Antihistamine Safety Questions, Liability Risks Cautioned By Aventis

A switch of Allegra to nonprescription status could create the potential for unknown consumer risks and open the door to costly lawsuits, Aventis Senior VP-Medical & Regulatory Affairs Francois Nader, MD, suggested to a joint FDA advisory panel.

"Until we have confidence that the switch will not harm patients, we are not prepared to subject physicians, pharmacists or the company to liability claims based on a premature entry into the over-the-counter marketplace," Nader asserted.

The contention that there are insufficient extant data to prove the safe use of Aventis' Allegra (fexofenadine), Schering-Plough's Claritin (loratadine) and Pfizer's Zyrtec (cetirizine) in an OTC setting was central to Aventis' and Schering-Plough's opposition to a petition from Blue Cross of California/WellPoint.

Nevertheless, FDA's Nonprescription Drugs and Pulmonary-Allergy Drugs Advisory Committees overwhelming voted in favor of eliminating the Rx restriction on all three second-generation antihistamines (¹ (Also see "Second-Generation Antihistamine OTC Labeling Could Resemble Monograph" - Pink Sheet, 14 May, 2001.)).

Several committee members questioned the drug makers on what issues caused their safety concerns.

"How much safety data is necessary, over what timeframe...regardless of whether the switching process is initiated by an insurance company or the drug manufacturer," NDAC's Francis Lam, University of Texas Health Science Center, asked Aventis.

Nader explained the drug "is still in clinical development...in asthma, in atopic dermatitis and additional pediatric development....We are also studying fexofenadine in a number of Phase IV safety and effectiveness trials," including some looking at the drug's effect on special populations, he noted.

Adverse event data are collected from all the trials, the Aventis exec added.

PADAC consultant Dan Roden, MD, Vanderbilt School of Medicine, described these efforts as "pretty ordinary" postmarketing surveillance, while his Vanderbilt colleague Alastair Wood, MD, asserted, "as I understand what we're being told, the manufacturers have serious safety concerns, [but none]...sufficiently severe as to have them mount any specific study of any sort."

Wood, an NDAC consultant, requested Aventis provide "an example of a specific safety concern that you are currently pursuing...with a hypothesis that says, 'this is a real concern to us and we're pursuing it right now and that's why we don't think [Allegra] should go over-the-counter.'"

Nader acknowledged, "to tell you that we picked up a signal and we're running, specifically, a trial to confirm the signal, is simply not happening."

In a similar exchange, NDAC's Richard Neill, MD, University of Pennsylvania College of Medicine, asked Schering-Plough reps "how would you design studies to address...[safety] concerns in the event that you, in the future, might bring [Claritin] to OTC? What type of study, how long?"

In response, Schering Senior VP-Medical Affairs/Chief Medical Officer Robert Spiegel, MD, steered the discussion to WellPoint's petition, saying it lacks data on "potential for misuse, misdiagnosis and for patients not to take it properly and get into trouble."

"The committee...is going to have to ask itself, with no data provided on OTC use for you to see what is the incidence of misdosing - which is a safety issue - and...delays in seeking medical care for complications of allergic rhinitis," whether the drugs are appropriate in an OTC environment, he averred.

Wood retorted, "I think that tells us that none of these issues are sufficiently important that they require specific action on the company's part."

In the absence of research by the drug makers, several panelists suggested safety data could be bolstered with information from regional poison control centers and the American Association of Poison Control Centers.

Edward Krenzelok, Children's Hospital, Pittsburgh, told FDA, "there's an incredible database for you potentially to mine," and NDAC member Hari Sachs, MD, a Rockville, Md.-based clinician, called poison control data "usually...quite useful" to advisory committees.

FDA Division of Pulmonary & Allergy Drugs Director Robert Meyer, MD, explained the agency typically does not use those data because they are "anecdotal" and have "a very different intent from rigorous safety evaluations of drugs."

Although the majority of the panel supported the safety of the three Rx antihistamines in an OTC setting, concerns suggested by Schering and Aventis did resonate with a minority of committee members.

Sachs questioned whether the cardiac effect seen in the 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 (Also see "Antihistamine OTC Switch: FDA Asking If Rx Products Have "Unique" Aspects" - Pink Sheet, 30 Apr, 2001.)).

"It does look like there are some signals...with these medicines," Sachs maintained. Noting 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 stated.

FDA's Meyer agreed 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."

However, Aventis VP-Global Pharmacovigilance Paul Lagarenne, MD, maintained 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," he said. 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...that I am getting a lot of the safety data that I'm used to seeing for going OTC."

A comparison also was drawn between Zyrtec and Roche's Rx acne drug Accutane (isotretinoin). NDAC 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 which was a suicide.

In 1998, Roche issued a "Dear Doctor" letter notifying health care professionals of Accutane's link to depression and added a boldface label notice about suicide. In January, the agency, which had received more than 140 case reports of suicide and hospitalized depression in connection with the drug, approved a new patient consent form and medication guide elaborating on the potential mental problems and risk of suicide associated with Accutane.

"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 we otherwise thought should be strongly considered in terms of the prescription marketing or the OTC marketing," he said.

Meyer acknowledged, however, "there are perhaps more CNS events, or penetration...with Zyrtec, than there are with the other two agents in question."

"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."