Drug Interactions between avapritinib and nabumetone

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of avapritinib. 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. Based on pharmacokinetic modeling, administration of avapritinib (300 mg once daily) in combination with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily) is predicted to increase avapritinib systemic exposure (AUC) by 600% at steady state, while administration with the moderate CYP450 3A4 inhibitor fluconazole (200 mg once daily) is predicted to increase avapritinib systemic exposure (AUC) by 210% 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 exposure to avapritinib may increase the risk and/or severity of serious adverse effects such as intracranial hemorrhage, cognitive impairment, mood disorders, hallucinations, edema, and decreases in hemoglobin, leukocytes, neutrophils, and platelets.

ADJUST DOSING INTERVAL: Food may increase the oral absorption of avapritinib. When avapritinib was administered with a high-calorie, high-fat meal (approximately 909 calories; 58 g carbohydrate, 56 g fat, 43 g protein), avapritinib Cmax and AUC increased by 59% and 29%, respectively, compared to administration in the fasted state.

MANAGEMENT: Avapritinib should be administered on an empty stomach at least 1 hour before or 2 hours after a meal. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with avapritinib.

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.