Drug Interaction Report

MONITOR: Concomitant treatment with other antihypertensive agents or vasodilators, including alpha-adrenoreceptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-adrenergic blockers, calcium channel blockers, diuretics and nitrates, may potentiate the hypotensive effects of hydralazine and dihydralazine.

MANAGEMENT: Blood pressure and heart rate should be closely monitored when hydralazine or dihydralazine is used with other agents that can induce hypotension.

MONITOR: Concomitant treatment with other antihypertensive agents or vasodilators, including alpha-adrenoreceptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-adrenergic blockers, calcium channel blockers, diuretics and nitrates, may potentiate the hypotensive effects of hydralazine and dihydralazine.

MANAGEMENT: Blood pressure and heart rate should be closely monitored when hydralazine or dihydralazine is used with other agents that can induce hypotension.

MONITOR: Concomitant treatment with other antihypertensive agents or vasodilators, including alpha-adrenoreceptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-adrenergic blockers, calcium channel blockers, diuretics and nitrates, may potentiate the hypotensive effects of hydralazine and dihydralazine.

MANAGEMENT: Blood pressure and heart rate should be closely monitored when hydralazine or dihydralazine is used with other agents that can induce hypotension.

MONITOR: The hypotensive effects of thiazide diuretics and alpha-adrenergic blockers may be additive. Postural hypotension may occur.

MANAGEMENT: Hemodynamic responses should be monitored during coadministration, especially during the first few weeks of therapy. Patients should be advised to take the alpha-blocker at bedtime and to notify their physician if they experience dizziness or syncope while awake.

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.

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medications affect them.

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medications affect them.

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medications affect them.