Noxafil Drug Interactions

The interactions described in the following subsections apply to NOXAFIL delayed release tablets and oral suspension unless otherwise specified.
Effects of other medicinal products on NOXAFIL delayed release tablets and oral suspension: NOXAFIL 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 NOXAFIL 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 NOXAFIL by 43% and 49%, respectively. Concomitant use of NOXAFIL and rifabutin should be avoided unless the benefit to the patient outweighs the risk.
Efavirenz (400 mg once a day) decreased the C_max and AUC of NOXAFIL by 45% and 50%, respectively. Concomitant use of NOXAFIL and efavirenz 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 NOXAFIL by 41% and 50%, respectively. Concomitant use of NOXAFIL and phenytoin should be avoided unless the benefit to the patient outweighs the risk.
H₂ Receptor Antagonists, Proton Pump Inhibitors (PPIs) and Antacids: NOXAFIL Delayed Release Tablets: No clinically relevant effects were observed when NOXAFIL delayed release tablets are concomitantly used with antacids, H₂-receptor antagonists and proton pump inhibitors. No dosage adjustment of NOXAFIL delayed release tablets is required when NOXAFIL delayed release tablets are concomitantly used with antacids, H₂-receptor antagonists and proton pump inhibitors.
NOXAFIL Oral Suspension: Posaconazole plasma concentrations (C_max and AUC) were reduced by 39% when posaconazole oral suspension was administered with cimetidine (400 mg twice a day) due to reduced absorption possibly secondary to a decrease in gastric acid production. Co-administration of posaconazole oral suspension with H₂ receptor antagonists should be avoided if possible.
Similarly, administration of 400 mg posaconazole oral suspension with esomeprazole (40 mg daily) decreased mean C_max and AUC by 46% and 32%, respectively, compared to dosing with 400 mg posaconazole alone. Co-administration of posaconazole oral suspension with proton pump inhibitors should be avoided if possible.
Gastrointestinal Motility Agents: NOXAFIL Delayed Release Tablets: No clinically meaningful effect on the pharmacokinetics of NOXAFIL was observed when NOXAFIL delayed release tablets were concomitantly administered with metoclopramide. No dosage adjustment of NOXAFIL delayed release tablets is required when given concomitantly with metoclopramide.
NOXAFIL Oral Suspension: Metoclopramide, when given with posaconazole oral suspension, decreases posaconazole plasma concentrations. If metoclopramide is concomitantly administered with posaconazole oral suspension, it is recommended to closely monitor for breakthrough fungal infections.
Loperamide does not affect NOXAFIL plasma concentrations. No dosage adjustment of NOXAFIL is required when loperamide and NOXAFIL are used concomitantly.
Glipizide: (10 mg single dose) had no clinically significant effect on NOXAFIL C_max and AUC.
Fosamprenavir: Combining fosamprenavir with NOXAFIL may lead to decreased NOXAFIL 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 NOXAFIL (200 mg oral suspension QD on the 1^st day, 200 mg oral suspension BID on the 2^nd day, then 400 mg oral suspension BID x 8 days) by 21% and 23%, respectively.
Terfenadine, astemizole, cisapride, pimozole and quinidine: Although not studied in vitro or in vivo, co-administration of NOXAFIL and certain drugs such as terfenadine, astemizole, cisapride, pimozole and quinidine, metabolizes through the CYP3A4 system may result in increased plasma concentrations of these drugs, leading to potentially serious and/or life threatening adverse events (QT prolongation and rare occurrences of torsade de pointes). Therefore, co-administration of these drugs with NOXAFIL is contraindicated.
Effects of NOXAFIL delayed release tablets and oral suspension on other medicinal products: NOXAFIL is not metabolized to a clinically significant extent through the cytochrome P450 system. However, NOXAFIL is an inhibitor of CYP3A4 and thus the plasma levels of drugs that are metabolized through this enzyme pathway may increase when administered with NOXAFIL.
