99-20362. Determination That Bendectin Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness  

  • [Federal Register Volume 64, Number 152 (Monday, August 9, 1999)]
    [Notices]
    [Pages 43190-43191]
    From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
    [FR Doc No: 99-20362]
    
    
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    DEPARTMENT OF HEALTH AND HUMAN SERVICES
    
    Food and Drug Administration
    [Docket Nos. 92P-0274 and 97P-0437]
    
    
    Determination That Bendectin Was Not Withdrawn From Sale for 
    Reasons of Safety or Effectiveness
    
    AGENCY: Food and Drug Administration, HHS.
    
    ACTION: Notice.
    
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    SUMMARY: The Food and Drug Administration (FDA) has determined that the 
    drug product Bendectin, a tablet composed of pyroxidine hydrochloride, 
    10 milligram (mg), and doxylamine succinate, 10 mg, for the prevention 
    of nausea during pregnancy was not withdrawn from sale for reasons of 
    safety or effectiveness. This determination will permit FDA to approve 
    abbreviated new drug applications (ANDA's) for the combination product 
    pyroxidine hydrochloride, 10 mg, and doxylamine succinate, 10 mg, 
    tablets.
    
    FOR FURTHER INFORMATION CONTACT: Andrea C. Masciale, Center for Drug 
    Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
    Fishers Lane, Rockville, MD 20857, 301-594-2041.
    
    SUPPLEMENTARY INFORMATION: In 1984 Congress enacted the Drug Price 
    Competition and Patent Term Restoration Act of 1984 (Public Law 98-417) 
    (the 1984 amendments), which authorized the approval of duplicate 
    versions of approved innovator drug products under an ANDA procedure. 
    ANDA sponsors generally must show that the drug for which they are 
    seeking approval contains the same active ingredient in the same 
    strength and dosage form as the ``listed drug,'' which is a drug that 
    was previously approved under a new drug application (NDA). Sponsors of 
    ANDA's are not required to repeat the extensive clinical testing 
    necessary to gain approval of an NDA. The only data from investigations 
    required in an ANDA are data to show that the drug that is the subject 
    of the ANDA is bioequivalent to the listed drug.
         The 1984 amendments include what is now section 505(j)(7) of the 
    Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355(j)(7)), 
    which requires FDA to publish a list of all approved drugs. FDA 
    publishes this list as part of the ``Approved Drug Products with 
    Therapeutic Equivalence Evaluations,'' which is generally known as the 
    ``Orange Book.'' Although they are technically drugs that should be 
    listed under section 505(j)(7) of the act, certain drug products, 
    including Bendectin, that were approved for safety and effectiveness 
    but were no longer marketed on September 24, 1984, are not included in 
    the Orange Book. In implementing the 1984 amendments, FDA decided not 
    to retrospectively review products withdrawn from the market prior to 
    the passage of the amendments. Rather, the agency decided to determine 
    whether such drugs were withdrawn from the market for safety or 
    effectiveness reasons on a case-by-case basis. A person interested in 
    obtaining marketing approval for such a drug product through the ANDA 
    process must petition the agency for a determination (21 CFR 
    314.122(d)).
         Under FDA's regulations, drugs are withdrawn from the list if the 
    agency withdraws or the Secretary of Health and Human Services suspends 
    approval of the drug's NDA or ANDA for reasons of safety or 
    effectiveness, or if FDA determines that the listed drug was withdrawn 
    from sale for reasons of safety or effectiveness (21 CFR 314.162). FDA 
    must make a determination as to whether a listed drug was withdrawn for 
    reasons of safety or effectiveness when a person petitions for such a 
    determination (Sec. 314.161(a)(3) (21 CFR 314.161(a)(3))). Regulations 
    also provide that the agency must make a determination as to whether a 
    listed drug was withdrawn from sale for reasons of safety or 
    effectiveness before an ANDA that refers to that listed drug may be 
    approved (Sec. 314.161(a)(1)). FDA may not approve an ANDA that does 
    not refer to a listed drug.
         Bendectin is the subject of approved NDA 10-598, currently held by 
    Hoechst Marion Roussel, Inc. (HMR). In 1956, FDA approved the NDA for 
    Bendectin tablets for use in the prevention of
    
