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Drug Interactions between ketoconazole and sirolimus protein-bound

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

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Major

ketoconazole sirolimus protein-bound

Applies to: ketoconazole and sirolimus protein-bound

GENERALLY AVOID: Coadministration of protein-bound sirolimus intravenous suspension with potent inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may significantly increase the systemic exposure to sirolimus, which is a known substrate for both the isoenzyme and efflux transporter. No formal studies evaluating the drug interaction potential of protein-bound sirolimus have been conducted. However, significant increases in systemic exposure have been reported for oral sirolimus coadministered with potent inhibitors of CYP450 3A4 and/or P-gp such as azole antifungal agents and protease inhibitors. When a single 5 mg dose of sirolimus was administered with the potent dual CYP450 3A4/P-gp inhibitor ketoconazole (200 mg/day orally for 10 days) in healthy study subjects, mean sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 4- and 11-fold, respectively. Likewise, the potent CYP450 3A4 inhibitor 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 the potent CYP450 3A4 inhibitor 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. The dual CYP450 3A4/P-gp 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. Another dual CYP450 3A4/P-gp inhibitor, telaprevir (1125 mg every 12 hours), increased the dose-normalized Cmax and AUC of sirolimus in ten liver transplant patients by 3- and 26-fold, respectively. Increased exposures to sirolimus may increase the risk of adverse effects such as stomatitis, nausea, diarrhea, vomiting, myelosuppression, infections, hypokalemia, hyperglycemia, interstitial lung disease, edema, rash, alopecia, and hemorrhage.

MANAGEMENT: Concomitant use of protein-bound sirolimus with potent CYP450 3A4 and/or P-gp inhibitors should generally be avoided.

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
  11. O'Leary JG, McKenna GJ, Klintmalm GB, Davis GL (2013) "Effect of telaprevir on the pharmacokinetics of sirolimus in liver transplant recipients." Liver Transpl, 19, p. 463-5
  12. (2022) "Product Information. Fyarro (sirolimus protein-bound)." Aadi Bioscience, Inc.
View all 12 references

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Drug and food interactions

Moderate

ketoconazole food

Applies to: 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 protein-bound food

Applies to: sirolimus protein-bound

GENERALLY AVOID: Coadministration of protein-bound sirolimus intravenous suspension with grapefruit juice may increase the systemic exposure to sirolimus. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of sirolimus by certain compounds present in grapefruit. However, grapefruit juice primarily inhibits CYP450 3A4-mediated first-pass metabolism in the gut wall and may have limited effects on medications that are not administered orally. No formal studies evaluating the drug interaction potential of protein-bound sirolimus have been conducted. 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.

MANAGEMENT: The manufacturer recommends avoiding grapefruit and grapefruit juice during treatment with protein-bound sirolimus.

References

  1. (2022) "Product Information. Fyarro (sirolimus protein-bound)." Aadi Bioscience, Inc.

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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.

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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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