Drug Interactions of Posaconazole

Introduction

Posaconazole (Noxafl^®) is a systemic triazole antifungal drug derived from itraconazole and exerts the same antifungal mechanism of action as other azole derivatives. Four formulations are currently available, namely an oral suspension (40 mg/mL), a delayed-release tablet (100 mg),  an intravenous formulation (18 mg/mL),and a PowderMix for delayed-release oral suspension (300 mg). The first three have been clinically used in China (Figure 1). The drug interactions of posaconazole are an area that deserves attention. [1-2]

Drug Interactions 

Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is a substrate of pglycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole.

The following information was derived from data with posaconazole oral suspension or early tablet formulation unless otherwise noted. All drug interactions with posaconazole oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to posaconazole injection, posaconazole delayed-release tablet, and Posaconazole PowderMix for delayed-release oral suspension as well .

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 iscontraindicated with sirolimus .

Tacrolimus: Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of Posaconazole treatment and the tacrolimus dose adjusted accordingly.

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.

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.

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.

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.

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 .

6 Anti-HIV Drugs 

Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasmaconcentrations ]. 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. 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.

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. 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.

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. 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.

9 Gastric Acid Suppressors/Neutralizers

Posaconazole Delayed-Release Tablet and Posaconazole PowderMix for Delayed-Release Oral Suspension: No clinically relevant effects on the pharmacokinetics were observed when its delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. No dosage adjustment of two alternatives is required when concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. 

Posaconazole Oral Suspension: Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with Posaconazole oral suspension results in decreased its plasma concentrations. It is recommended to avoid concomitant use of cimetidine and esomeprazole with it unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. No clinically relevant effects were observed when this durg is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. No dosage adjustment is required when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine.

10 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.

11 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.

12 Gastrointestinal Motility Agents

Posaconazole Delayed-Release Tablet and Posaconazole PowderMix for Delayed-Release Oral Suspension: Concomitant administration of metoclopramide with its delayed-release tablets did not affect the pharmacokinetics. No dosage adjustment of two alternatives is required when given concomitantly with metoclopramide.

Posaconazole Oral Suspension: Metoclopramide may decrease posaconazole plasma concentrations. If metoclopramide is concomitantly administered with this durg, it is recommended to closely monitor for breakthrough fungal infections.

Loperamide does not affect posaconazole plasma concentrations. No dosage adjustment is required when loperamide and this durg are used concomitantly.

13 Alcohol

Posaconazole was found to release faster from Posaconazole PowderMix for delayed-release oral suspension in the presence of alcohol in vitro, which may interfere with its delayed release characteristics. Administration of Posaconazole PowderMix for delayed-release oral suspension with alcohol is not recommended.

See full prescribing information for Posaconazole (Noxafl®), please refer to the latest FDA report.

References

[1]Chen L, Krekels EHJ, Verweij PE, Buil JB, Knibbe CAJ, Brüggemann RJM. Pharmacokinetics and Pharmacodynamics of Posaconazole. Drugs. 2020;80(7):671-695.

[2]https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/205053s011,205596s013lbl.pdf

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