Posaconazoleinteractions

Table 15 and Table 17 include drugs with clinically important drug interactions when administered concomitantly with posaconazole and posaconazole PowderMix and instructions for preventing or managing them. Table 16 includes important drug interactions specific to the absorption of posaconazole administered as either posaconazole oral suspension or posaconazole PowderMix. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy. The following information was derived from data with posaconazole oral suspension or another posaconazole tablet formulation unless otherwise noted. All clinically important drug interactions with posaconazole oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to clinically important drug interactions with posaconazole injection, posaconazole delayed-release tablets, and posaconazole PowderMix for delayed-release oral suspension [Clinical Pharmacology ]. Consult the labeling of concomitantly used drugs to obtain further information about interactions with posaconazole. Interaction Drug Interaction Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole Avoid coadministration unless the benefit outweighs the risks Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity Digoxin Monitor digoxin plasma concentrations Fosamprenavir, metoclopramide Monitor for breakthrough fungal infections

7.1 Effects of

Other Drugs on Posaconazole Posaconazole is primarily metabolized via UDP-glucuronosyltransferase and is a substrate of p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Concomitant use of posaconazole with drugs that can decrease the plasma posaconazole concentrations should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Table 15: Drug Interactions Affecting Posaconazole When Administered Concomitantly with Other Drugs UDP-Glucuronidase Inducers Mechanism and Clinical Effect(s) Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of posaconazole with UDP-glucuronidase inducers may decrease posaconazole exposure, which may reduce the effectiveness of posaconazole. Prevention or Management Efavirenz Avoid concomitant use of posaconazole with efavirenz, unless the benefit outweighs the risks. Rifabutin Avoid concomitant use of posaconazole with rifabutin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor closely for breakthrough fungal infections. See Table 17 for rifabutin monitoring considerations when posaconazole affects rifabutin via CYP3A4 inhibition. Phenytoin Avoid concomitant use of posaconazole with phenytoin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor for breakthrough fungal infections. See Table 17 for phenytoin monitoring considerations when posaconazole affects phenytoin via CYP3A4 inhibition. Fosamprenavir Mechanism and Clinical Effect(s) Concomitant use of posaconazole with fosamprenavir may lead to decreased posaconazole plasma concentrations, which may reduce effectiveness of posaconazole. Prevention or Management If concomitant use of posaconazole with fosamprenavir is needed, monitor closely for breakthrough fungal infections.

Table 16: Drug Interactions Affecting Posaconazole Oral Suspension Absorption When Administered Concomitantly with Other Drugs Posaconazole Oral Suspension Cimetidine and Esomeprazole Mechanism and Clinical Effect(s) Concomitant use of posaconazole oral suspension with cimetidine or esomeprazole resulted in decreased posaconazole plasma concentrations, which may reduce effectiveness of posaconazole. Prevention or Management Avoid concomitant use of posaconazole oral suspension with cimetidine or esomeprazole unless the benefit outweighs the risks. If concomitant use is needed, monitor closely for breakthrough fungal infections. Metoclopramide Mechanism and Clinical Effect(s) Concomitant use of posaconazole oral suspension with metoclopramide decreased posaconazole plasma concentrations, which may reduce effectiveness of posaconazole oral suspension. Prevention or Management If posaconazole oral suspension is concomitantly administered with metoclopramide, closely monitor for breakthrough fungal infections.

7.2 Effects of

Posaconazole on Other Drugs Posaconazole is a strong CYP3A4 inhibitor. Therefore, concomitant use of posaconazole may increase plasma concentrations of drugs that are CYP3A4 substrates. Table 17: Drug Interactions Affecting Drugs Administered Concomitantly with Posaconazole Digoxin Clinical Effect(s) Increased digoxin plasma concentrations have been reported in patients who received concomitant posaconazole and digoxin. Prevention or Management Monitor digoxin plasma concentrations during concomitant use of posaconazole. Glipizide Clinical Effect(s) No dosage modification of glipizide is needed when used concomitantly with posaconazole. However, glucose concentrations decrease in some patients concomitantly administered posaconazole and glipizide. Prevention or Management Increase monitoring of glucose concentrations when used concomitantly. CYP3A Substrates Immunosuppressants that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Posaconazole is a strong CYP3A4 inhibitor. Therefore, plasma concentrations of CYP3A4 substrates may be increased by posaconazole use. Prevention or Management Sirolimus Posaconazole is contraindicated with sirolimus. Tacrolimus

At initiation of posaconazole treatment, reduce the tacrolimus dosage to approximately one-third of the original tacrolimus dosage.

Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dosage should be modified accordingly. Cyclosporine

At initiation of posaconazole treatment reduce the cyclosporine dosage to approximately three-fourths of the original dosage.

Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dosage should be modified accordingly. CYP3A4 Substrates that Prolong QTc Interval Mechanism and Clinical Effect(s) Concomitant use of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of the CYP3A4 substrates leading to QTc interval prolongation and torsades de pointes. Prevention or Management Pimozide Concomitant use with posaconazole is contraindicated. Quinidine HMG-CoA Reductase Inhibitors (Statins) that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Concomitant use of posaconazole with simvastatin increased simvastatin plasma concentrations which can lead to rhabdomyolysis. Prevention or Management Atorvastatin, Lovastatin, Simvastatin Concomitant use with posaconazole is contraindicated. Benzodiazepines that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Concomitant use of posaconazole with midazolam increased midazolam plasma concentrations which could potentiate and prolong hypnotic and sedative effects. Prevention or Management Midazolam, Alprazolam, Triazolam Closely monitor for adverse reactions associated with high plasma concentrations of benzodiazepines that are CYP3A4 substrates during concomitant use, and a benzodiazepine receptor antagonist should be available to reverse effects. Calcium Channel Blockers that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Posaconazole may increase the plasma concentrations of calcium channel blockers that are substrates of CYP3A4. Prevention or Management Verapamil, Diltiazem, Nifedipine, Nicardipine, Felodipine Monitor frequently for adverse reactions and toxicity with concomitant use of posaconazole with calcium channel blockers that are CYP3A4 substrates. Dosage reduction of the calcium channel blocker may be needed. Anti-HIV Drugs that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Ritonavir and atazanavir are CYP3A4 substrates and posaconazole increased plasma concentrations of these drugs. Prevention or Management Ritonavir and Atazanavir Monitor frequently for adverse reactions and toxicity of ritonavir and atazanavir during concomitant use. Antineoplastic Drugs that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Posaconazole may increase plasma concentrations of oncology drugs that are CYP3A4 substrates, which may increase the risk of serious adverse reactions. Prevention or Management Venetoclax CLL/SLL patients: Concomitant use of posaconazole with venetoclax during initiation and ramp-up phase is contraindicated. AML patients: With concomitant use, venetoclax dosage reduction and safety monitoring is recommended across all dosing phases. Vinca alkaloids (e.g., vincristine, vinblastine) Reserve concomitant use for patients with no alternative antifungal treatment options. Ergot Alkaloids Mechanism and Clinical Effect(s) Most of the ergot alkaloids are CYP3A4 substrates. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Prevention or Management Ergotamine, Dihydroergotamine Concomitant use with posaconazole is contraindicated. Phenytoin Mechanism and Clinical Effect(s) Phenytoin is a CYP3A4 substrate. Concomitant use of posaconazole with phenytoin increased phenytoin plasma concentrations. Prevention or Management Avoid concomitant use of posaconazole with phenytoin unless the benefit outweighs the risk. frequently monitor phenytoin concentrations and consider a dosage reduction of phenytoin. See Table 15 for additional monitoring considerations when phenytoin affects posaconazole via UDP-glucuronosyltransferase inhibition. Rifabutin Mechanism and Clinical Effect(s) Rifabutin is a CYP3A4 substrate. Concomitant use of posaconazole with rifabutin increased rifabutin plasma concentrations. Prevention or Management Avoid concomitant use of posaconazole with rifabutin unless the benefit outweighs the risk. Frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) during concomitant use are recommended. See Table 15 for additional monitoring considerations when rifabutin affects posaconazole via UDP-glucuronosyltransferase inhibition.

7.3 Absence of

Clinically Important Interaction with Posaconazole Additional clinical studies demonstrated that no clinically important 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 drugs when coadministered with posaconazole 200 mg once daily. No clinically relevant effects on the pharmacokinetics of posaconazole oral suspension were observed during concomitant use with antacids, H 2 -receptor antagonists (other than cimetidine), and loperamide. No dosage adjustment of posaconazole oral suspension is required during concomitant use with these drugs (other than cimetidine).