Ergot alkaloids: Although not studied in vitro or in vivo, NOXAFIL may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine), which may lead to ergotism. Coadministration of NOXAFIL and ergot alkaloids is contraindicated.
Vinca alkaloids: Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including NOXAFIL, with vincristine has been associated with serious adverse reactions (see Precautions). NOXAFIL may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including NOXAFIL, 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, NOXAFIL oral suspension 200 mg once daily increased cyclosporine concentrations requiring dose reductions. When initiating treatment with NOXAFIL in patients already receiving cyclosporine, the dose of cyclosporine should be reduced (e.g., to about three-fourths of the current dose). Thereafter blood levels of cyclosporine should be monitored carefully during coadministration and upon discontinuation of NOXAFIL treatment, the dose of cyclosporine should be adjusted as necessary.
Tacrolimus: NOXAFIL increased C_max and AUC of tacrolimus (0.05 mg/kg single dose) by 121% and 358%, respectively. When initiating NOXAFIL 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 NOXAFIL, and the dose of tacrolimus should be adjusted as necessary.
Sirolimus: Repeat dose administration of oral NOXAFIL (400 mg oral suspension 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 NOXAFIL treatment, with sirolimus doses adjusted accordingly.
Rifabutin: NOXAFIL increased the C_max and AUC of rifabutin by 31% and 72%, respectively. Concomitant use of NOXAFIL 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: In a study in healthy volunteers, posaconazole (200 mg once daily for 10 days) increased the exposure (AUC) of IV midazolam (0.05 mg/kg) by 83%. In another study in healthy volunteers, repeat dose administration of oral NOXAFIL (200 mg oral suspension twice daily for 7 days) increased the C_max and AUC of IV midazolam (0.4 mg single dose) an average of 1.3- and 4.6-fold, respectively; NOXAFIL 400 mg oral suspension twice daily for 7 days increased the IV midazolam C_max and AUC by 1.6- and 6.2-fold, respectively. Both doses of NOXAFIL increased C_max and AUC of oral midazolam (2 mg single oral dose) by 2.2- and 4.5-fold, respectively. In addition, oral NOXAFIL (200 mg or 400 mg oral suspension) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to 8-10 hours during coadministration.
Due to the risk of prolonged sedation, it is recommended that dose adjustments of benzodiazepines, metabolized by CYP3A4, be considered during coadministration with NOXAFIL.
Zidovudine (AZT), lamivudine (3TC), ritonavir, indinavir: Clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, ritonavir, indinavir were observed when administered with NOXAFIL; therefore, no dose adjustments are required for these co-administered drugs. Although not considered clinically significant, ritonavir exposure was increased by 30% with the addition of NOXAFIL.
HIV protease inhibitors: As HIV protease inhibitors are CYP3A4 substrates, it is expected that NOXAFIL will increase plasma levels of these antiretroviral agents. Repeat dose administration of NOXAFIL (400 mg oral suspension 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 NOXAFIL (400 mg oral suspension 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 NOXAFIL.
HMG-CoA reductase inhibitors primarily metabolized through CYP3A4: Repeat dose administration of oral NOXAFIL (50, 100, and 200 mg oral suspension 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 NOXAFIL 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 NOXAFIL. Dose adjustment of calcium channel blockers may be required.
Digoxin: Administration of other azoles has been associated with increases in digoxin levels. Therefore, NOXAFIL may increase plasma concentration of digoxin and digoxin levels need to be monitored when initiating or discontinuing NOXAFIL treatment.
Venetoclax: Concomitant use of venetoclax (a CYP3A4 substrate) with NOXAFIL increases venetoclax C_max and AUC_0-INF, which may increase venetoclax toxicities (see Precautions).
Sulfonylureas: Glucose concentrations decreased in some healthy volunteers when glipizide was co-administered with NOXAFIL. Monitoring of glucose concentration is recommended in diabetic patients.
Laboratory Test Interactions: None known.