[Federal Register Volume 88, Number 196 (Thursday, October 12, 2023)]
[Notices]
[Pages 70665-70666]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-22494]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket Nos. FDA-2020-P-1344 and FDA-2023-P-2655]


Determination That CYTOXAN (Cyclophosphamide) for Injection 
(Sterile Dry Powder Excipient-Free Formulation), 500 Milligrams/Vial, 1 
Gram/Vial, and 2 Grams/Vial, and CYTOXAN (Cyclophosphamide) for 
Injection (Sterile Dry Powder With Sodium Chloride Formulation), 500 
Milligrams/Vial, 1 Gram/Vial, and 2 Grams/Vial, Were Not Withdrawn From 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 or the Agency) has 
determined that the sterile dry powder excipient-free formulation of 
CYTOXAN (cyclophosphamide) for Injection, 500 milligrams (mg)/vial, 1 
gram (g)/vial, and 2 g/vial, and the sterile dry powder with sodium 
chloride formulation of CYTOXAN (cyclophosphamide) for Injection, 500 
mg/vial, 1 g/vial, and 2 g/vial, were not withdrawn from sale for 
reasons of safety or effectiveness. This determination means that FDA 
will not begin procedures to withdraw approval of abbreviated new drug 
applications (ANDAs) that refer to the sterile dry powder excipient-
free formulation or the sterile dry powder with sodium chloride 
formulation of these drug products, and it will allow FDA to continue 
to approve ANDAs that refer to these formulations of CYTOXAN as long as 
they meet relevant legal and regulatory requirements.

FOR FURTHER INFORMATION CONTACT: Tereza Hess, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6221, Silver Spring, MD 20993-0002, 202-
768-5659, [email protected].

SUPPLEMENTARY INFORMATION: Section 505(j) of the Federal Food, Drug, 
and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)) allows the submission of 
an ANDA to market a generic version of a previously approved drug 
product. To obtain approval, the ANDA applicant must show, among other 
things, that the generic drug product: (1) has the same active 
ingredient(s), dosage form, route of administration, strength, 
conditions of use, and (with certain exceptions) labeling as the listed 
drug, which is a version of the drug that was previously approved, and 
(2) is bioequivalent to the listed drug. ANDA applicants do not have to 
repeat the extensive clinical testing otherwise necessary to gain 
approval of a new drug application (NDA).
    Section 505(j)(7) of the FD&C Act 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 
known generally 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).
    A person may petition the Agency to determine, or the Agency may 
determine on its own initiative, whether a listed drug was withdrawn 
from sale for reasons of safety or effectiveness. This determination 
may be made at any time after the drug has been withdrawn from sale, 
but must be made: (1) whenever a listed drug is voluntarily withdrawn 
from sale and ANDAs that referred to the listed drug have been approved 
and (2) prior to approving an ANDA that refers to the listed drug 
(Sec.  314.161 (21 CFR 314.161)). FDA may not approve an ANDA that does 
not refer to a listed drug.
    CYTOXAN (cyclophosphamide) for Injection (sterile dry powder with 
sodium chloride formulation), with the 500 mg/vial, initially approved 
on May 4, 1964, the 1 g/vial, initially approved on August 30, 1982, 
and the 2 g/vial, initially approved on August 30, 1982, are the 
subjects of NDA 012142, held by Baxter Pharmaceuticals. Subsequently, 
CYTOXAN (cyclophosphamide) for Injection (lyophilized powder with 
mannitol) was also approved under NDA 012142, with the 500 mg/vial 
approved on January 4, 1984; the 1 g/vial approved on September 24, 
1985; and the 2 g/vial approved on December 10, 1985. On November 7, 
2003, the lyophilized powder with mannitol formulation in 500 mg/vial, 
1 g/vial, and 2 g/vial strengths was reformulated and approved as a 
sterile dry powder excipient-free formulation under Supplement 107 to 
NDA 012142. On March 31, 2012, the CYTOXAN (cyclophosphamide) for 
Injection, sterile dry powder with sodium chloride formulation in 500 
mg/vial, 1 g/vial, and 2 g/vial strengths was reformulated and approved 
as a lyophilized powder with mannitol formulation under Supplement 113. 
CYTOXAN is indicated for treatment of malignant lymphomas: Hodgkin's 
disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic 
lymphoma, Burkitt's lymphoma, multiple myeloma, leukemias, mycosis 
fungoides, neuroblastoma, adenocarcinoma of the ovary, retinoblastoma, 
breast carcinoma, and minimal change nephrotic syndrome in pediatric 
patients.
    FDA previously determined that certain CYTOXAN (cyclophosphamide) 
for Injection formulations and strengths were not discontinued from 
sale for reasons of safety or effectiveness, but these determinations 
did not address all previously approved formulations and strengths. In 
the Federal Register of March 1, 2004 (69 FR 9630), FDA issued a 
determination that CYTOXAN (cyclophosphamide) for Injection (non-
lyophilized formulation), 2 g/vial, was not withdrawn from sale for 
reasons of safety or effectiveness. In the Federal Register of August 
5, 2013 (78 FR 47321), FDA issued a determination that CYTOXAN 
(cyclophosphamide) for Injection (lyophilized formulations), 100 mg/
vial, 200 mg/vial, 500 mg/vial, 1 g/vial, and 2 g/vial, and CYTOXAN 
(cyclophosphamide) for Injection (non-lyophilized formulations), 100 
mg/vial and 200 mg/vial, were not withdrawn from sale for reasons of 
safety or effectiveness. Neither of the previous Federal Register 
notices expressly indicate that the determinations were made for the 
sterile dry powder excipient-free formulation of CYTOXAN 
(cyclophosphamide) for Injection in the 500 mg/vial, 1 g/vial, and 2 g/
vial strengths or the sterile dry powder with sodium chloride 
formulation of CYTOXAN (cyclophosphamide) for Injection, 500 mg/vial, 1 
g/vial, and 2 g/vial.
    The sterile dry powder excipient-free formulation of CYTOXAN 
(cyclophosphamide) for Injection, 500 mg/vial, 1 g/vial, and 2 g/vial, 
and the sterile dry powder with sodium chloride formulation of CYTOXAN 
(cyclophosphamide) for Injection, 500 mg/vial, 1 g/vial, and 2 g/vial, 
are discontinued.
    Lachman Consultant Services, Inc., submitted a citizen petition 
dated May 5, 2020 (Docket No. FDA-2020-P-1344), under 21 CFR 10.30, 
requesting that the Agency determine whether discontinued formulations 
of all strengths of CYTOXAN (cyclophosphamide) for Injection approved 
under NDA 012142, including the sterile dry powder excipient-free 
formulation of CYTOXAN (cyclophosphamide) for Injection, 500 mg/vial, 1 
g/vial, and 2 g/vial, were withdrawn from sale for reasons of safety or 
effectiveness. Epic Pharma,

