Drug Interaction Report

MONITOR CLOSELY: Apomorphine may potentiate the hypotensive effects of vasodilators, antihypertensive agents, or agents with hypotensive properties. Apomorphine alone has been associated with orthostatic hypotension, hypotension, syncope, and dose-dependent decreases in systolic and diastolic blood pressure. In clinical studies of the subcutaneous formulation of apomorphine in patients with advanced Parkinson's disease, hypotension (10% vs 4%), myocardial infarction (3% vs. 1%), serious pneumonia (5% vs. 3%), serious falls (9% vs. 3%), and bone and joint injuries (6% vs. 2%) were experienced more commonly in patients receiving concomitant antihypertensive medications or vasodilators (n=94) compared to those not receiving these medications (n=456). Some of these events may be related to the increased incidence of hypotension.

MANAGEMENT: Caution and close monitoring for altered efficacy and safety are recommended if patients receive apomorphine with an antihypertensive agent, vasodilator, or agents with hypotensive properties. Patients should be made aware of the possible side effects (e.g., dizziness, lightheadedness, orthostasis) and be cautioned about driving, operating machinery, or performing other hazardous tasks. They should also be advised to avoid rising abruptly from a sitting or recumbent position and to contact their physician if they experience symptoms of hypotension such as dizziness, lightheadedness, or fainting.

GENERALLY AVOID: Alcohol and apomorphine may have additive hypotensive and sedative effects. Coadministration of 0.6 or 0.3 g/kg of ethanol with apomorphine in healthy subjects resulted in greater decreases in blood pressure compared to apomorphine alone. The mean largest decrease (the mean of each subject's largest drop in blood pressure measured within 6 hours after apomorphine administration) in standing systolic and diastolic blood pressure was 6.7 and 8.4 mmHg, respectively, with apomorphine alone. When coadministered with 0.6 g/kg of ethanol (equivalent to approximately 3 standardized alcohol-containing beverages), the mean largest decrease in standing systolic and diastolic blood pressure was 11.3 and 12.6 mmHg, respectively (standing systolic and diastolic blood pressure decreased by as much as 61 and 51 mmHg, respectively, in this group). When coadministered with 0.3 g/kg of ethanol, the mean largest decrease in standing systolic and diastolic blood pressure was 8.4 and 7.1 mmHg, respectively.

MANAGEMENT: Patients should be advised to avoid consumption of alcohol during apomorphine treatment.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of macitentan, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has not been studied with grapefruit juice but has been reported for ketoconazole, a potent CYP450 3A4 inhibitor. In ten healthy subjects, coadministration of a single 10 mg oral dose of macitentan on day 5 of treatment with ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure compared to administration alone. However, the clinical significance of the interaction is unclear. 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.

MANAGEMENT: Until further information is available, patients receiving macitentan therapy should avoid the consumption of grapefruit or grapefruit juice.