[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]
[[Page 70665]]
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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Milligrams/Vial, 1 Gram/Vial, and 2 Grams/Vial, Were Not Withdrawn From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mg/vial, 1 g/vial, and 2 g/vial, were not withdrawn from sale for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,
[[Page 70666]]
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