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Drug Interactions between Nizoral and sirolimus

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

ketoconazole sirolimus

Applies to: Nizoral (ketoconazole) and sirolimus

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may significantly increase the plasma concentrations of sirolimus following oral administration. Sirolimus is a substrate of both CYP450 3A4 isoenzyme and P-gp efflux transporter, thus their inhibition in the intestine can enhance the absorption of sirolimus. In 23 healthy volunteers, administration of a single 5 mg dose of sirolimus with the potent dual CYP450 3A4/P-gp inhibitor ketoconazole (200 mg/day orally for 10 days) increased mean sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 4- and 11-fold, respectively. Likewise, posaconazole (400 mg oral suspension twice a day for 16 days) increased mean Cmax and AUC of a single 2 mg dose of sirolimus by nearly 7- and 9-fold, respectively, while voriconazole (400 mg orally every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the same values by 7- and 11-fold, respectively. Another dual inhibitor, boceprevir (800 mg three times a day for 11 days), increased the Cmax and AUC of a single 2 mg dose of sirolimus by 10- and 17-fold, respectively. When sirolimus 2 mg once a day was coadministered with the moderate dual inhibitor erythromycin (ethylsuccinate salt 800 mg every 8 hours) in 24 study subjects, sirolimus Cmax and AUC increased by more than 4-fold each, while erythromycin Cmax and AUC also increased by more than 1.5-fold each.

MANAGEMENT: Concomitant use of sirolimus with potent CYP450 3A4 and/or P-gp inhibitors should generally be avoided. The manufacturers of posaconazole and voriconazole consider coadministration with sirolimus to be contraindicated. Some authorities recommend avoiding concomitant use of sirolimus during and for 2 weeks after treatment with itraconazole.

References

  1. (2002) "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals
  2. (2001) "Product Information. Rapamune (sirolimus)." Wyeth-Ayerst Laboratories
  3. Claesson K, Brattstrom C, Burke JT (2001) "Sirolimus and erythromycin interaction: two cases." Transplant Proc, 33, p. 2136
  4. Floren LC, Christians U, Zimmerman JJ, et al. (1999) "Sirolimus oral bioavailability increases ten-fold with concomitant ketoconazole." Clin Pharmacol Ther, 65, p. 159
  5. (2002) "Product Information. VFEND (voriconazole)." Pfizer U.S. Pharmaceuticals
  6. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  7. (2006) "Product Information. Noxafil (posaconazole)." Schering-Plough Corporation
  8. Cerner Multum, Inc. "Australian Product Information."
  9. Dodds-Ashley E (2010) "Management of drug and food interactions with azole antifungal agents in transplant recipients." Pharmacotherapy, 30, p. 842-54
  10. (2011) "Product Information. Victrelis (boceprevir)." Schering-Plough Corporation
View all 10 references

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Drug and food interactions

Moderate

ketoconazole food

Applies to: Nizoral (ketoconazole)

GENERALLY AVOID: Excessive use of alcohol or products containing alcohol together with ketoconazole or levoketoconazole may potentiate the risk of liver injury. Serious hepatotoxicity has been reported with levoketoconazole. Hepatotoxicity requiring liver transplantation has been reported with the use of oral ketoconazole, of which levoketoconazole is an enantiomer. Some patients had no obvious risk factors for liver disease. In addition, use of alcohol or products containing alcohol during ketoconazole or levoketoconazole therapy may result in a disulfiram-like reaction in some patients. Symptoms of disulfiram-like reaction include flushing, rash, peripheral edema, nausea, and headache.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of ketoconazole or levoketoconazole. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Inhibition of hepatic CYP450 3A4 may also contribute. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

When administered to healthy volunteers with a high-fat meal (875 calories; 62% fat), levoketoconazole systemic exposure (AUC) increased by 30% while peak plasma concentration (Cmax) did not change and the time to reach Cmax (Tmax) was delayed from 2 to 4 hours, compared to fasted conditions.

MANAGEMENT: Levoketoconazole may be administered with or without food. Excessive consumption of alcohol should generally be avoided during ketoconazole or levoketoconazole therapy. Patients should preferably avoid or limit consumption of grapefruit, grapefruit juice, or any supplement containing grapefruit extract during ketoconazole or levoketoconazole therapy. Patients receiving ketoconazole or levoketoconazole should be instructed to contact their doctor immediately if they experience swelling, skin rash, itching, loss of appetite, fatigue, nausea, vomiting, abdominal pain, dark colored urine, light colored stools, and/or yellowing of the skin or eyes, as these may be signs and symptoms of liver damage.

References

  1. (2019) "Product Information. Ketoconazole (ketoconazole)." Mylan Pharmaceuticals Inc
  2. (2022) "Product Information. Recorlev (levoketoconazole)." Xeris Pharmaceuticals Inc
  3. Auchus R, Pivonello R, Fleseriu M, et al. (2022) Levoketoconazole: a novel treatment for endogenous Cushing's syndrome. https://www.tandfonline.com/doi/pdf/10.1080/17446651.2021.1945440
  4. (2021) "Product Information. Ketoconazole (ketoconazole)." Burel Pharmaceuticals Inc
View all 4 references

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Moderate

sirolimus food

Applies to: sirolimus

ADJUST DOSING INTERVAL: Consumption of food can decrease the rate and extent of gastrointestinal absorption of sirolimus. Also, the consumption of grapefruit juice may result in increased sirolimus trough concentrations.

MANAGEMENT: Experts recommend that this drug be taken either at least one hour prior to eating or consistently with or without food to avoid variations in sirolimus blood levels. The manufacturer recommends against using grapefruit juice for dilution of sirolimus doses. Patients should be monitored for clinical and laboratory evidence of altered immunosuppressant effects.

References

  1. (2001) "Product Information. Rapamune (sirolimus)." Wyeth-Ayerst Laboratories

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

See also

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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