Antihistamines That Do Not Prolong QT Interval
Cetirizine, loratadine, desloratadine, fexofenadine, and levocetirizine are safe antihistamines that do not prolong the QT interval and should be your first-line choices when cardiac safety is a concern. 1, 2, 3, 4
Safe Antihistamines (No QT Prolongation)
The following antihistamines have been extensively studied and shown NOT to prolong the QT interval:
Fexofenadine (the active metabolite of terfenadine) does not block cardiac K+ channels and is not associated with QT prolongation even when combined with erythromycin or ketoconazole 5, 2, 3, 4
Loratadine and its metabolite desloratadine do not significantly inhibit cardiac K+ channels at clinically achievable blood levels and are not associated with torsades de pointes 1, 3, 6, 4
Cetirizine and its active enantiomer levocetirizine are completely devoid of inhibitory action on cardiac potassium channels (HERG) at concentrations up to 30 μmol/L 1, 3, 6, 4
Acrivastine is available in the UK and is taken three times daily due to its short half-life, with no documented QT prolongation risk 5
Antihistamines to AVOID (QT Prolongation Risk)
The following antihistamines DO prolong the QT interval and should be avoided when cardiac safety is a concern:
Terfenadine and astemizole are potent blockers of cardiac K+ channels (HERG) with nanomolar affinities (330 and 480 nmol/L respectively) and have been withdrawn from most markets due to torsades de pointes risk 5, 3, 6, 4
Mizolastine is contraindicated in clinically significant cardiac disease and when there is prolongation of the QT interval, and should not be taken with drugs that inhibit hepatic metabolism via cytochrome P450 (including macrolide antibiotics and imidazole antifungals) or with drugs that have potential arrhythmic properties 5
Ebastine produces significant QT interval prolongation and arrhythmogenic effects in animal models 6
Practical Prescribing Algorithm
For patients WITHOUT cardiac risk factors:
- Prescribe cetirizine 10 mg once daily, loratadine 10 mg once daily, desloratadine 5 mg once daily, fexofenadine 120-180 mg once daily, or levocetirizine 5 mg once daily 5, 2
For patients WITH cardiac risk factors (prolonged baseline QT, cardiac disease, electrolyte abnormalities, or taking other QT-prolonging drugs):
- Strongly prefer fexofenadine, loratadine, desloratadine, cetirizine, or levocetirizine 1, 3, 4
- Absolutely avoid terfenadine, astemizole, mizolastine, and ebastine 5
For patients taking CYP3A4 inhibitors (macrolide antibiotics, azole antifungals):
- Use fexofenadine, cetirizine, or levocetirizine as these do not undergo significant CYP3A4 metabolism and have no cardiac effects even with enzyme inhibitors 5, 2, 4
- Avoid loratadine in patients taking amiodarone or other enzyme inhibitors due to rare case reports of interactions 1
Important Clinical Caveats
Cetirizine considerations: While cetirizine does not prolong QT, reduce the dose by half in moderate renal impairment and avoid in severe renal impairment (creatinine clearance <10 mL/min) 5. Two vague case reports exist linking cetirizine to QT prolongation, but one involved overdose and renal failure, making causality uncertain 1
Desloratadine pharmacology: The FDA label shows that at supratherapeutic doses (45 mg daily for 10 days, nine times the recommended dose), desloratadine increased mean heart rate by 9.2 bpm and QTc by 8.1 msec using Bazett's correction, but only 0.4 msec using Fridericia's correction, with no clinically relevant adverse events reported 7. At therapeutic doses (5 mg daily), desloratadine does not prolong QT 7, 1
Hydroxyzine warning: Cetirizine is the active metabolite of hydroxyzine, which has been associated with QT prolongation in studies from the 1960s and rare cases of cardiac arrhythmia 1. Therefore, avoid hydroxyzine in patients with cardiac concerns and use cetirizine instead 1
Drug interaction principle: The vast majority of terfenadine-associated torsades de pointes cases involved inhibition of CYP3A4 metabolism due to advanced liver disease, overdose, or concomitant use of specific inhibitor drugs (erythromycin, ketoconazole) 5. This underscores the importance of checking for drug interactions even with "safe" antihistamines 5