Aventis Studying Allegra For Dermatitis And Asthma, Firm Tells OTC Cmte.

Aventis is pursuing an atopic dermatitis indication for the antihistamine Allegra, Senior VP-Medical & Regulatory Francois Nader, MD, told the FDA OTC switch advisory committee May 11.

Aventis is also seeking an indication for Allegra in asthma. Aventis presented Phase II asthma data to analysts May 16 in New York. Allegra is approved for seasonal allergic rhinitis and uncomplicated skin manifestations of chronic idiopathic urticaria.

The company is also studying antihistamine line extensions. Flash Dose rapid-dissolving tablets (30 mg for pediatrics, 180 mg for adults) and once-daily Allegra-D are expected to be approved in the first quarter of 2004. Aventis is also developing a liquid pediatric formula.

Nader outlined the Allegra development projects in response to questions asked by members of the Pulmonary-Allergy and Nonprescription Drugs Advisory Committees during the review of Wellpoint/ Blue Cross of California's citizen petition to switch Allegra (fexofenadine), Schering-Plough's Claritin (loratadine) and Pfizer's Zyrtec (cetirizine) to OTC status.

Aventis and Schering-Plough maintain that sufficient data do not yet exist to demonstrate that the prescription antihistamines can be used safely over the counter. Committee members asked Aventis what steps it is taking to collect the data the company says is necessary to demonstrate an appropriate level of safety.

By a sizable majority, the committees voted that there are sufficient data to allow safe use of the products OTC (¹ (Also see "Antihistamine OTC Switch Moves To Legal Arena After Committee Votes" - Pink Sheet, 14 May, 2001.)).

The safety concerns suggested by Schering and Aventis did resonate with a minority of the committee.

Nonprescription Drugs committee member Hari Sachs, MD, Coleman, Coleman and Sachs, questioned whether the cardiac effect seen in the three drugs could be a signal similar to that in fexofenadine's parent compound Seldane (terfenadine). Seldane was withdrawn from the market in 1998.

In a safety review of the three drugs, FDA found 86 cases of ventricular arrhythmias associated with loratadine use and 39 cases with fexofenadine. The cetirizine database listed 27 cases of arrhythmias, sudden cardiac death and QT prolongation (² ).

"It does look like there are some signals...with these medicines," Sachs maintained. Noting that there were warning signs of cardiac effects at Seldane's approval, she said: "I'm just curious about the relative strength of the signal that we're hearing from these medicines as opposed to Seldane."

Seldane should be considered a "separate package" from the three antihistamines, Office of Drug Evaluation II Director John Jenkins, MD, said. "The signal of the cardiac safety profile of terfenadine was a very specific cardiac arrhythmia torsades de pointes. When you look at terfenadine, all the pieces fit to the puzzle."

Claritin, Allegra and Zyrtec "have been carefully evaluated for those effects on cardiac repolarization, and the findings are absent....That's why we have fexofenadine, because we learned that fexofenadine was not the bad actor in the terfenadine experience," Jenkins said.

Pulmonary and Allergy Drugs Division Director Robert Meyer, MD, agreed that the adverse events reported with the three antihistamines "are not of the nature that would lead us to reconsider whether these drugs should be available at all, nor [require] substantive changes in the labeling."

"I would like to stress that these are not signals that worry us otherwise," Meyer said. "If you had a very significant torsades de pointes [like] what was seen with terfenadine, we'd be having an approvability issue altogether, not just whether the drugs should be OTC versus prescription."

The OTC review put the manufacturers in the unusual position of arguing for a more cautious interpretation of postmarketing adverse event data than FDA.

Aventis VP-Global Pharmacovigilance Paul Lagarenne, MD, noted that "some of these signals are not easily identified." It will "take some time as well as significant...patient exposure on the market to be able to identify such critical signals." Of the 24 mil. years of patient exposure with Seldane, 18 mil. years occurred prior to the identification of the safety signal, Lagarenne pointed out.

Sachs expressed concern that in other switch discussions, "the criteria have always seemed to be slightly more rigorous than getting an approval for use in a prescription....My concern is that I do not feel at least so far that I am getting a lot of the safety data that I'm used to seeing for going OTC."

"I think my perspective also comes from my experience with [Wyeth-Lederle's ] Rotashield rotavirus vaccine," she said. "Again, there was a signal in the original data...that was not really realized until it was used more widely," Sachs said. The rotavirus vaccine was withdrawn in 1999.

A comparison was also drawn between Zyrtec and the acne drug Accutane (isotretinoin). Nonprescription Drugs committee voting consultant Leslie Clapp, MD, Main Pediatrics, asked for FDA's perspective on the number of psychiatric events and 16 deaths in Zyrtec patients. One of the deaths was a suicide.

"I'm wondering about the significance...of the experience of Accutane...and what body of evidence was needed to relabel Accutane," Clapp said. She also asked FDA to compare isotretinoin "to the consideration of making Zyrtec OTC in light of these reports."

In response, Meyer said that while he could not "speak to the specifics of Accutane,...you're talking about a fairly young, healthy population that are given antihistamines and there are certain background risks with this kind of an event." The Zyrtec "suicide did not stand out as any kind of a signal that were otherwise thought should be strongly considered in terms of the prescription marketing or the OTC marketing.

Meyer acknowledged, however, "there is perhaps more CNS events, or penetration...with Zyrtec, then there is with the other two agents in question....Not to directly compare, but I guess we can't help it to some extent."

"If you cut through the data for the others, there were actually fairly frequent CNS effects for the others as well," he added. "It stood out a little bit more with the Zyrtec database, but it did not seem too unique."

Nonprescription Drugs committee member Louis Cantilena, MD/PhD, Uniformed Services University of the Health Sciences, asked FDA if the Claritin safety review included recent data indicating a potential interaction with nefazodone (Bristol-Myers Squibb's Serzone).

The study, published in the March issue of Clinical Pharmacology and Therapeutics by Darrell Abernethy, MD/PhD, National Institute on Aging, found concomitant use of loratadine and nefazodone to be associated with QTc prolongation.

Meyer said FDA was aware of the findings but questioned the study's methodology. "We have some concerns as to whether that is a meaningful study," he said. "We have other data that this stands in contradistinction to."