LETTERS - Brief Article

0 Comments | Family Practice News, June 1, 2001

Allegra Criticism Unfounded

Dr. Alan B. Fleischer Jr.'s comments that fexofenadine is "one of the least effective antihistamines ever produced" and that it has cardiotoxic side effects are completely unfounded ("Chronic Urticaria: Boost Antihistamine Dosage," March 1, 2001, p. 21).

The effectiveness and safety of fexofenadine for the treatment of chronic idiopathic urticaria (CIU) have been evaluated in over 1,000 patients in three large, randomized, placebo-controlled, multi-center clinical trials ranging from 4 to 6 weeks in duration.

Two of these studies of fexofenadine doses ranging from 20 mg to 240 mg b.i.d. demonstrated significant relief of CIU symptoms for all active dosage groups versus placebo (J. Allergy Clin. Immunol. 104[5]:1071-78, 1999; Ann. Allergy Asthma Immunol. 84[5]:517-22, 2000).

Fexofenadine and placebo groups had similar adverse event rates in all of the studies.

In a placebo-controlled study that measured peripheral [H.sub.1] receptor blockade of fexofenadine and loratadine, single-dose fexofenadine 120 mg demonstrated a significantly faster onset of action and more suppression of histamine-induced wheal and flare in the first few hours compared with loratadine 10 mg (Ann. Allergy Asthma Immunol. 79[6]:530-32, 1997).

Dr. Fleischer's comments pertaining to cardiotoxic effects with fexofenadine are unsubstantiated as well. Fexofenadine has been studied in doses as high as 690 mg b.i.d. for 4 weeks in healthy volunteers with no evidence of any serious adverse events including cardiac adverse events (data on file).

In over 1,100 seasonal allergic rhinitis patients using fexofenadine therapy with doses up to 240 mg b.i.d. for 2 weeks, ECG effects were similar to placebo (Clin. Exp. Allergy 29[Suppl. 3]:212-16, 1999). A study of the long-term safety of fexofenadine in doses up to 240 mg once daily for 1 year demonstrated ECG findings similar to placebo (Clin. Drug Invest. 18[4]:317-28, 1999).

Postmarketing surveillance of adverse events reported to Aventis Pharmaceuticals from all sources since the launch of fexofenadine and careful clinical evaluation of cardiovascular events have revealed no evidence of serious drug-related cardiac safety concerns.

This experience, in the context of over 1.7 billion patient days of exposure to fexofenadine worldwide through the end of year 2000, supports the cardiovascular safety of fexofenadine.

Vijay K. Sammeta, M.D.

Medical Information Services

Aventis Pharmaceuticals

Bridgewater, N.J.

Dr. Fleischer replies:

I completely agree with Dr. Sammeta that the risk of cardiotoxicity with fexofenadine is low. However, he recognizes that rare reactions occur. Fexofenadine appears to be significantly safer than terfenadine (Seldane). It may not, however, be free of drug interactions.

A recent controlled trial demonstrated that, in the presence of azithromycin, fexofenadine concentrations increased by 69%. This increase is trivial and insignificant for most patients, but how many can expect to have susceptibility to cardiotoxicity? One in 10,000? One in 1,000,000? One in 1 billion? I personally have met an otherwise healthy young adult who had QT-interval elongation while he was being treated with fexofenadine, which normalized upon cessation.

I cannot quantitate the cardiotoxic risk from fexofenadine, but I suspect that it must be less than the risk of peanuts. Kids asphyxiate on peanuts and anaphylactic reactions occur, but I support the availability of peanuts.

There is a separate issue: Should the dose of fexofenadine be increased beyond 180 mg/day in adults? I suggest that this is unwise. I also recognize that the magnitude of the risk of high-dose fexofenadine is low.

I have no doubt that fexofenadine is more effective than placebo. This, however, is a point to start a discussion, not to end one. We have many antihistaminic agents from which to choose. Fexofenadine and loratadine are similarly tolerated, but how do they compare in efficacy? There are convincing data suggesting that fexofenadine is absorbed quickly and suppresses histamine-induced wheal suppression quickly.

Loratadine is not as quickly absorbed and active as fexofenadine. We know this from histamine-wheal suppression studies. What about treating real diseases, like urticaria? We have no data on the comparative efficacy of fexofenadine in treating urticaria. There are, however, data regarding allergic rhinitis. In one 4-week study, loratadine was significantly more effective than fexofenadine (Clin. Ther. 22[6]:760 69, 2000).

Is this treatment advantage limited to al lergic rhinitis? I hypothesize not. I would love to see comparative efficacy data for fexofenadine versus other active agents, in cluding cetirizine, acrivastine, and others. If Aventis is convinced that fexofenadine is comparable or superior to other agents in treating chronic urticaria, why have there been no published trials comparing active agents? Readers should come to their own conclusions.

I think there is tremendous value in well-conducted randomized controlled trials, but for clinicians to make intelligent decisions, these trials need to be against other active agents. I still believe that the standard antihistaminic doses recommended are insufficient to treat many patients. Whether fexofenadine is appropriate to use in doses of 360 mg or higher is unclear.