    [[Page 43191]]
    
    nausea during pregnancy. The original formulation of the antinauseant 
    included dicyclomine hydrochloride, pyroxidine hydrochloride, and 
    doxylamine succinate. The drug was reviewed in the agency's Drug 
    Efficacy Study Implementation program, in which FDA concluded that 
    dicyclomine hydrochloride did not contribute to the effectiveness of 
    the other two ingredients in Bendectin tablets. Therefore, the drug 
    product was reformulated in 1976 to include only pyroxidine 
    hydrochloride, 10 mg, and doxylamine succinate, 10 mg.
         On June 9, 1983, Merrell Dow, HMR's predecessor in interest, 
    withdrew Bendectin tablets from sale in the United States and 
    worldwide. Other companies have continued to market this product in 
    other areas of the world. To FDA, to the press, and in letters to 
    customers using Bendectin tablets, Merrell Dow, in explaining its 
    decision, stated that the withdrawal of the drug product was due to 
    nonmedical reasons, noting significant adverse publicity and the 
    burdens of litigation. At the same time, Merrell Dow asserted its view 
    that ``available medical evidence does not demonstrate a cause and 
    effect relationship between the use of Bendectin and birth defects.'' 
    In an FDA Talk Paper issued on the day Bendectin was withdrawn from 
    sale, the agency stated that Merrell Dow's decision was ``independent'' 
    of action by FDA. HMR and predecessors in interest to HMR have 
    continually maintained that the withdrawal of Bendectin tablets was for 
    reasons other than safety or effectiveness.
         On June 24, 1992, Townley & Updike, on behalf of Pharmaceutical 
    Development and Licensing, Inc., submitted a citizen petition under 21 
    CFR 10.30 (Docket No. 92P-0274/CP1) regarding the status of Bendectin. 
    A similar citizen petition was filed by Cato Research on behalf of 
    Duchesnay Inc., on October 20, 1997 (Docket No. 97P-0437/CP1). Both 
    petitions request that the agency determine whether Bendectin was 
    withdrawn from sale for reasons of safety or effectiveness and, if the 
    agency determines that the drug was not withdrawn from sale for reasons 
    of safety or effectiveness, relist the drug in the Orange Book.
         Under Sec. 314.161, the relevant inquiry is whether the 
    manufacturer withdrew the drug from the market for reasons of safety or 
    effectiveness. Where, as here, a substantial amount of time has elapsed 
    since a drug was withdrawn from the market, the agency's inquiry 
    considers not only the reasons the manufacturer initially ceased 
    marketing the product, but also any relevant information that has 
    become available since the market withdrawal. Because a finding that a 
    product was not withdrawn for safety or effectiveness reasons will 
    permit the approval of ANDA's for the drug, the agency considers all 
    relevant information, not just information available at the time of the 
    initial withdrawal, to determine whether a drug is no longer on the 
    market due to safety or effectiveness concerns.
         The agency's review of the withdrawal of Bendectin from the market 
    has considered the sponsor's explanation of the basis for the 
    withdrawal of the product in 1983 and information available to the 
    agency regarding safety or effectiveness concerns for Bendectin. As 
    noted previously, the sponsor has consistently maintained that it 
    withdrew Bendectin from the market for reasons other than safety or 
    effectiveness. The agency has reviewed information submitted with the 
    petitions, published studies, U.S. and foreign adverse event reports, 
    and FDA records. The current evidence supports the conclusion that 
    Bendectin was not withdrawn from the market for reasons of safety or 
    effectiveness.
         Doxylamine succinate is an active ingredient in several over-the-
    counter (OTC) antihistamines and sleep aids. The labeling of these OTC 
    products bears statements that pregnant women should seek the advice of 
    a health professional before using the products or that the products 
    should not be taken by pregnant women. These statements do not 
    contradict FDA's present determination because the combination product 
    pyroxidine hydrochloride, 10 mg, and doxylamine succinate, 10 mg, is a 
    prescription drug product. As with all prescription drug products that 
    are being considered for use in a pregnant woman, a health professional 
    may appropriately assess the risks and benefits of pyroxidine 
    hydrochloride and doxylamine succinate for its intended use.
         Pyroxidine hydrochloride is also known as vitamin B6. 
    As an individual product, it is readily available to U.S. consumers 
    without the requirement of a prescription.
         The agency has determined under Sec. 314.161 that Bendectin was 
    not withdrawn from the market for reasons of safety or effectiveness. 
    Accordingly, the agency will list Bendectin tablets in the 
    ``Discontinued Drug Product List'' section of the Orange Book. The 
    ``Discontinued Drug Product List'' delineates, among other items, drug 
    products that have been discontinued from marketing for reasons other 
    than safety or effectiveness. ANDA's that refer to the combination 
    product pyroxidine hydrochloride, 10 mg, and doxylamine succinate, 10 
    mg, tablets may be approved by the agency.
    
        Dated: July 28, 1999.
    Margaret M. Dotzel,
    Acting Associate Commissioner for Policy.
    [FR Doc. 99-20362 Filed 8-6-99; 8:45 am]
    BILLING CODE 4160-01-F
    
    
    

Document Information

Published:
08/09/1999
Department:
Food and Drug Administration
Entry Type:
Notice
Action:
Notice.
Document Number:
99-20362
Pages:
43190-43191 (2 pages)
Docket Numbers:
Docket Nos. 92P-0274 and 97P-0437
PDF File:
99-20362.pdf