FDA's review of safety and birth registry data to determine whether Schering-Plough's Claritin (loratadine) could be linked to hypospadia is expected to take approximately three months.

An agency decision on Schering's supplemental NDAs to switch the Claritin franchise OTC will have to await evaluation of such data, FDA said. However, a review lasting several months should still give the agency ample time to act on the switch NDAs by the Nov. 28 target date.

FDA's Office of Drug Safety is expected to review domestic and international birth registry data, as well as reports from Sweden of a possible link between use of the second-generation antihistamine by pregnant women and hypospadia.

The Division of Pulmonary & Allergy Drug Products will review the original NDA database for Claritin, as well as preclinical, animal and other drug safety data. The Division of OTC Drug Products will be involved from an "informational perspective," the agency said.

FDA said it has been in contact with Schering concerning its review, which was prompted by the European Agency for the Evaluation of Medicinal Products' (EMEA) decision to examine loratadine.

EMEA announced April 25 that its Committee for Proprietary Medicinal Products has begun safety and efficacy reviews of loratadine and desloratadine following a referral from Swedish authorities (¹ Also see "Improper OTC Loratadine Use Concerns Hinge On Delayed Physician Treatment" - Pink Sheet, 29 April, 2002., p. 11).

FDA learned of EMEA's plans a few weeks prior to the public announcement, which came three days after a Nonprescription Drugs Advisory Committee meeting on Schering's request to switch Claritin OTC for chronic idiopathic urticaria (² Also see "Claritin OTC Approval For CIU Would Reduce Off-Label Drug Use – Schering" - Pink Sheet, 29 April, 2002., p. 6).

The issue of hypospadia was not raised during the April 22 meeting and did not come up during the original NDA reviews for loratadine and desloratadine, the agency said.

In boys born with hypospadia, the urethra does not extend to the tip of the penis and the urethra opening is located along the underside of the penis. The condition, which usually can be repaired surgically, is described as relatively common, affecting one in every 100 boys.

While a clear cause cannot be identified for most cases, possible contributing factors include genetics, drugs used during pregnancy that disrupt normal sex hormone pathways in the developing fetus and environmental pollutants known as endocrine disrupters, according to the Centers for Disease Control & Prevention.

In Sweden, the national birth registry tracks drugs used by pregnant women as well as birth outcomes. Authorities there reported 15 cases of hypospadia out of 2,780 children (boys and girls) born from women taking loratadine early in pregnancy, compared to an estimated baseline incidence of one case out of every 500 children, according to EMEA. Loratadine is available both with and without a prescription in Sweden.

EMEA said it is unaware of reports linking loratadine and hypospadia from other countries but would inquire about such data from regulatory authorities and S-P.

Schering said it has been in contact with Sweden's Medical Products Agency since 1999 regarding "rare reports" of hypospadia. "At the MPA's request and with its input, Schering-Plough in 1999 conducted a very specific preclinical study that conclusively showed that loratadine has no anti-androgenic activity - which is the only nongenetic mechanism known to produce hypospadias," the firm said.

"This study demonstrates that there is no biological reason to explain how loratadine might cause this effect, nor is there any scientific basis to suggest any possible linkage," the company stated.

S-P noted current product labeling states that loratadine and desloratadine should be used during pregnancy only after special consideration. Schering's proposed label for OTC Claritin in the U.S. directs pregnant or breastfeeding women to ask a doctor before use.

FDA's hypospadia review may extend to Clarinex , which, like Claritin, is the subject of a WellPoint Health Networks petition requesting the agency force an OTC switch (³ Also see "Clarinex Clinical, Safety Characteristics Support OTC Use – WellPoint" - Pink Sheet, 22 April, 2002., p. 9).

FDA does not appear to be ruling out a Clarinex forced switch based upon desloratadine's status as a new molecular entity. However, the Clarinex petition, filed April 15, will proceed on its own timeline; WellPoint's Claritin petition was filed in July 1998 and is still pending.

FDA Claritin Hypospadia Review Targeted For Summer Completion

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