[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]


-----------------------------------------------------------------------

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Determination That Bendectin Was Not Withdrawn From Sale for 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.

-----------------------------------------------------------------------

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of nausea during pregnancy was not withdrawn from sale for reasons of 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