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Executive Summary

QUAD CYTARABINE NEUROTOXICITY STATEMENT FOR PHYSICIANS about reports associated with high-dose cytarabine therapy was recommended by FDA's Oncology Drugs Advisory Committee at a Dec. 14 special meeting. Although the committee was split on whether the reported incidence of neurotoxicity using the chemotherapeutic in high-dose therapy was unexpected, the majority of panel members suggested that issuance of such a statement would be in the best interests of the company and of public health. Panel member Albert Bernath Jr., MD, Geisinger Medical Center, Danville, Pennsylvania, noted that the issue is currently being circulated as a rumor and one of the best things that could be done "is for the drug company to in fact notify either the physicians involved or the hospital pharmacists or maybe both . . . that the use of high-dose ara-C [cytarabine] has raised questions regarding neurotoxicity and these are by no means definite, by no means conclusive, but as a prudent measure . . . until studies are completed we feel more comfortable if you didn't use it for high-dose treatment." Cytarabine, introduced in 1969 by Upjohn, is indicated for induction of remission in leukemia and non-Hodgkin's lymphoma. Quad began manufacture of its generic version, a lyophilized ready-for-injection formulation, in late 1987. The University of Wisconsin switched from the brandname product to the generic when it first became available at the beginning of 1988. Quad is understood to be working on a letter that will be sent to physicians. Prior to the meeting, FDA and Quad had developed a draft letter that says: "Detailed chemical analysis of both products [Quad and Upjohn's] have been conducted by Quad and the FDA. To date, no significant differences have been found that would plausibly account for a differential toxicity." The letter will express concern with the use of any cytarabine product for high-dose therapy. The short-notice meeting of the advisory committee was sparked by a report earlier in the year from the cancer center at the University of Wisconsin of a possible increase in serious neurological damage associated with cytarabine produced by Quad. The report came, however, from physicians using cytarabine for an unapproved high-dosage regimen. "In late 1988, clinicians and hematologists at the University of Wisconsin noticed what they thought was an increase in unexpected neurotoxicity [using high-dose cytarabine]," Heidi Jolson, MD, FDA Office of Epidemiology and Biostatistics told the committee. She added: "they discussed this problem with their pharmacist, and the pharmacist identified a switch to the generic manufacturer as a possible cause of the increase." In May, the hospital reported the increase to Quad and in June it reported the problem to FDA. The hospital pharmacy switched back to the brandname product. Labeling for cytarabine warns of "severe and at times fatal CNS toxicity (different from that seen with conventional therapy regimens) . . . following some experimental dose schedules." The usual dosage cited in the labeling is 100-200 mg per square meter of body surface, administered over 24 hours by continuous I.V. infusion for seven days in combination with other chemotherapeutic drugs. However, at least eight major cancer centers, including the University of Wisconsin, have recently been using high-dose regimens of 1-3 mg per square meter given in one hour infusion, twice daily for two to six days, in severely ill leukemics who have failed on other chemotherapies, according to Jolson. Jolson participated in the office's field investigation that took place in reponse to the Wisconsin report. She told the committee that FDA conducted a historical cohort study at the site using patient medical records and pharmacy logs from January 1986 through August 1989. The cohort study looked at 63 patients who underwent high ara-C therapy during those years, 34 of whom had received Upjohn's product, 25 who received Quad's, and four who had been exposed to both. The study found three cases of severe neurotoxicity after exposure to the Upjohn product, and 11 under exposure to Quad's cytarabine, a difference that FDA investigators found "not statistically significant." FDA is currently conducting a detailed analysis of the Wisconsin data. Committee member Bernath recommended that "the institutional reviews that are in progress should be completed." Quad is currently gathering patient data from the seven cancer centers for analysis and gave the panel some interim results, which the firm said, show no differences in toxicity between the Upjohn and Quad products. The other centers are the Cleveland Clinic, Emory University, Kenneth Norris Institute, University of Arizona, University of Chicago, Henry Ford Hospital, and St. Peter's Hospital of Albany, New York. Although Quad conducted chemical analyses of the lots of cytarabine from the Wisconsin hospital to test purity, Bernath suggested that such tests "need to be repeated" with "updated and more sophisticated toxicology and chemical analyses." Quad said it plans to conduct in vitro testing of its drug and Upjohn's to look at toxicity at the cellular level. In a presentation by Quad, Dulal Chatterji, PhD, head of R&D, pointed out that the company's product is a lyophilized cytarabine solution containing no inactive ingredients other than the hydrochloric acid used to adjust pH, and as a direct I.V. solution, "is not subject to the bioavailability problems inherent in oral products . . . There is an absolute match between our product, the Upjohn product, and U.S. Pharmacopeia standards," he asserted. He later stated that Quad buys its cytarabine from two other unnamed manufacturers. Chatterji told the committee that since being alerted to the University of Wisconsin report, Quad had conducted testing of samples from the seven lots from which the University was supplied, including extensive chromotography testing. "We analyzed the raw material . . . the finished product . . . and the results clearly indicated that there is no difference between our product and the Upjohn product."

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