Fexofenadine

Fexofenadine hydrochloride (brand names include Allegra and Telfast) is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms. It was developed as a successor of and alternative to terfenadine (brand names include Triludan and Seldane), an antihistamine with potentially serious contraindications. Fexofenadine, like other second and third-generation antihistamines, does not readily enter the brain from the blood, and so causes less drowsiness than first-generation histamine-receptor antagonists. It works by being an antagonist to the H₁ receptor.^[1]

Additional recommended knowledge

Daily Visual Balance Check

Essential Laboratory Skills Guide

Guide to balance cleaning: 8 simple steps

Common side effects

• Nausea
• Vomiting
• Weakness
• Drowsiness, sleepiness

Dosing

For seasonal allergies the recommended dose for adults and children 12 years or older is 60 mg twice daily or 180 mg once daily. Children 6-11 years of age should be given 30 mg twice daily. For chronic urticaria, adults and children 12 years or older should use 60 mg twice daily, and children 6-11 years of age should use 30 mg twice daily. Take Fexofenadine with water (not fruit juice).^[2] Fexofenadine can be taken with or without food.

Drug Interactions

In controlled clinical studies there were no interactions with other drugs that significantly affected the safety or effectiveness of fexofenadine.

Overdose

Reports of fexofenadine overdose are infrequent, and because of this, the effects are not well established. No deaths occurred in testing on mice, at 5000 mg/kg, which is 110 times the maximum recommended dose for an adult human. Further research shows no deaths in rats at the same concentration, which equates four hundred times the recommended dose in an adult human. Research on humans ranges from a single 800 mg dose, to a twice-daily 690 mg dose for a month, with no clinically significant adverse effects, when compared to a placebo.

History

The older antihistaminic agent terfenadine was found to metabolize into the related carboxylic acid, fexofenadine. Fexofenadine was found to retain all of the biological activity of its parent while giving fewer adverse reactions in patients, so terfenadine was replaced in the market by its metabolite.^[3] Fexofenadine was developed by Hoechst Marion Roussel (now part of Sanofi-Aventis) and approved by the Food and Drug Administration (FDA) in 1996. AMRI holds the patents to the intermediates and production of fexofenadine HCl along with Roussel. Since that time, it has achieved blockbuster drug status with global sales of $1.87B USD in 2004 (with $1.49B USD coming from the United States). AMRI received royalty payments from Aventis that enabled the growth of AMRI.

Synthesis

Fexofenadine may be synthesized as shown from piperidine-4-carboxylate ester and 4-bromophenylacetonitrile (where Ph=phenyl).^[3]

To produce the piperidine piece, two phenyl groups are first introduced using a Grignard reaction on the ester, giving a tertiary alcohol. The amine group is then alkylated with a protected aldehyde, then the aldehyde is recovered by deprotection with acid. The remaining piece of the molecule is produced by a double alkylation by iodomethane of the carbanion derived from the nitrile. The nitrile group is then hydrolyzed to a carboxylic acid. The aryl bromide is then lithiated to produce the organolithium compound, which can be coupled with the aldehyde piece to give (after workup) fexofenadine.

Notes

References

• Synthesis: J. Org. Chem. 1994, 59, 2620.
• Biological effects: Mol. Pharmacol. 1993, 44, 1240.