Drug Interactions between Adderall and selumetinib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of selumetinib, which undergoes metabolism primarily by CYP450 3A4 and to a lesser extent by CYP450 2C19, 1A2, 2C9, 2E1 and 3A5, as well as glucuronidation by UGT1A1 and UGT1A3. 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 coadministered with itraconazole, a potent CYP450 3A4 inhibitor, selumetinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 19% and 49%, respectively. When coadministered with fluconazole, a potent CYP450 2C19 and moderate CYP450 3A4 inhibitor, selumetinib Cmax and AUC increased by 26% and 53%, respectively. Concomitant use of erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase selumetinib Cmax and AUC by 23% and 41%, respectively. 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 selumetinib may increase the risk and/or severity of serious adverse effects such as cardiomyopathy (decrease in left ventricular ejection fraction by 10% or more below baseline), ocular toxicity (blurred vision, photophobia, cataracts, ocular hypertension, retinal pigment epithelial detachment, retinal vein occlusion), gastrointestinal toxicity (diarrhea, colitis), skin toxicity (dermatitis acneiform, maculopapular rash, eczema), and musculoskeletal toxicity (creatine phosphokinase elevations, myalgia, rhabdomyolysis).

MANAGEMENT: Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with selumetinib.

GENERALLY AVOID: Alcohol may potentiate the cardiovascular effects of amphetamines. The exact mechanism of interaction is unknown. In one study, concurrent administration of methamphetamine (30 mg intravenously) and ethanol (1 gm/kg orally over 30 minutes) increased heart rate by 24 beats/minute compared to methamphetamine alone. This increases cardiac work and myocardial oxygen consumption, which may lead to more adverse cardiovascular effects than either agent alone. Subjective effects of ethanol were diminished in the eight study subjects, but those of methamphetamine were not affected. The pharmacokinetics of methamphetamine were also unaffected except for a decrease in the apparent volume of distribution at steady state. The interaction was suspected in a case report of a 20-year-old male who experienced retrosternal chest pain shortly after drinking alcohol and taking a double dose of his amphetamine/dextroamphetamine medication (Adderall 15 mg X 2) to stay alert. The patient had no family history of cardiovascular diseases, and his past medical history was remarkable only for ADHD. Prior to the episode, the patient had not taken his medication for weeks and had been drinking whiskey the previous three nights before going to bed. The patient was diagnosed with myocardial infarction likely secondary to amphetamine-induced coronary vasospasm.

MANAGEMENT: Concomitant use of amphetamines and alcohol should be avoided if possible, especially in patients with a history of heart disease.

GENERALLY AVOID: Alcohol may potentiate the cardiovascular effects of amphetamines. The exact mechanism of interaction is unknown. In one study, concurrent administration of methamphetamine (30 mg intravenously) and ethanol (1 gm/kg orally over 30 minutes) increased heart rate by 24 beats/minute compared to methamphetamine alone. This increases cardiac work and myocardial oxygen consumption, which may lead to more adverse cardiovascular effects than either agent alone. Subjective effects of ethanol were diminished in the eight study subjects, but those of methamphetamine were not affected. The pharmacokinetics of methamphetamine were also unaffected except for a decrease in the apparent volume of distribution at steady state. The interaction was suspected in a case report of a 20-year-old male who experienced retrosternal chest pain shortly after drinking alcohol and taking a double dose of his amphetamine/dextroamphetamine medication (Adderall 15 mg X 2) to stay alert. The patient had no family history of cardiovascular diseases, and his past medical history was remarkable only for ADHD. Prior to the episode, the patient had not taken his medication for weeks and had been drinking whiskey the previous three nights before going to bed. The patient was diagnosed with myocardial infarction likely secondary to amphetamine-induced coronary vasospasm.

MANAGEMENT: Concomitant use of amphetamines and alcohol should be avoided if possible, especially in patients with a history of heart disease.