Noxafil Drug Interactions

Summary of Drug Interactions: (See Table 16.)

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Note that the majority of the interaction studies were carried out in healthy volunteers with a repeat dose regimens of posaconazole 400 mg (suspension) twice daily administered with a meal or nutritional supplement. See as follows for further information.
Effect of Other Drugs on Posaconazole: Posaconazole is 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.
Rifabutin: (300 mg once a day) decreased the C_max (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole by 43% and 49%, respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk.
Phenytoin: (200 mg once a day) decreased the C_max and AUC of posaconazole by 41% and 50%, respectively. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk.
Cimetidine: (400 mg twice a day): decreased the C_max and AUC of posaconazole 200 mg once a day each by 39%. Concomitant use of posaconazole and cimetidine should be avoided unless the benefit outweighs the risk.
MR Tablet: No clinically relevant effects were observed when posaconazole modified release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. No dosage adjustment of posaconazole modified release tablets is required when posaconazole modified release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.
Oral Suspension: The effect of other H2 receptor antagonists and proton pump inhibitors that may suppress gastric acidity has not been studied. Reduction in bioavailability may occur, therefore co-administration of posaconazole with H2 receptor antagonists and proton pump inhibitors should be avoided if possible.
Antacids: (20 mL single dose of liquid antacid equivalent to 25.4 mEq acid neutralizing capacity/5 mL) had no clinically significant effect on posaconazole C_max and AUC. No posaconazole dosage adjustments are required.
Glipizide: (10 mg single dose) had no clinically significant effect on posaconazole C_max and AUC. No posaconazole dosage adjustments are required.
Ritonavir: (600 mg twice a day) had no clinically significant effect on posaconazole C_max and AUC. No posaconazole dosage adjustments are required.
Efavirenz: (400 mg once a day) decreased the C_max and AUC of posaconazole by 45% and 50%, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk.
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. Repeat dose administration of fosamprenavir (700 mg BID x 10 days) decreased the C_max and AUC of posaconazole (200 mg QD on the 1^st day, 200 mg BID on the 2^nd days, then 400 mg BID x 8 Days) by 21% and 23% respectively.
Effects of Posaconazole on Other Drugs: Posaconazole is not metabolized to a clinically significant extent through the cytochrome P450 system. However, posaconazole is an inhibitor of CYP3A4 and thus the plasma levels of drugs that are metabolized through this enzyme pathway may increase when administered with posaconazole.
Terfenadine, astemizole, cisapride, pimozide, and quinidine: Although not studied in vitro or in vivo, co-administration of posaconazole and certain drugs such as terfenadine, astemizole, cisapride, pimozide, and quinidine, metabolized through the CYP3A4 system may result in increased plasma concentrations of these drugs, leading to potentially serious and/or life threatening adverse events (QT_c prolongation and rare occurrences of torsade de pointes). Therefore, co-administration of these drugs with posaconazole is contraindicated (see Contraindications).
Ergot alkaloids: Although not studied in vitro or in vivo, posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine), which may lead to ergotism. Coadministration of posaconazole and ergot alkaloids is contraindicated (see Contraindications).
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 Precautions). 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.
Cyclosporine: In heart transplant patients on stable doses of cyclosporine, posaconazole 200 mg once daily increased cyclosporine concentrations requiring dose reductions. Cases of elevated cyclosporine levels resulting in serious adverse events, including nephrotoxicity and one fatal case of leukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment with posaconazole in patients already receiving cyclosporine, the dose of cyclosporine should be reduced (e.g. to about three quarters of the current dose). Thereafter blood levels of cyclosporine should be monitored carefully during co-administration, and upon discontinuation of posaconazole treatment, and the dose of cyclosporine should be adjusted as necessary.
Tacrolimus: Posaconazole increased C_max and AUC of tacrolimus (0.05 mg/kg single dose) by 121% and 358%, respectively. Clinically significant interactions resulting in hospitalisation and/or posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored carefully during co-administration, and upon discontinuation of posaconazole, and the dose of tacrolimus should be adjusted as necessary.
Sirolimus: Repeat dose administration of oral posaconazole (400 mg twice daily for 16 days) increased the C_max and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9 fold, respectively, in healthy subjects. When initiating therapy in patients already taking sirolimus, the dose of sirolimus should be reduced (e.g., to about 1/10 of the current dose) with frequent monitoring of sirolimus whole blood trough concentrations. Sirolimus concentrations should be performed upon initiation, during coadministration, and at discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly.
Rifabutin: Posaconazole increased the C_max and AUC of rifabutin by 31% and 72%, respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. If the drugs are coadministered, careful monitoring of full blood counts and adverse effects related to increased rifabutin levels (e.g., uveitis) is recommended.
Midazolam: Repeat dose administration of oral posaconazole 200 mg or 400 mg twice daily with a high fat meal, significantly increased the midazolam C_max by 2.2 fold (~7.03 to 15.4 ng/mL): AUC by approximately 5 fold (~31.9 to 159 h.ng/mL); and prolonged the mean terminal half-life of midazolam 8 to 10 hours in healthy subjects. It is recommended that dose adjustments of benzodiazepines, including midazolam metabolised by CYP3A4, be considered during co-administration with posaconazole.
Zidovudine (AZT), lamivudine (3TC), indinavir: In HIV infected patients on stable doses of zidovudine (300 mg twice a day or 200 mg every 8 hours), lamivudine (150 mg twice a day), and/or indinavir (800 mg every 8 hours), posaconazole had no clinically significant effect on the C_max and AUC of these medicinal products.
HMG-CoA reductase inhibitors primarily metabolized through CYP3A4: Repeat dose administration of oral posaconazole (50, 100 and 200 mg once daily for 13 days) increased the C_max and AUC of simvastatin (40 mg single dose) an average of 7.4- to 11.4-fold, and 5.7- to 10.6-fold, respectively. Increased HMG-CoA reductase inhibitor concentrations in plasma can be associated with rhabdomyolysis. Coadministration of posaconazole and HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 is contraindicated.
Calcium channel blockers metabolized through CYP3A4: Although not studied in vitro or in vivo, frequent monitoring for adverse effects and toxicity related to calcium channel blockers is recommended during coadministration with posaconazole. Dose adjustment of calcium channel blockers may be required.
Digoxin: Administration of other azoles has been associated with increases in digoxin levels. Therefore, posaconazole may increase plasma concentration of digoxin and digoxin levels need to be monitored when initiating or discontinuing posaconazole treatment.
Sulfonylureas: Glucose concentrations decreased in some healthy volunteers when glipizide was co-administered with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.
HIV protease inhibitors: As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase plasma levels of these antiretroviral agents. Repeat dose administration of oral posaconazole (400 mg twice daily for 7 days) increased the C_max and AUC of atazanavir (300 mg once a day for 7 days) an average of 2.6-fold and 3.7-fold, respectively, in healthy subjects. Repeat dose administration of oral posaconazole (400 mg twice daily for 7 days) increased the C_max and AUC of atazanavir to a lesser extent when administered as a boosted regimen with ritonavir (300 mg atazanavir plus ritonavir 100 mg once a day for 7 days) with an average of 1.5-fold and 2.5-fold, respectively, in healthy subjects. Frequent monitoring for adverse events and toxicity related to antiretroviral agents that are substrates of CYP3A4 is recommended during co-administration with posaconazole.
Venetoclax: Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax C_max and AUC_0-INF, which may increase venetoclax toxicities (see Precautions).