lost to follow-up patients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. these patients were considered failures. 24 (8%) 30 (10%) the second study (oral suspension study 2) was a randomized, open-label study that compared posaconazole oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against ifis in neutropenic patients who were receiving cytotoxic chemotherapy for aml or mds. as in oral suspension study 1, efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable ifis, death, or treatment with systemic antifungal therapy (patients might have met more than one of these criteria). this study assessed patients while on treatment plus 7 days and 100 days post-randomization. the mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). table 25 contains the results from oral suspension study 2. table 25: results from open-label clinical study 2 in prophylaxis of ifi in all randomized patients with hematologic malignancy and prolonged neutropenia: oral suspension study 2 posaconazole n=304 fluconazole/itraconazole n=298 on therapy plus 7 days clinical failure 95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%). , patients may have met more than one criterion defining failure. 82 (27%) 126 (42%) failure due to: proven/probable ifi 7 (2%) 25 (8%) (aspergillus) 2 (1%) 20 (7%) (candida) 3 (1%) 2 (1%) (other) 2 (1%) 3 (1%) all deaths 17 (6%) 25 (8%) proven/probable fungal infection prior to death 1 (<1%) 2 (1%) saf use of systemic antifungal therapy (saf) criterion is based on protocol definitions (empiric/ifi usage >3 consecutive days). 67 (22%) 98 (33%) through 100 days post-randomization clinical failure 158 (52%) 191 (64%) failure due to: proven/probable ifi 14 (5%) 33 (11%) (aspergillus) 2 (1%) 26 (9%) (candida) 10 (3%) 4 (1%) (other) 2 (1%) 3 (1%) all deaths 44 (14%) 64 (21%) proven/probable fungal infection prior to death 2 (1%) 16 (5%) saf 98 (32%) 125 (42%) event free lost to follow-up patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. these patients were considered failures. 34 (11%) 24 (8%) in summary, 2 clinical studies of prophylaxis were conducted with the posaconazole oral suspension. as seen in the accompanying tables ( tables 24 and 25 ), clinical failure represented a composite endpoint of breakthrough ifi, mortality and use of systemic antifungal therapy. in oral suspension study 1 ( table 24 ), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% ci for the difference posaconazole–comparator -11.5% to 3.7%) while in oral suspension study 2 ( table 25 ) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% ci for the difference posaconazole–comparator -22.9% to -7.8%). all-cause mortality was similar at 16 weeks for both treatment arms in oral suspension study 1 [pos 58/301 (19%) vs. flu 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in oral suspension study 2 [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.

ath. are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole. 17.3 serious and potentially serious adverse reactions advise patients to inform their physician immediately if they: notice a change in heart rate or heart rhythm, or have a heart condition or circulatory disease. posaconazole can be administered with caution to patients with potentially proarrhythmic conditions. are pregnant, plan to become pregnant, or are nursing. have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu. have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.