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DIGOXIN NDA AND ANDA SUBMISSIONS TO RESOLVE DISSOLUTION PROBLEMS

Executive Summary

DIGOXIN NDA AND ANDA SUBMISSIONS TO RESOLVE DISSOLUTION PROBLEMS was recommended in a recent report by FDA's Therapeutic Inequivalency Action Coordinating Committee (TIACC). Based on results of assays and dissolutions of digoxin tablets, the committee recommended "that an NDA be submitted for the innovator and ANDAs be required for all generic manufacturers for premaketing approval." A pre-1938 drug, digoxin was grandfathered when the FD&C Act was passed. New manufacturers currently must submit the first three lots of their product for certification to FDA's St. Louis District office. The lots are then cleared by the Office of Compliance. FDA reportedly has decided to adopt the committee's recommendation and require an NDA submission by digoxin (Lanoxin) innovator Burroughs Wellcome. The agency would most likely not require new clinical data. The company said that it has discussed with FDA the possibility of submitting an NDA for digoxin. An announcement of the new requirement would appear in the Federal Register. Digoxin tablet dissolution problems were brought to the attention of the committee following reports of patients experiencing widely varying blood levels after they had switched from generic digoxin to Lanoxin. The complaints reviewed by the committee involved Zenith's digoxin 0.25 mg tablets. In the first case described in the report, a patient using generic digoxin recorded serum levels of .31 ng/ml and .34 ng/ml in consecutive monthly exams. When the patient was switched to Lanoxin the following month, she recorded serum levels of 1.08 ng/ml. Another patient, with a serum level of .67 ng/ml while on the generic, recorded a serum level of 1.14 ng/ml two months later after being switched to Lanoxin. In another case, a patient who had been taking Zenith's digoxin for two years was found to have a digoxin blood level of zero upon receiving a new lot of the product. However, when FDA tested the remaining tablets from the bottle they were found to fall within the dissolution specifications. In January 1990, FDA's Product Surveillance Branch collected samples of Zenith's product and Lanoxin and submitted them to dissolution testing. One lot of Zenith digoxin had a dissolution range of 62%-103% at 15 minutes and 100%-112% at 60 minutes. One of the lots of Lanoxin showed dissolution ranging from 89% to 95% at 60 minutes. The committee report notes that FDA regulations require that "products over 90% in 15 minutes and 95% in 60 minutes submit an NDA and be approved for marketing [as] a rapid- releasing product." Since FDA established TIACC in 1987 to investigate reports of therapeutic inequivalence, over 30 reports have issued and only two have resulted in recommendations for corrective action. The other generic found by the committee to demonstrate bioequivalence problems is methylphenidate (Ciba-Geigy's Ritalin). "A recommendation should be proposed to change the therapeutic equivalency code for methylphenidate hydrochloride from 'A' to 'B'" in the catalog of Approved Drug Products with Therapeutic Equivalence Evaluations (the "Orange Book"), the committee decided. FDA received six complaints of therapeutic failure from patients taking MD Pharmaceutical's methylphenidate 10 mg and 20 mg. The complaints ranged from allegations that the product was "virtually noneffective" to that it "only lasted a few hours with vague aches and cramps all over," to complaints of side effects such as vomiting, dizziness and crankiness. Data obtained from MD Pharmaceutical, the committee said, "clearly showed that [the firm's] methylphenidate has a significantly more rapid rate of dissolution than Ciba's Ritalin." Studies conducted for FDA by independent consultants found that although MD Pharmaceutical's product was absorbed faster than Ritalin at one hour, mean plasma levels were equal for the generic and the innovator products at four hours. Furthermore, the extent of absorption, Cmax and AUC values were equivalent. However, the committee noted that FDA had received numerous other complaints that the generic version of Ritalin made children lethargic and did not last as long as the Ciba product. In addition, complaints by patients and physicians asserted that the generic has not been effective in children with attention deficit disorders, hyperkinetic syndrome, short attention span and emotional impulsivity. As a result of the report, FDA, in the April supplement of the "Orange Book," proposed "a change in the therapeutic equivalence code from "AA" to "BP" for listed [methylphenidate] phenidate] tablets." The proposed change, FDA noted, "requires that firms submitting an ANDA for MPD tablets submit an acceptable in vivo bioequivalence study to gain approval in addition to submission of all previously required information." Presumably, MD Pharmaceutical would not be required to conduct a new biostudy since its product already has been tested by FDA. The agency is in the process of reviewing comments submitted in response to its proposal, which it will consider before issuing a final therapeutic equivalence code for the product.
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