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Executive Summary

ALLERGAN DISTRIBUTION OF BETAGAN MONOGRAPH WAS "INADVERTENT," the company claimed in an Aug. 2 response to an FDA warning letter. The FDA letter, sent July 10, said that an Allergan monograph on the levobunolol ophthalmic product promoted unapproved uses and made unsubstantiated claims ("The Pink Sheet" July 22, p. 19). The company received a five-day extension of the normal 15-day period allowed for a response, the letter notes. The monograph was "a scientific review of published data on levobunolol" that "was intended solely for distribution outside the U.S.," Allergan maintained in its response. "Unfortunately, through inadvertence the monograph achieved distribution domestically, although that distribution was extremely limited," Allergan said. Allergan sales representatives received 115 copies of the monograph, the company said. "Discussions of the monograph were held with 25 physicians and other health care professionals. Of these 25, only 13 copies were left behind, eight with physicians and five with other health care professionals, e.g. pharmacists," the company told FDA. As of Aug. 2, Allergan has "achieved 100% effectiveness in removing the monographs from the field," the company said. "Allergan hereby commits that the monographs will not in the future be distributed in the U.S.," the letter says. Allergan also has prepared a letter to be sent "to all physicians and health care professionals with whom copies of the monograph were left." The monograph was prepared in a three-ring binder designed for international use, Allergan said in its response. The monograph included both the U.S. and overseas tradename (Vistagan), Allergan noted. The intent was to remove pages from editions for different countries where certain information was inappropriate, Allergan said. "In short, the monograph contained certain materials which, while truthful, accurate,and regulatorily appropriate in other nations, are not appropriate for distribution in the U.S.," Allergan told FDA. As an example, the company noted that the monograph discussed a .1% levobunolol product that it does not market in the U.S. "Adding to the confusion is the fact that the monograph was, through an additional inadvertence, sent to the agency" as a routine submission on Aug. 30, the company said in the letter. However, "what limited distribution did occur did not commence until six months later," the company said. "These internal errors are a source of considerable embarrassment to us," Allergan said. "Please let me assure you that we have already taken steps to modify our internal processes" to ensure proper submissions to FDA of regulatory materials and proper subsequent use,the company added. The company response also addresses specific FDA concerns raised in the warning letter. Allergan agrees "with your general premise as to references to polyvinyl alcohol," an ingredient of the Betagan Liquifilm suspension. FDA told Allergan in its warning letter that it considered references to PVA's use as a viscosity agent to constitute "a new indication for which Liquifilm sterile ophthalmic solution is not approved." Allergan responded that it would "in future U.S. materials limit the discussion of PVA to its functional role in the Betagan formulation." Allergan, however, questioned the agency's construction of references to two other beta blockers, timolol and betaxolol. Materials on switching patients from timolol to levobunolol were not "comparative," Allergan maintained; instead they were to show only that there was no cross-reactivity between the two. "We submit that it is useful for physicians to know whether it is reasonable to switch drugs within the same class," Allergan said, "it would be appropriate in future materials to continue such limited, truthful discussions." Allergan also said that its discussion of levobunolol's active metabolite was not meant to suggest any superiority to timolol. "It was clearly stated both in the overview as well as in the text following the discussion of drug metabolism that levobunolol and timolol are equal in efficacy and safety," Allergan said. The company added that it also believes "it is appropriate to continue citing" data from a comparative study to betaxolol. Allergan quotes the summary basis for approval of Betagan, which says that ".25% levobunolol appears to show equal or greater efficacy to both .5% levobunolol and .5% betaxolol."

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