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Drug Interactions between Cerdelga and ketoconazole

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

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Interactions between your drugs

Major

ketoconazole eliglustat

Applies to: ketoconazole and Cerdelga (eliglustat)

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of eliglustat, which is primarily metabolized by CYP450 2D6 and, to a lesser extent, CYP450 3A4. Eliglustat at substantially elevated plasma concentrations is predicted to cause prolongation of the PR, QTc and QRS cardiac intervals, which may increase the risk of bradycardia, atrioventricular block, cardiac arrest, and serious ventricular arrhythmias such as torsade de pointes. In 31 subjects who were CYP450 2D6 extensive metabolizers (EMs), eliglustat peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 4.0- and 4.4-fold, respectively, following coadministration of eliglustat (84 mg twice daily) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily). Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that ketoconazole may increase eliglustat Cmax by 4.4-fold and AUC by 5.4-fold in CYP450 2D6 intermediate metabolizers (IMs). PBPK modeling also suggest that ketoconazole may increase eliglustat Cmax by 4.3-fold and AUC by 6.2-fold in CYP450 2D6 poor metabolizers (PMs) given eliglustat 84 mg once daily (half the dosage used in EMs). The magnitude of interaction is expected to increase further with the addition of a CYP450 2D6 inhibitor like paroxetine. Simulations using PBPK models suggest that the combination of ketoconazole (400 mg once daily) and paroxetine (30 mg once daily) may increase eliglustat Cmax by 16.7-fold and AUC by 24.2-fold in EMs given eliglustat 84 mg twice daily. For IMs, the estimated increases in eliglustat Cmax and AUC are 7.5- and 9.8-fold, respectively.

MANAGEMENT: The use of eliglustat with a potent CYP450 3A4 inhibitor is considered contraindicated in CYP450 2D6 poor metabolizers (PMs) and intermediate metabolizers (IMs). The contraindication is extended to extensive metabolizers (EMs) when a moderate or potent CYP450 2D6 inhibitor is given concomitantly with a moderate or potent CYP450 3A4 inhibitor. In the absence of a concomitant CYP450 2D6 inhibitor, eliglustat may be prescribed at a reduced dosage of 84 mg once daily to EMs treated with a potent CYP450 3A4 inhibitor. Potent CYP450 3A4 inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, ceritinib, idelalisib, mibefradil, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. Potent and moderate CYP450 2D6 inhibitors include abiraterone, bupropion, celecoxib, cimetidine, cinacalcet, clobazam, darifenacin, diphenhydramine, dronedarone, duloxetine, flecainide, fluoxetine, methotrimeprazine, mirabegron, paroxetine, propafenone, propoxyphene, quinidine, ranolazine, sertraline, and terbinafine. Some drugs such as cobicistat, delavirdine, mibefradil, adagrasib and ritonavir are dual CYP450 3A4 and 2D6 inhibitors, and they should not be used with eliglustat in any patient regardless of their CYP450 2D6 metabolizer status. The product labeling for itraconazole states that concomitant use with eliglustat is contraindicated in CYP450 2D6 EMs taking a strong or moderate CYP450 2D6 inhibitor, CYP450 2D6 IMs and PMs during and for 2 weeks after treatment with itraconazole.

References

  1. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals PROD (2002):
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  3. Cerner Multum, Inc. "Australian Product Information." O 0
  4. "Product Information. Cerdelga (eliglustat)." Genzyme Corporation (2014):
View all 4 references

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Drug and food interactions

Major

eliglustat food

Applies to: Cerdelga (eliglustat)

GENERALLY AVOID: Grapefruit juice may significantly increase the systemic exposure to eliglustat. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because eliglustat is predicted to cause prolongation of the PR, QTc, and QRS cardiac intervals at substantially elevated plasma concentrations, consumption of grapefruit juice during treatment may increase the risk of bradycardia, atrioventricular block, cardiac arrest, and serious ventricular arrhythmias such as torsade de pointes.

MANAGEMENT: Patients treated with eliglustat should avoid consumption of grapefruit and grapefruit juice.

References

  1. "Product Information. Cerdelga (eliglustat)." Genzyme Corporation (2014):

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

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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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