[Federal Register Volume 67, Number 247 (Tuesday, December 24, 2002)]
[Notices]
[Pages 78476-78478]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-32344]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 78N-0227; DESI 11853]


Trimethobenzamide Hydrochloride Injection and Capsules; Drug 
Efficacy Study Implementation; Final Evaluation

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) announces the 
resolution of issues concerning trimethobenzamide hydrochloride 
injection and capsules. This notice announces the approval of a 
supplemental new drug application (NDA) for Tigan (trimethobenzamide 
hydrochloride) Capsules, 300 milligrams (mg), and states that continued 
marketing of unapproved trimethobenzamide hydrochloride injection and 
capsule products is unlawful and is subject to FDA regulatory action.

ADDRESSES: Requests for FDA's opinion on whether a supplement to an 
abbreviated new drug application (ANDA) is required for a specific 
trimethobenzamide hydrochloride injection product should be identified 
with Docket No. 78N-0227 and reference number DESI 11853 and be 
directed to the Office of Generic Drugs (HFD-600), Center for Drug 
Evaluation and Research, Food and Drug Administration, 7500 Standish 
Pl., rm. 150, Rockville, MD 20855-2773. Requests for an opinion on the 
applicability of this notice to a specific trimethobenzamide 
hydrochloride injection or capsule product should be identified with 
Docket No. 78N-0227 and reference number DESI 11853 and directed to the 
Division of Prescription Drug Compliance and Surveillance (HFD-330), 
Center for Drug Evaluation and Research, Food and Drug Administration, 
7500 Standish Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT: Brian L. Pendleton, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    As part of its Drug Efficacy Study Implementation (DESI) program, 
in a notice published in the Federal Register of February 24, 1971 (36 
FR 3435) (the 1971 notice), FDA announced its conclusion that certain 
drug products containing trimethobenzamide hydrochloride were: (1) 
Probably effective for nausea and vomiting due to radiation therapy or 
travel sickness and for emesis associated with operative procedures, 
labyrinthitis, or Meniere's syndrome; (2) lacking substantial evidence 
of effectiveness for the treatment of nausea and vomiting due to 
infections, underlying disease processes, or drug administration; and 
(3) possibly effective for all other labeled indications. The 1971 
notice listed three trimethobenzamide hydrochloride products: Tigan 
Solution for Injection (NDA 11-853), Tigan Capsules (NDA 11-854), and 
Tigan Suppositories (NDA 11-855). Roche Laboratories held the NDAs for 
these three products.
    In the Federal Register of January 9, 1979 (44 FR 2017) (the 1979 
notice), FDA published a notice announcing that the agency was 
reclassifying trimethobenzamide hydrochloride injection and capsules to 
effective for certain indications and to lacking substantial evidence 
of effectiveness for their other (previously designated) less-than-
effective indications. Specifically, FDA concluded that 
trimethobenzamide hydrochloride injection and capsules are effective 
for the treatment of postoperative nausea and vomiting and for nausea 
associated with gastroenteritis. The agency also concluded that 
trimethobenzamide hydrochloride injection and capsules lack substantial 
evidence of effectiveness for their other labeled indications. (In the 
same issue of the Federal Register (44 FR 2021), FDA published a notice 
reclassifying trimethobenzamide hydrochloride suppositories to lacking 
substantial evidence of effectiveness and proposed to withdraw approval 
of NDAs for trimethobenzamide hydrochloride suppositories.)
    The 1979 notice stated that two NDAs for trimethobenzamide 
hydrochloride injection and capsules not included in the February 1971 
notice were affected by the new notice: NDA 17-530, for Tigan 
Injection, and NDA 17-531, for Tigan Capsules, both held by Beecham 
Laboratories (Beecham) (44 FR 2017 at 2018). The 1979 notice stated 
that, according to bioavailability studies submitted by Beecham, the 
relative bioavailability or extent of absorption of a 250-mg capsule 
was 56-62 percent of that of the 200-mg intramuscular injection. Based 
on these studies, FDA concluded that the oral dose of trimethobenzamide 
hydrochloride should be approximately two times the intramuscular dose. 
FDA noted that on May 2, 1978, Beecham supplemented its NDA for Tigan 
Capsules to reformulate the capsule dosage form from 100 mg

