Improper use of OTC Claritin for skin conditions other than chronic idiopathic urticaria would not cause direct harm but might lead to a delay in seeking appropriate medical treatment, FDA advisory committee members and Schering-Plough representatives said.

Use of loratadine by individuals with undiagnosed, underlying conditions might change "their threshold for seeking appropriate medical intervention," said Mark Dykewicz, MD, St. Louis University School of Medicine and chairman of FDA's Pulmonary-Allergy Drugs Advisory Committee.

Speaking at the April 22 Nonprescription Drugs Advisory Committee hearing on Schering's request to market Claritin OTC for CIU, Dykewicz pointed to several scenarios "where inappropriate use might lead to some adverse outcomes."

For instance, he wondered how frequently individuals might use OTC loratadine to treat or prevent a food allergy, despite label warnings against such use.

The PADAC chairman also pointed to the "less common but real issue of a patient who has some connective tissue disorder or urticarial vasculitis, where they may be getting some benefit with their skin condition by use of the OTC product, but then be less likely to seek the attention of a physician...and thereby allow the progression of the underlying disease process."

Dykewicz, along with several members of PADAC and the Dermatologic & Ophthalmologic Drugs Advisory Committee, participated as voting consultants at the NDAC meeting, which focused on the appropriateness of OTC treatment of CIU and hives in general.

In May 2001, NDAC and PADAC determined that loratadine and other second-generation antihistamines have a safety profile acceptable for OTC marketing. Discussion at that meeting, which was prompted by WellPoint Health Networks' citizen petition requesting that FDA switch the antihistamines OTC, generally centered on use of the drugs in treating allergic rhinitis (¹ Also see "Second-Generation Antihistamine OTC Labeling Could Resemble Monograph" - Pink Sheet, 14 May, 2001., p. 3).

With regard to CIU, Schering presented new label comprehension study data that raised concerns among FDA reps and committee members about the ability of the general population and acute hives sufferers to correctly de-select OTC Claritin specifically labeled for chronic, recurring hives of an unknown source.

The Chronic Idiopathic Urticaria Self-Recognition & Label Comprehension Study, conducted by West Pharmaceutical Services in November and December, sought to determine how well 565 subjects across five cohorts could understand specific points on Schering's proposed labeling for OTC Claritin.

The five cohorts constituted: previously diagnosed CIU sufferers; general population; low literacy; subjects that were pregnant, breast-feeding or had liver or kidney disease, bringing them within the parameters of "ask a doctor before use" instructions on labeling; and sufferers of acute urticaria, who fall within the "do not use" instructions on product labeling. Individuals could be part of more than one cohort.

Among acute hives sufferers, 54% either correctly de-selected the product or said they would ask their doctor before use, according to Schering's briefing book. Approximately 70% of the general population and 65% of the low-literacy population who were not appropriate candidates for the product correctly de-selected or said they would consult a physician before use.

In a review of the label comprehension study prepared for NDAC, FDA notes that approximately 42% of the general population cohort and 44% of the acute hives cohort thought Claritin could be used for a one-time outbreak of hives, contrary to product labeling.

In addition, approximately 16% of the general population cohort and 21% of the acute hives cohort believed the product could be used for food allergies, FDA's review indicates.

Schering consultant Eugene Monroe, MD, Medical College of Wisconsin, said the potential for delayed diagnosis "would cause no serious clinical concerns or consequences" for the conditions most likely to be confused with CIU, including acute or chronic urticaria, eczema and contact dermatitis.

Monroe said that 90%-95% of chronic urticaria cases are idiopathic, "so the percentage that have an underlying disease would be very small to begin with."

"The more serious ones that would concern me the most are systemic in nature, such as a connective tissue disease or vasculitis," the Schering consultant stated. "I would say the incidence might be less than 1%-2% of the total, [and] those patients also should have other signs and symptoms."

Another condition that could be confused with urticaria is angioedema, which is characterized by giant hives or hives involving mucous membranes and tissues around the eyes, lips or genitalia, Monroe said.

In general, angioedema "presents no additional serious consequences to the patient if the diagnosis...is confused with urticaria," he maintained, although he added a caveat for laryngeal or oral angioedema, which he described as "a very rare situation in chronic urticaria."

Schering-Plough's proposed OTC Claritin label warns consumers to seek emergency medical attention if they have symptoms such as trouble swallowing, wheezing or breathing problems, and hives or swelling in or around the mouth.

NDAC member Alastair Wood, MD, Vanderbilt University, questioned whether "bad things are going to happen to patients with other skin diseases" who might take OTC loratadine.

"I would say no," responded William Rosenberg, MD, University of Tennessee, and a voting dermatology consultant to the committee.

Noting that representatives from dermatology and allergy medical societies did not request an opportunity to speak during the public portion of the meeting, Rosenberg said, "I think that answers your question, like the dog that didn't bark."

Committee members seemed most troubled by the possibility that OTC loratadine use could delay treatment for anaphylaxis, possibly resulting in death.

"An area of potential concern in the acute setting relates to the rare situation in which acute urticaria is the presenting symptom of an anaphylactic reaction," Monroe said. Hives are present in 90% of anaphylactic reactions, which also can involve the respiratory, cardiovascular or gastrointestinal systems, he noted.

"The incidence of anaphylaxis is rare," Monroe maintained. "Chronic urticaria is not associated with, nor is it a risk factor for, the development of anaphylaxis. Acute urticaria is an associated symptom with anaphylaxis, but the rapid simultaneous onset of cardiovascular or respiratory symptoms will cause the patient to seek immediate medical attention."

FDA Division of OTC Drug Products Director Charles Ganley, MD, said the committee should consider the frequency and significance of conditions such as angioedema and anaphylaxis associated with hives.

"I've heard the terms 'rare' and 'infrequent' and it's hard to really get an understanding of what that actually means, especially when you have a product that would go OTC and be available to tens of millions or hundreds of millions of people, and things that are rare in one setting may become a little more common in another setting," Ganley noted.

Schering's briefing book for the meeting states: "In Canada and the UK, where loratadine have been OTC for more than 10 years, there have been no spontaneous case reports of anaphylaxis in treatment of chronic urticaria and only one case report in acute urticaria."

"This was the only case report in over an estimated 38 mil. courses of treatment with loratadine," Schering says. "The rarity of this occurrence is likely due to the high recognition and knowledge of proper treatment of anaphylactic reactions."

Responding to Schering's assertion that foreign post-marketing experience of OTC Claritin has shown no increase in the incidence of complications or death due to delayed anaphylaxis treatment, NDAC member Frank Davidoff, MD, editor emeritus of the Annals of Internal Medicine, noted "absence of evidence is not the same as evidence of absence."

"I think it would be feasible to gather information from the other countries that have had OTC non-sedating antihistamines to look at their cases of fatal anaphylaxis and try to get a direct body of information on whether or not there has been a contribution to delay and perhaps to fatality," Davidoff suggested.

A potential adverse event-related obstacle to a switch could be the European Agency for the Evaluation of Medicinal Products' recent decision to review loratadine's safety in light of reports of birth defects in Sweden. Authorities there reported 15 cases of hypospadia out of 2,780 children born from women taking Claritin in early pregnancy. The Committee for Proprietary Medicinal Products' review is expected to be complete in three to six months.

Improper OTC Loratadine Use Concerns Hinge On Delayed Physician Treatment

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