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LLC submitted a citizen petition dated June 27, 2023 (Docket No. FDA-
2023-P-2655), also requesting that the Agency determine whether the 
sterile dry powder excipient-free formulation of CYTOXAN 
(cyclophosphamide) for Injection, 500 mg/vial, 1 g/vial, and 2 g/vial, 
were withdrawn from sale for reasons of safety or effectiveness. 
Although the citizen petitions did not specifically address the sterile 
dry powder with sodium chloride formulation of CYTOXAN 
(cyclophosphamide) for Injection, 500 mg/vial, 1 g/vial, and 2 g/vial, 
this formulation also has been discontinued. We have also determined 
whether the sterile dry powder with sodium chloride formulation of 
CYTOXAN (cyclophosphamide) for Injection, 500 mg/vial, 1 g/vial, and 2 
g/vial, was withdrawn for safety or effectiveness.
    After considering the citizen petitions and reviewing Agency 
records and based on the information we have at this time, FDA has 
determined under Sec.  314.161 that CYTOXAN (cyclophosphamide) for 
Injection (sterile dry powder excipient-free formulation), 500 mg/vial, 
1 g/vial, and 2 g/vial, and CYTOXAN (cyclophosphamide) for Injection 
(sterile dry powder with sodium chloride formulation), 500 mg/vial, 1 
g/vial, and 2 g/vial, were not withdrawn for reasons of safety or 
effectiveness. The petitioners have identified no data or other 
information suggesting that the sterile dry powder excipient-free 
formulation of CYTOXAN (cyclophosphamide) for Injection, 500 mg/vial, 1 
g/vial, and 2 g/vial, or the sterile dry powder with sodium chloride 
formulation of CYTOXAN (cyclophosphamide) for Injection, 500 mg/vial, 1 
g/vial, and 2 g/vial, were withdrawn for reasons of safety or 
effectiveness. We have carefully reviewed our files for records 
concerning the withdrawal of the sterile dry powder excipient-free 
formulation of CYTOXAN (cyclophosphamide) for Injection, 500 mg/vial, 1 
g/vial, and 2 g/vial, and the sterile dry powder with sodium chloride 
formulation of CYTOXAN (cyclophosphamide) for Injection, 500 mg/vial, 1 
g/vial, and 2 g/vial, from sale. We have also independently evaluated 
relevant literature and data for possible postmarketing adverse events. 
We have found no information that would indicate that these drug 
products were withdrawn from sale for reasons of safety or 
effectiveness.
    Accordingly, the Agency has determined that the sterile dry powder 
excipient-free formulation of CYTOXAN (cyclophosphamide) for Injection, 
500 mg/vial, 1 g/vial, and 2 g/vial, and the sterile dry powder with 
sodium chloride formulation of CYTOXAN (cyclophosphamide) for 
Injection, 500 mg/vial, 1 g/vial, and 2 g/vial, drug products have been 
discontinued from marketing for reasons other than safety or 
effectiveness. FDA will not begin procedures to withdraw approval of 
approved ANDAs that have the sterile dry powder excipient-free 
formulation or the sterile dry powder with sodium chloride formulation. 
ANDAs that refer to CYTOXAN (cyclophosphamide) for Injection, 500 mg/
vial, 1 g/vial, and 2 g/vial may be approved by the Agency as long as 
they meet all other 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: October 5, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-22494 Filed 10-11-23; 8:45 am]
BILLING CODE 4164-01-P