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Drug Interactions between clopidogrel and fedratinib

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

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Interactions between your drugs

Moderate

clopidogrel fedratinib

Applies to: clopidogrel and fedratinib

MONITOR: Coadministration with inhibitors of CYP450 2C19 may reduce the efficacy of clopidogrel, whose antiplatelet effect is dependent in part on bioactivation by the isoenzyme to a pharmacologically active metabolite. This is consistent with studies that reported decreased effectiveness of clopidogrel and poorer clinical outcome in patients who have common genetic polymorphisms of CYP450 2C19 resulting in reduced or absent enzyme activity. The interaction has been studied with omeprazole, a potent CYP450 2C19 inhibitor. In 72 healthy subjects administered clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg) simultaneously for 5 days, systemic exposure to the active metabolite of clopidogrel decreased by 46% (Day 1) and 42% (Day 5) during coadministration with omeprazole, while mean inhibition of platelet aggregation (IPA) diminished by 47% (24 hours) and 30% (Day 5). Similar results were reported when the same doses of clopidogrel and omeprazole were administered 12 hours apart in another study. Data are not available for less potent inhibitors of CYP450 2C19. However, ineffective inhibition of platelet aggregation has been reported in association with a potential interaction with amiodarone, whose active metabolite, desethylamiodarone, has been shown to inhibit CYP450 2C19 in vitro.

MANAGEMENT: Based on existing data, it may be advisable to closely monitor the therapeutic efficacy of clopidogrel during concomitant treatment with CYP450 2C19 inhibitors.

References (19)
  1. (2002) "Product Information. Cordarone (amiodarone)." Wyeth-Ayerst Laboratories
  2. (2001) "Product Information. Plavix (clopidogrel)." Bristol-Myers Squibb
  3. Ohyama K, Nakajima M, Suzuki M, Shimada N, Yamazaki H, Yokoi T (2000) "Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: Prediction of in vivo drug interactions." Br J Clin Pharmacol, 49, p. 244-53
  4. Hulot JS, Bura A, Villard E, et al. (2006) "Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects." Blood
  5. Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J (2006) "Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin." J Thromb Haemost, 4, p. 2508-9
  6. Small DS, Farid NA, Payne CD, et al. (2008) "Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel." J Clin Pharmacol, 48, p. 475-84
  7. Frere C, Cuisset T, Morange PE, et al. (2008) "Effect of Cytochrome P450 Polymorphisms on Platelet Reactivity After Treatment With Clopidogrel in Acute Coronary Syndrome." Am J Cardiol, 101, p. 1088-1093
  8. Gilard M, Arnaud B, Cornily JC, et al. (2008) "Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study." J Am Coll Cardiol, 51, p. 256-60
  9. Pezalla E, Day D, Pulliadath I (2008) "Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors." J Am Coll Cardiol, 52, p. 1038-9
  10. Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B (2009) "Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel." Am Heart J, 157, 148.e1-5
  11. (2009) "Product Information. Kapidex (dexlansoprazole)." Takeda Pharmaceuticals America
  12. Juurlink DN, Gomes T, Ko DT, et al. (2009) "A population-based study of the drug interaction between proton pump inhibitors and clopidogrel." CMAJ, 180, p. 713-8
  13. Li XQ, Andersson TB, Ahlstrom M, Weidolf L (2004) "Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities." Drug Metab Dispos, 32, p. 821-7
  14. Collet JP, Hulot JS, Pena A, et al. (2009) "Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study." Lancet, 373, p. 309-17
  15. Mega JL, Close SL, Wiviott SD, et al. (2009) "Cytochrome p-450 polymorphisms and response to clopidogrel." N Engl J Med, 360, p. 354-62
  16. Lau WC, Gurbel PA (2009) "The drug-drug interaction between proton pump inhibitors and clopidogrel." CMAJ, 180, p. 699-700
  17. Moayyedi P, Sadowski DC (2009) "Proton pump inhibitors and clopidogrel -- hazardous drug interaction or hazardous interpretation of data?" Can J Gastroenterol, 23, p. 251-2
  18. Simon T, Verstuyft C, Mary-Krause M, et al. (2009) "Genetic determinants of response to clopidogrel and cardiovascular events." N Engl J Med, 360, p. 363-75
  19. Varenhorst C, Janes S, Erlinge D, et al. (2009) "Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease." Eur Heart J, 30, p. 1744-52

Drug and food interactions

Moderate

fedratinib food

Applies to: fedratinib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of fedratinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When a single 300 mg oral dose of fedratinib (0.75 times the recommended dose) was coadministered with 200 mg twice daily ketoconazole, a potent CYP450 3A4 inhibitor, fedratinib total systemic exposure (AUC(inf)) increased by approximately 3-fold. Using physiologically based pharmacokinetic (PBPK) simulations, coadministration of fedratinib 400 mg once daily and ketoconazole 400 mg once daily is predicted to increase fedratinib AUC at steady state by 2-fold. Coadministration with the moderate CYP450 3A4 inhibitors, erythromycin (500 mg three times daily) or diltiazem (120 mg twice daily), is predicted to increase fedratinib AUC by approximately 1.5- to 2-fold following single-dose administration and by approximately 1.2-fold at steady state. 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. Increased fedratinib exposure may potentiate the risk of adverse reactions such as nausea, vomiting, diarrhea, anemia, thrombocytopenia, neutropenia, encephalopathy (including Wernicke's), liver (ALT, AST) and pancreatic (amylase, lipase) enzyme elevations, increased blood creatinine, and secondary malignancies.

Food does not affect the oral bioavailability of fedratinib to a clinically significant extent. Administration of a single 500 mg dose (1.25 times the recommended dose) with a low-fat, low-calorie meal (162 calories; 6% from fat, 78% from carbohydrate, 16% from protein) or a high-fat, high-calorie meal (815 calories; 52% from fat, 33% from carbohydrate, 15% from protein) increased fedratinib peak plasma concentration (Cmax) and systemic exposure (AUC) by up to 14% and 24%, respectively.

MANAGEMENT: Fedratinib may be taken with or without food. However, administration with a high-fat meal may help reduce the incidence of nausea and vomiting. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with fedratinib.

References (3)
  1. Wu F, Krishna G, Surapaneni S (2020) "Physiologically based pharmacokinetic modeling to assess metabolic drug-drug interaction risks and inform the drug label for fedratinib." Cancer Chemother Pharmacol, 86, p. 461-73
  2. (2022) "Product Information. Inrebic (fedratinib)." Bristol-Myers Squibb
  3. (2021) "Product Information. Inrebic (fedratinib)." Bristol-Myers Squibb Pharmaceuticals Ltd

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.

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