[Federal Register Volume 69, Number 40 (Monday, March 1, 2004)]
[Notices]
[Pages 9630-9631]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-4505]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 01P-0333]


Determination That Cytoxan (Cyclophosphamide for Injection), 2 
Gram Vials (NDA 12-142 054), Was Not Withdrawn From Sale for Reasons of 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 
although Bristol Myers Squibb (Bristol) has discontinued marketing 
CYTOXAN, 2 gram (g) vials (cyclophosphamide for injection), this 
formulation was not withdrawn from sale for reasons of safety and 
effectiveness. As a result of this determination, approved abbreviated 
new drug applications (ANDAs) for cyclophosphamide for injection that 
referenced Bristol's cyclophosphamide for injection will not be removed 
from the market. Because Bristol has supplemented its CYTOXAN NDA and 
obtained approval for a new formulation, cyclophosphamide lyophilized, 
any unapproved ANDAs seeking to reference CYTOXAN as a reference listed 
drug must reference the currently approved formulation, 
cyclophosphamide lyophilized.

FOR FURTHER INFORMATION CONTACT: Howard P. Muller, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20855, 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 
sponsors 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 under a 
new drug application (NDA). Sponsors of ANDAs do not have to repeat the 
extensive clinical testing otherwise necessary to gain approval of an 
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 Sec.  314.162 (21 CFR 314.162), drugs are withdrawn 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 voluntarily withdrawn from sale by the sponsor 
for reasons of safety or effectiveness.
    Regulations also provide that 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 (Sec.  314.161(a)(1) (21 CFR 314.161(a)(1))). If the agency 
determines that a listed drug was withdrawn for reasons of safety or 
effectiveness, the drug must be removed from the list of approved drug 
products, and ANDAs referencing that drug may not be approved (Sec.  
314.162). Under Sec.  314.161(a)(2), the agency must also determine 
whether a listed drug was withdrawn from sale for reasons of safety or 
effectiveness if ANDAs that referred to the listed drug have already 
been approved prior to its market withdrawal. If the agency determines 
that a listed drug was withdrawn from sale for reasons of safety or 
effectiveness, and there are approved ANDAs that reference that listed 
drug, FDA will initiate a proceeding to determine whether the 
suspension of the ANDAs is also required (21 CFR 314.153(b)).
    On August 30, 1982, Bristol received approval for CYTOXAN 
(cyclophosphamide for injection), 2 g vials, under NDA 12-142 054. 
CYTOXAN is an alkylating agent used to treat various types of cancer. 
It interferes with the growth of cancer cells, which are eventually 
destroyed. On January 4, 1984, Bristol received approval for a new 
formulation of CYTOXAN, cyclophosphamide lyophilized, under NDA 12-142 
058. Bristol's lyophilized formulation was approved on the basis of a 
showing of bioequivalence to the previously approved formulation. No 
additional clinical trials were required to demonstrate the safety or 
effectiveness of cyclophosphamide lyophilized. ANDAs were approved 
before the time the cyclophosphamide lyophilized formulation was 
approved. These ANDAs referenced cyclophosphamide for injection. 
Bristol discontinued marketing cyclophosphamide for injection, 2 g 
vials, in 1997. Cyclophosphamide for injection was moved from the 
prescription drug product list to the ``Discontinued Drug Product 
List'' section of the Orange Book in May 1997.
    On July 26, 2001, ASTA Medica, Inc., submitted a citizen petition 
(Docket No. 01P-0333/CP1) to FDA under 21 CFR 10.30 requesting that the 
agency determine whether CYTOXAN, cyclophosphamide for injection, 2 g 
vials, was withdrawn from sale for reasons of safety or effectiveness. 
This determination not only affects whether an ANDA may be submitted 
and approved under Sec. Sec.  314.122 and 314.161 using CYTOXAN, 
cyclophosphamide for injection, 2 g, as the reference listed drug, but 
also affects whether the agency is required to initiate withdrawal 
proceedings for the ANDAs that reference cyclophosphamide for injection 
and were approved before its market withdrawal.
    The agency has determined that Bristol did not withdraw 
cyclophosphamide for injection from sale for reasons of safety or 
effectiveness. Three grounds support the agency's finding. First, 
Bristol continues to market cyclophosphamide lyophilized (which is 
pharmaceutically and therapeutically equivalent to Bristol's withdrawn 
cyclophosphamide for injection) in a variety of strengths. FDA has no 
reason to believe that cyclophosphamide lyophilized has a different 
safety or effectiveness profile than cyclophosphamide for injection, 
and required Bristol to conduct no clinical trials (other than 
bioequivalence trials) to support the formulation change. Second, the 
petitioner identified no adverse event data or other information 
suggesting that Bristol withdrew cyclophosphamide for injection from 
sale as a result of safety

[[Page 9631]]

or effectiveness concerns. Third, FDA has independently evaluated 
relevant literature and internal agency data for possible postmarketing 
reports associated with cyclophosphamide for injection, 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 its records, 
FDA determines that, for the reasons outlined above, Bristol's 
cyclophosphamide for injection was not withdrawn from sale for reasons 
of safety or effectiveness. Thus, FDA will not initiate proceedings to 
suspend the approvals of ANDAs referencing cyclophosphamide for 
injection. However, because Bristol has supplemented its CYTOXAN NDA 
and obtained approval for a new formulation, cyclophosphamide 
lyophilized, any unapproved ANDAs seeking to reference CYTOXAN (NDA 12-
142 054) must reference the currently approved formulation.

    Dated: February 15, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-4505 Filed 2-27-04; 8:45 am]
BILLING CODE 4160-01-S