[Federal Register Volume 72, Number 152 (Wednesday, August 8, 2007)]
[Notices]
[Pages 44559-44560]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-15490]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2006P-0520]


Determination That Methotrexate Injection, USP, Preservative 
Free, Equivalent to 500 Milligrams Base/20 Milliliters (25 Milligrams/
Milliliter), Was Not Withdrawn From Sale for Reasons of Safety or 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 
methotrexate injection, USP, preservative free, equivalent to (Eq.) 500 
milligrams (mg) base/20 milliliters (mL) (25 mg/mL), was not withdrawn 
from sale for reasons of safety or effectiveness. This determination 
will allow FDA to approve abbreviated new drug applications (ANDAs) for 
methotrexate injection, preservative free, Eq. 500 mg base/20 mL (25 
mg/mL).

FOR FURTHER INFORMATION CONTACT: Elena Cohen, 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 drug products approved under an ANDA procedure. ANDA 
applicants must, with certain exceptions, 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 
typically a version of the drug that was previously approved. ANDA 
applicants do not have to repeat the extensive clinical testing 
otherwise necessary to gain approval of a new drug application (NDA). 
The only clinical data 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 (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.'' Under FDA regulations, drugs are removed from the list if the 
agency withdraws or 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).
    Under 21 CFR 314.161(a)(1), the agency must determine 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. FDA may not approve an ANDA that does not refer to a listed 
drug.
    Methotrexate injection, USP, preservative free, Eq. 500 mg base/20 
mL (25 mg/mL), is the subject of approved NDA 11-719 currently held by 
Mayne Pharma USA (Mayne). Although NDA 11-719 was originally approved 
in 1959, this formulation and dosage was approved in April 2005 (S-
108). Methotrexate is an antifolate cytotoxic drug used in the 
treatment of a variety of malignancies, including acute lymphoblastic 
leukemia, osteosarcoma, advanced metastatic breast cancer, and others. 
It is also used to treat some inflammatory conditions such as 
rheumatoid arthritis. To date, Mayne has not marketed methotrexate 
injection, USP, preservative free, Eq. 500 mg base/20 mL (25 mg/mL). At 
the request of the sponsor, the product was moved to the discontinued 
section of the Orange Book in June 2005. In previous instances (see, 
e.g., the Federal Register document of December 30, 2002 (67 FR 79640), 
addressing a relisting request for Diazepam Autoinjector), the agency 
has determined that, for purposes of Sec. Sec.  314.161 and 314.162, 
never marketing an approved drug product is equivalent to withdrawing 
the drug from sale.
    SICOR Pharmaceuticals, Inc., submitted a citizen petition dated

[[Page 44560]]

December 15, 2006 (Docket No. 2006P-0520/CP1), under 21 CFR 10.30, 
requesting that the agency determine whether methotrexate injection, 
preservative free, Eq. 500 mg base/20 mL (25 mg/mL), was withdrawn from 
sale for reasons of safety or effectiveness. The petitioner has 
identified no data or other information suggesting that methotrexate 
injection, preservative free, Eq. 500 mg base/20 mL (25 mg/mL), was 
withdrawn from sale for reasons of safety or effectiveness. FDA has 
independently evaluated relevant literature and data for possible 
postmarketing adverse events and has found no information that would 
indicate this product was withdrawn for reasons of safety or 
effectiveness.
    After considering the citizen petition and reviewing agency 
records, FDA has determined that, for the reasons outlined in this 
document, methotrexate injection, preservative free, Eq. 500 mg base/20 
mL (25 mg/mL), was not withdrawn from sale for reasons of safety or 
effectiveness. Accordingly, the agency will continue to list 
methotrexate injection, preservative free, Eq. 500 mg base/20 mL (25 
mg/mL), 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. ANDAs that refer to 
methotrexate injection, preservative free, Eq. 500 mg base/20 mL (25 
mg/mL), may be approved by the agency as long as they meet all relevant 
legal and regulatory requirements for the approval of ANDAs. If FDA 
determines that labeling for these drug products should be revised to 
meet current standards, the agency will advise ANDA applicants to 
submit such labeling.

    Dated: July 30, 2007.
Randall W. Lutter,
Deputy Commissioner for Policy.
[FR Doc. E7-15490 Filed 8-7-07; 8:45 am]
BILLING CODE 4160-01-S