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Drug Interactions between ketoconazole and siponimod

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

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Interactions between your drugs

Major

ketoconazole siponimod

Applies to: ketoconazole and siponimod

GENERALLY AVOID: Coadministration with drugs that cause moderate inhibition of CYP450 2C9 and moderate or strong inhibition of CYP450 3A4 may increase the plasma concentrations of siponimod, which is primarily metabolized by these isoenzymes. This interaction includes concomitant use of siponimod with a moderate CYP450 2C9/3A4 dual inhibitor or a moderate CYP450 2C9 inhibitor in combination with a separate moderate or strong CYP450 3A4 inhibitor. In healthy CYP450 2C9*1/*1 genotype volunteers, coadministration of a moderate CYP450 2C9/3A4 dual inhibitor (fluconazole 200 mg daily at steady-state) and siponimod (a single 4 mg dose) resulted in 2-fold and 50% increases in siponimod AUC and terminal half-life, respectively. According to in silico (computer-based) evaluation, use of fluconazole resulted in a 2- to 4-fold increase in the steady-state AUC of siponimod across different CYP450 2C9 genotypes. The CYP450 2C9 genotype influences the fractional contributions of CYP450 2C9 and 3A4 to overall elimination. If the metabolic activity of CYP450 2C9 is decreased, a larger contribution of CYP450 3A4 can be anticipated.

MANAGEMENT: Concomitant use of siponimod with a moderate or strong CYP450 2C9/3A4 dual inhibitor (e.g., fluconazole, mifepristone) or a moderate CYP450 2C9 inhibitor (e.g., abiraterone, amiodarone, fenofibrate, gemfibrozil, nitisinone, oxandrolone) in combination with a moderate or strong CYP450 3A4 inhibitor (e.g., amprenavir, aprepitant, atazanavir, boceprevir, ceritinib, chloramphenicol, ciprofloxacin, clarithromycin, cobicistat, conivaptan, crizotinib, dalfopristin-quinupristin, darunavir, delavirdine, diltiazem, dronedarone, erythromycin, fedratinib, fluvoxamine, fosamprenavir, fosaprepitant, fosnetupitant, fusidic acid, idelalisib, imatinib, indinavir, isavuconazole, itraconazole, ketoconazole, letermovir, mibefradil, nefazodone, nelfinavir, netupitant, posaconazole, ribociclib, ritonavir, saquinavir, stiripentol, telaprevir, telithromycin, troleandomycin, verapamil, voriconazole, voxelotor) is not recommended. Caution is advised if siponimod is used in combination with moderate CYP450 2C9 inhibitors.

References

  1. Cerner Multum, Inc. "Australian Product Information."
  2. (2019) "Product Information. Mayzent (siponimod)." Novartis Pharmaceuticals

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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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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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