What are the drug interactions between astemizole (Hismanal) and erythromycin?

Serious and Potentially Fatal Drug Interaction Between Astemizole (Hismanal) and Erythromycin

Astemizole and erythromycin must never be prescribed together due to the risk of fatal cardiac arrhythmias, specifically torsades de pointes—this combination is absolutely contraindicated. 1, 2, 3

Mechanism of the Interaction

This interaction occurs through two synergistic mechanisms that dramatically increase cardiac risk:

Pharmacokinetic Mechanism

• Erythromycin is a potent inhibitor of the CYP3A4 enzyme system, which is responsible for metabolizing astemizole to inactive compounds 1, 3
• When erythromycin blocks this metabolism, astemizole accumulates to toxic levels in the bloodstream 1, 4
• The primary metabolite desmethylastemizole also accumulates and is equally cardiotoxic, with steady-state concentrations exceeding astemizole by more than 30-fold 5

Pharmacodynamic Mechanism

• Both astemizole and erythromycin directly block cardiac potassium channels (specifically HERG/IKr channels), which prolongs cardiac repolarization 1, 3, 5
• Astemizole blocks HERG channels with extraordinary potency (half-maximal block at 0.9 nM), making it one of the most potent HERG antagonists studied 5
• This dual blockade causes additive QT interval prolongation on the electrocardiogram 1, 4

Clinical Consequences

Cardiac Arrhythmias

• The combination causes acquired long QT syndrome, which predisposes to torsades de pointes—a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation 1, 4, 6
• Fatal cardiac arrests have been documented with this drug combination 1, 3, 4
• Even in children treated with recommended doses, QT prolongation has been observed, though clinical significance varies 7

Real-World Occurrence

• Concurrent prescribing of these medications increased more than threefold between 1991-1992, with 122 documented episodes in Oregon Medicaid data alone 8
• In 48% of cases, patients received prescriptions from different physicians who were unaware of the interaction 8
• Most episodes (94%) involved terfenadine (a related antihistamine with identical risks), but astemizole carries the same danger 8

Absolute Contraindications

The following combinations are explicitly contraindicated by FDA labeling and CDC guidelines:

• Erythromycin with astemizole 1, 2, 3
• Erythromycin with terfenadine (chemically related antihistamine) 1, 3
• Erythromycin with cisapride or pimozide (other QT-prolonging drugs) 1, 3

Safe Alternatives

For Antibiotic Therapy

If a macrolide antibiotic is needed in a patient taking astemizole:

• Azithromycin is the preferred alternative because it does not significantly inhibit CYP3A4 enzymes and has minimal cardiac effects compared to erythromycin 1, 9, 2
• Azithromycin can prolong QT interval through pharmacodynamic effects, but lacks the dangerous pharmacokinetic interaction 9

For Antihistamine Therapy

If antihistamine therapy is needed in a patient requiring erythromycin:

• Loratadine or cetirizine are safe alternatives that do not produce torsades de pointes and show no significant QT prolongation even when combined with erythromycin 4, 7
• These second-generation antihistamines lack the cardiotoxic profile of astemizole 4, 7

Clinical Monitoring Pitfalls

Common Prescribing Errors

• Nearly half of dangerous concurrent prescriptions occur when patients see different physicians who are unaware of existing medications 8
• Pharmacy-level screening could prevent 97% of these interactions, as patients typically use the same pharmacy 8

High-Risk Scenarios

• Patients with underlying QT prolongation (congenital long QT syndrome) are at extreme risk—even a single case report documents torsades de pointes requiring temporary cardiac pacing 6
• Elderly patients with reduced hepatic function have impaired drug metabolism, increasing risk 3
• Concurrent use of other QT-prolonging medications amplifies the danger 1

Regulatory Status

Note: Astemizole (Hismanal) has been withdrawn from the market in most countries, including the United States, specifically due to these life-threatening cardiac risks 1. If a patient reports taking this medication, it should be discontinued immediately and replaced with a safer alternative.