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Drug Interactions between irinotecan and mavacamten

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

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Interactions between your drugs

Moderate

irinotecan mavacamten

Applies to: irinotecan and mavacamten

MONITOR: Coadministration with inducers of the CYP450 3A4 isoenzyme may decrease the plasma concentrations of irinotecan and its pharmacologically active metabolite, SN-38. Irinotecan is partially metabolized by CYP450 3A4, and induction of this process results in less of the drug available in the plasma for conversion to SN-38 via carboxylesterases. The interaction has been reported with St. John's wort and the enzyme-inducing anticonvulsants carbamazepine, phenobarbital, and phenytoin. An approximately 40% reduction in SN-38 systemic exposure (AUC) has been reported in the presence of St. John's wort and greater than 60% reductions have been reported in the presence of enzyme-inducing anticonvulsants. However, all of these agents are known to be potent inducers of CYP450 3A4 as well as other enzymatic pathways (e.g., UDP-glucuronosyl transferase, or UGT; carboxylesterases) and drug transporters (e.g., multispecific organic anion transporter, or MRP2; P-glycoprotein) that may be involved in the clearance of irinotecan and/or SN-38. The extent, if any, to which irinotecan may interact with less potent CYP450 3A4 inducers is unknown.

MANAGEMENT: The antitumour activity of irinotecan may be reduced in patients treated with CYP450 3A4 inducers. Pharmacologic response to irinotecan should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the irinotecan dosage adjusted as necessary.

References (15)
  1. (2001) "Product Information. Camptosar (irinotecan)." Pharmacia and Upjohn
  2. De Bruijn P, De Jonge MJ, Mathijssen RH, Sparreboom A, Verweij J (2002) Modulation of irinotecan(CPT-11)metabolism by St. John's wort in cancer patients. http:aacr02.agora.com/planner/displayabstract.asp?presentationid=2603
  3. Murry DJ, Cherrick I, Salama V, et al. (2002) "Influence of phenytoin on the disposition of irinotecan: a case report." J Pediatr Hematol Oncol, 24, p. 130-3
  4. Mathijssen RH, Verweij J, De Bruijn P, Loos WJ, Sparreboom A (2002) "Effects of St. John's Wort on Irinotecan Metabolism." J Natl Cancer Inst, 94, p. 1247-9
  5. Kuhn JG (2002) "Influence of anticonvulsants on the metabolism and elimination of irinotecan. A North American Brain Tumor Consortium preliminary report." Oncology (Williston Park, 16(8 Suppl 7), p. 33-40
  6. Friedman HS, Petros WP, Friedman AH, et al. (1999) "Irinotecan therapy in adults with recurrent or progressive malignant glioma." J Clin Oncol, 17, p. 1516-25
  7. Santos A, Zanetta S, Cresteil T, et al. (2000) "Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans." Clin Cancer Res, 6, p. 2012-20
  8. Yonemori K, Takeda Y, Toyota E, Kobayashi N, Kudo K (2004) "Potential interactions between irinotecan and rifampin in a patient with small-cell lung cancer." Int J Clin Oncol, 9, p. 206-9
  9. Innocenti F, Undevia SD, Ramirez J, et al. (2004) "A phase I trial of pharmacologic modulation of irinotecan with cyclosporine and phenobarbital." Clin Pharmacol Ther, 76, p. 490-502
  10. Di YM, Li CG, Xue CC, Zhou SF (2008) "Clinical drugs that interact with St. John's wort and implication in drug development." Curr Pharm Des, 14, p. 1723-42
  11. Crews KR, Stewart CF, Jones-Wallace D, et al. (2002) "Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy." Clin Cancer Res, 8, p. 2202-9
  12. Radomski KM, Gajjar AJ, Kirstein MN, et al. (2000) "Irinotecan clearance is increased by concomitant administration of enzyme inducers in a patient with glioblastoma multiforme." Pharmacotherapy, 20, p. 353
  13. Minami H, Lad TE, Nicholas MK, Vokes EE, Ratain MJ (1999) "Pharmacokinetics and pharmacodynamics of 9-aminocamptothecin infused over 72 hours in phase II studies." Clin Cancer Res, 5, p. 1325-30
  14. Zamboni WC, Gajjar AJ, Heideman RL, et al. (1998) "Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma." Clin Cancer Res, 4, p. 783-9
  15. (2015) "Product Information. Onivyde (irinotecan liposomal)." Merrimack Pharmaceuticals

Drug and food interactions

Major

mavacamten food

Applies to: mavacamten

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of mavacamten. 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. According to the prescribing information, mavacamten is primarily metabolized by CYP450 2C19 (74%) and to a lesser extent by CYP450 3A4 (18%) and 2C9 (8%). When mavacamten (25 mg) was coadministered with the moderate CYP450 3A4 inhibitor verapamil (sustained-release 240 mg) in intermediate and normal metabolizers of CYP450 2C19, mavacamten systemic exposure (AUC) increased by 15% and peak plasma concentration (Cmax) increased by 52%. Concomitant use of mavacamten with diltiazem, another moderate CYP450 3A4 inhibitor, in CYP450 2C19 poor metabolizers is predicted to increase mavacamten AUC and Cmax by up to 55% and 42%, respectively. Concomitant use of mavacamten (15 mg) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily) is predicted to increase mavacamten AUC and Cmax by up to 130% and 90%, respectively. Because mavacamten reduces systolic contraction and left ventricular ejection fraction, increased exposure may potentiate the risk of heart failure. 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.

Food does not affect the extent of absorption of mavacamten. No clinically significant difference in mavacamten exposure was observed following administration with a high-fat meal. However, the time to reach peak plasma concentration (Tmax) was increased by 4 hours.

MANAGEMENT: Mavacamten may be administered with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with mavacamten.

References (2)
  1. (2022) "Product Information. Camzyos (mavacamten)." MyoKardia Inc
  2. (2023) "Product Information. Camzyos (mavacamten)." (Obsolete) Bristol-Myers Squibb Australia Pty Ltd, 2

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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