Drug Interactions between allopurinol / lesinurad and amlodipine / benazepril

MONITOR CLOSELY: Coadministration of allopurinol with angiotensin converting enzyme (ACE) inhibitors has been associated with a risk of severe hypersensitivity reactions, neutropenia, agranulocytosis, and serious infections. The mechanism of interaction is unknown, but impaired renal function may be a predisposing factor. Case reports, albeit rare, have mostly involved captopril. Fever, myalgia, arthralgia, exfoliative dermatitis, and Stevens-Johnson syndrome (including one fatality) have been reported, with the latter occurring 3 to 5 weeks after initiation of allopurinol. In an isolated case involving enalapril, a man who had been receiving enalapril without incident developed generalized pruritus, urticaria, severe chest pain, severe nausea, peripheral cyanosis, hypotension, sinus tachycardia, and mild bronchospasm approximately 20 minutes after the first dose of allopurinol 100 mg prescribed for acute gout. Serial electrocardiograms and cardiac enzyme studies revealed evidence of acute myocardial infarction. Following recovery, the patient continued to take enalapril uneventfully without allopurinol. No pharmacokinetic interactions have been reported between allopurinol and ACE inhibitors. In a study of 12 healthy volunteers, allopurinol had no significant effect on the bioavailability of captopril.

MANAGEMENT: Caution is advised if allopurinol is prescribed in combination with an ACE inhibitor, particularly in the elderly and patients with renal impairment. Periodic monitoring of white blood cell counts is recommended. Patients should be advised to promptly discontinue these medications and seek medical attention if they develop dyspnea; throat constriction; swelling of the face, lips, or tongue; urticaria; rash; fever; arthralgia; or myalgia. Patients should also contact their physician if they notice signs of infection or experience fever, chills, sore throat, lethargy, body aches, or other flu-like symptoms.

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MONITOR: Coadministration with lesinurad may decrease the plasma concentrations of drugs that are sensitive CYP450 3A4 substrates. Lesinurad is a weak CYP450 3A4 inducer. In drug interaction studies conducted in healthy subjects, lesinurad reduced systemic exposure (AUC) to sildenafil and amlodipine, both CYP450 3A4 substrates, by approximately 30% to 40%. In contrast, lesinurad had no clinically significant effects on the pharmacokinetics of atorvastatin and colchicine, also CYP450 3A4 substrates.

MANAGEMENT: Patients receiving concomitant drugs that are sensitive CYP450 3A4 substrates or substrates with narrow therapeutic ranges should be monitored for potentially diminished therapeutic response to those drugs during treatment with lesinurad. Alternative treatments or dosage adjustments may be required if an interaction is suspected.

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Calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors may have additive hypotensive effects. While these drugs are often safely used together, careful monitoring of the systemic blood pressure is recommended during coadministration, especially during the first one to three weeks of therapy.

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