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Fexofenadine (Allegra®): A new H1 Antagonist

Karen Shalansky, Pharm.D.
This article appeared in Vancouver Hospital Drug & Therapeutics Newsletter 1998;5(2):5

Fexofenadine is a second generation selective non-sedating histamine (H1) antagonist indicated for the relief of symptoms associated with seasonal allergic rhinitis. It is the predominant active metabolite of terfenadine (Seldane®).

Pharmacokinetics

Following a 60mg oral dose, antihistaminic effects occur within one hour, peak at 6 hours and last at least 12 hours.1 Fexofenadine is only 0.5-1.5% metabolized to an inactive metabolite in the liver via the cytochrome p450 3A4 isoenzyme system (CYP 3A4). It is primarily eliminated unchanged in the feces (80%) and urine (11%) with an elimination half-life of 11-16 hours.

Comparison to Non-sedating Antihistamines

Fexofenadine has been directly compared to cetirizine (Reactine®) in a double-blind, randomized, placebo-controlled trial of 839 patients.2 Fexofenadine 120mg and 180mg daily, and cetirizine 10mg daily administered for 14 days were similar and superior to placebo for the treatment of seasonal allergic rhinitis. Adverse effects (headache and drowsiness) were similar in all three treatment groups.

Potential Advantages over Other Antihistamines

Two non-sedating antihistamines, terfenadine and astemizole (Hismanal®), have been associated with causing potentially life-threatening arrhythmias, especially when taken with interacting drugs or foods. Similar in effect to quinidine, both drugs have the propensity to block cardiac muscle potassium channels resulting in QT prolongation and cardiac arrhythmias.3,4 As well, both drugs are metabolized extensively in the liver via CYP-3A4 and drugs which inhibit this system, (e.g. erythromycin, ketoconazole) may produce potentially cardiotoxic concentrations of these drugs.

A 10 year review (1986-1996) of adverse events of non-sedating antihistamines from 17 countries, using the WHO ADR database, indicated that cetirizine and loratadine (Claritin®) have also been implicated with cardiac rate and rhythm disturbances (primarily ventricular dysrhythmias).3 Of note, both terfenadine and astemizole have been changed to prescription status in Canada due to their cardiotoxic and drug interaction potential.5

In contrast, fexofenadine has not been shown to prolong the QTc interval or affect potassium channels, even at higher dosages.4 As well, due to its minimal metabolism by CYP 3A4, significant drug/food interactions are unlikely; specifically fexofenadine has not been shown to interact with erythromycin or ketoconazole.1

Adverse Effects

Most common adverse effects reported include headache (3.1%), nausea (1.3%), drowsiness (1.3%) and fatigue (1.0%). There is not an increase in adverse events with higher doses.1

Dose/Cost

Similar to terfenadine, the dosage is 60mg BID, reduced to 60mg daily for creatinine clearances less than 40mL/minute. The cost of fexofenadine is $0.72/day (60mg BID) which is similar to terfenadine.

Conclusions

Fexofenadine is a safer, non-sedating antihistamine compared to terfenadine due to its lack of cardiotoxic or drug interaction potential. As well, it has a comparable cost and dose to terfenadine. As a result, fexofenadine has been added to formulary and terfenadine has been deleted from the VHHSC formulary.

References

1. Fexofenadine product monograph, Hoechst Marion Roussel Canada, 1997.

2. Comparative study of Allegra® and Reactine®. Data on file, Hoechst Marion Roussel Canada, Inc.

3. Lindquist M et al. Risks of non-sedating antihistamines. Lancet 1997;349:1322 (letter).

4. Woosley RL et al. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269:1532-6.

5. Losos JZ.Health Protection Branch Dear Doctor 1997;48(Nov).