[[Page 78477]]

and 250 mg to 200 mg and 400 mg, respectively. The agency stated that 
the reformulated products were being handled through the normal 
supplemental NDA procedures (44 FR 2017 at 2019).
    FDA stated in the 1979 notice that the agency was prepared to 
approve ANDAs and abbreviated supplements to previously approved NDAs 
for trimethobenzamide hydrochloride injection and capsules under 
certain conditions pertaining to the form of the drug (i.e., the drug 
product was in sterile aqueous solution suitable for intramuscular 
administration or in capsule form suitable for oral administration) and 
in its labeling. Labeling was to state, among other things, that the 
drug was indicated for the treatment of postoperative nausea and 
vomiting and for nausea associated with gastroenteritis. The section on 
dosage and administration was to specify the following:
    For the treatment of nausea secondary to gastroenteritis: 200 mg 
intramuscularly or 400 mg orally.
    For the treatment of nausea and vomiting postoperatively: 200-mg 
intramuscular injection followed in 1 hour by a second 200-mg 
intramuscular injection, or 400 mg orally.
    (44 FR 2017 at 2019)
    The 1979 notice stated that the marketing of trimethobenzamide 
hydrochloride injection and capsule products that were the subject of 
an approved or effective NDA could be continued provided that, on or 
before March 12, 1979, the holder of the application submitted a 
supplement for revised labeling and a supplement to provide other 
specified information. In addition, for the capsule dosage form, each 
application holder was required to submit, by July 9, 1979, evidence 
demonstrating the in vivo bioavailability of the drug product by 
comparing the oral capsule product with Beecham's intramuscular 
injection and with an oral solution. The notice also stated that 
approval of an ANDA must be obtained prior to marketing other 
trimethobenzamide hydrochloride injection and capsule products (44 FR 
2017 at 2019).
    In the 1979 notice, FDA gave notice of an opportunity for a hearing 
to the holders of NDAs for trimethobenzamide hydrochloride injection 
and capsules, and to all other interested persons, that the agency 
proposed to issue an order under section 505(e) of the Federal Food, 
Drug, and Cosmetic Act (the act) (21 U.S.C. 355(e)) withdrawing 
approval of the NDAs and all amendments and supplements thereto 
providing for the indications determined by the agency to lack 
substantial evidence of effectiveness (44 FR 2017 at 2020). The agency 
stated that the notice of an opportunity for a hearing encompassed all 
issues relating to the legal status of the drug products subject to the 
notice, including identical, related, or similar drug products as 
defined in Sec.  310.6 (21 CFR 310.6). In accordance with section 505 
of the act and parts 310 and 314 (21 CFR parts 310 and 314), FDA gave 
the applicants and all other persons who manufacture or distribute a 
drug product that is identical, related, or similar to a drug product 
named in the notice an opportunity for a hearing to show why approval 
of the NDAs providing for the claims involved (i.e., those claims found 
to be lacking substantial evidence of effectiveness) should not be 
withdrawn, and an opportunity to raise, for administrative 
determination, all issues relating to the legal status of a named drug 
product and all identical, related, or similar drug products (44 FR 
2017 at 2020).
    The 1979 notice stated that the failure of an applicant or any 
other person subject to the notice to file a timely written appearance 
and request for a hearing as required by Sec.  314.200 constituted an 
election by such person not to make use of the opportunity for a 
hearing and a waiver of any contentions concerning the legal status of 
any drug product subject to the notice. The notice further stated that 
any such drug product labeled for the indications lacking substantial 
evidence of effectiveness specified in the notice could not thereafter 
lawfully be marketed, and the agency would initiate appropriate 
regulatory action to remove any such drug products from the market (44 
FR 2017 at 2020).
    In a letter dated January 30, 1979, Beecham requested a hearing on 
the proposed NDA withdrawals. In a letter dated March 5, 1979, Beecham 
submitted data in support of its request for a hearing. Beecham was the 
only party to request a hearing.

II. King Pharmaceuticals' Supplemental NDAs for Tigan Injection and 
Capsules

    On November 12, 1999, King Pharmaceuticals, Inc. (King), purchased 
the NDAs for three Tigan (trimethobenzamide hydrochloride) products 
previously held by Beecham: NDA 17-530 (injection), NDA 17-531 
(capsules), and NDA 17-529 (suppositories). FDA subsequently initiated 
discussions with King on bringing the Tigan products into compliance 
with the 1979 notices on trimethobenzamide hydrochloride drugs.

A. Supplemental NDA for Tigan Capsules

    As a step toward resolution of the issues in the 1979 notice 
regarding trimethobenzamide hydrochloride injection and capsules, and 
pending resolution of Beecham's request for a hearing, in December 
1999, FDA agreed to allow King to attempt to demonstrate that a 300-mg 
trimethobenzamide hydrochloride capsule product is bioequivalent to the 
200-mg Tigan injection product. In a supplemental NDA dated February 8, 
2001, and received by FDA on February 14, 2001, King requested approval 
of a 300-mg Tigan (trimethobenzamide hydrochloride) capsule product.
    In an agreement that became effective on August 16, 2001 (the 
Agreement), FDA and King agreed to take several actions to resolve the 
matter of the compliance of Tigan products with the 1979 notices. Among 
other things, King agreed to withdraw the request for a hearing 
(originally submitted by Beecham) on matters related to NDAs 17-529 
(Tigan Suppositories), 17-530 (Tigan Injection), and 17-531 (Tigan 
Capsules), and all amendments and supplements thereto, within 10 days 
of the effective date of the Agreement. In a letter dated August 24, 
2001, King withdrew its request for a hearing on these matters in 
accordance with the Agreement.
    In a letter dated December 13, 2001, FDA approved King's 
supplemental NDA for 300-mg Tigan Capsules. The approval letter states 
that the supplemental NDA provides for the following in response to the 
1979 notice classifying the drug as effective for postoperative nausea 
and vomiting and nausea associated with gastroenteritis: Draft 
labeling; results of bioavailability studies; and updated 
manufacturing, control, and testing procedures.

B. Supplemental NDA for Tigan Injection

    In a letter dated December 19, 2001, King submitted a supplemental 
NDA, in accordance with the Agreement and Sec.  314.70(c), to 
incorporate in NDA 17-530 (Tigan Injection) the new Tigan labeling 
approved by FDA on December 13, 2001, as part of the approval of King's 
supplemental NDA for Tigan Capsules. Among other things, the labeling 
states that Tigan is indicated for the treatment of postoperative 
nausea and vomiting and for nausea associated with gastroenteritis (the 
indication specified in the 1979 notice and in the recently-approved 
labeling for Tigan Capsules), and that the dosage of Tigan Capsules is 
300 mg. Under Sec.  314.70(c),

[[Page 78478]]

the supplemental NDA for Tigan Injection did not require prior agency 
approval.

III. Marketing of Other Trimethobenzamide Hydrochloride Injection and 
Capsule Products

    In light of King's withdrawal of its hearing requests, FDA's 
approval of 300-mg Tigan Capsules, and King's revision of the labeling 
for Tigan Injection, FDA is issuing this notice in final resolution of 
all matters in this proceeding involving trimethobenzamide 
hydrochloride injection and capsules. (At a later date, FDA intends to 
issue a notice resolving all matters in FDA Docket No. 78N-0224 (DESI 
11853) involving trimethobenzamide hydrochloride suppositories.)
    As stated above, no party other than Beecham submitted a request 
for a hearing in response to the 1979 notice. Therefore, all other 
parties waived any possible contentions regarding the legal status of 
their trimethobenzamide hydrochloride injection and capsule products 
(including those products listed in the 1971 notice).
    Trimethobenzamide hydrochloride capsule products made by several 
different manufacturers are currently listed with FDA. Continued 
marketing of an unapproved trimethobenzamide hydrochloride capsule 
product is unlawful and is subject to regulatory action. Any person 
wishing to market a trimethobenzamide hydrochloride capsule product 
must submit and obtain FDA approval of a new NDA or ANDA.
    With respect to trimethobenzamide hydrochloride injection, the FDA 
publication entitled ``Approved Drug Products With Therapeutic 
Equivalence Evaluations'' (the Orange Book), 22d ed. (2002), includes 
two products other than Tigan Injection on the ``Prescription Drug 
Product List.'' Four trimethobenzamide hydrochloride injection products 
are on the Orange Book's ``Discontinued Drug Product List.'' For some 
of these trimethobenzamide hydrochloride injection products, an ANDA 
supplement to revise product labeling may be required for continued or 
renewed marketing. To determine whether an ANDA supplement is required 
for a particular product, write to the Office of Generic Drugs (see 
ADDRESSES).
    Any drug product that is identical, related, or similar to the 
trimethobenzamide hydrochloride injection and capsule products named 
above, and is not the subject of an approved application, is covered by 
the applications named above (i.e., NDAs 17-530 and 17-531) and is 
subject to this notice (21 CFR 310.6). Any person who wishes to 
determine whether a specific product is covered by this notice should 
write to the Division of Prescription Drug Compliance and Surveillance 
(see ADDRESSES).
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (secs. 201(n), 502, 505, 52 Stat. 1041, 1050-1053), as amended (21 
U.S.C. 321(n), 352, 355), and under the authority delegated to the 
Director of the Center for Drug Evaluation and Research (21 CFR 5.100).

    Dated: December 18, 2002.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 02-32344 Filed 12-23-02; 8:45 am]
BILLING CODE 4160-01-S