[Federal Register Volume 90, Number 237 (Friday, December 12, 2025)]
[Notices]
[Pages 57766-57767]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2025-22676]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2025-N-4732]
Determination That ZANTAC (Ranitidine Hydrochloride) Injection,
Equivalent to 25 Milligrams Base/Milliliter, Has Not Been Withdrawn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 Agency) has
determined that ZANTAC (ranitidine hydrochloride (HCl)) injection,
equivalent to (EQ) 25 milligram (mg) base/milliliter (mL), has not been
withdrawn from sale for reasons of safety or effectiveness to the
extent that the drug can be manufactured or formulated in a manner that
satisfies any applicable acceptable intake limit for nitrosamine
impurities. This determination means that FDA will not begin procedures
to withdraw approval of abbreviated new drug applications (ANDAs) that
refer to this drug product, and it will allow FDA to continue to
approve ANDAs that refer to the product as long as they meet relevant
legal and regulatory requirements, including satisfying any applicable
acceptable intake limit for nitrosamine impurities.
FOR FURTHER INFORMATION CONTACT: Robin Fastenau, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6236, Silver Spring, MD 20993-0002, 240-
893-4962, [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 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.
ZANTAC (ranitidine HCl) injection, EQ 25 mg base/mL, is the subject
of NDA 019090, held by Pharmaceutical Associates, Inc. (PAI) Pharma,
and initially approved on October 19, 1984. ZANTAC (ranitidine HCl)
injection, EQ 25 mg base/mL is indicated in some hospitalized patients
with pathological hypersecretory conditions or intractable duodenal
ulcers, or as an alternative to the oral dosage form for short-term use
in patients who are unable to take oral medication.
On March 31, 2020, FDA requested that all manufacturers voluntarily
withdraw their ranitidine products from the market because accumulated
data showed levels of N-Nitrosodimethylamine (NDMA) above the
acceptable daily intake limit in many ranitidine-containing
products.\1\ This request applied to all ranitidine applicants,
including the applicant for ZANTAC (ranitidine HCl) injection, EQ 25 mg
base/mL, NDA 019090. ZANTAC (ranitidine HCl) injection, EQ 25 mg base/
mL, NDA 019090, was withdrawn from sale prior to March 31, 2020. ZANTAC
(ranitidine HCl) injection, EQ 25 mg base/mL, is currently listed in
the ``Discontinued Drug Product List'' section of the Orange Book.
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\1\ Nitrosamine impurities in the drug supply are an important
public health concern. As explained in the guidance for industry
entitled ``Control of Nitrosamine Impurities in Human Drugs''
published September 2024 (available at https://www.fda.gov/media/141720/download) (at 4-5), ``Nitrosamine compounds are potent
genotoxic agents in several animal species and some are classified
as probable or possible human carcinogens by the International
Agency for Research on Cancer. They are referred to as cohort of
concern compounds in the International Council for Harmonisation of
Technical Requirements for . . . Human Use (ICH) guidance for
industry M7(R2) Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk
(July 2023).'' Many drug products have been found to contain levels
of nitrosamines that are unacceptable or require further evaluation.
FDA's current understanding is that nitrosamine levels in affected
drug products have different causes and may be controlled using
different strategies, including formulation design (i.e., adding
antioxidants or adding pH adjusters that modify the microenvironment
to base or neutral pH) and supplier qualification programs.
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After reviewing Agency records and based on the information we have
at this time, FDA has determined under Sec. 314.161 that ZANTAC
(ranitidine HCl) injection, EQ 25 mg base/mL, has not been withdrawn
for reasons of safety or effectiveness to the extent that the drug can
be manufactured or formulated in a manner that satisfies any applicable
acceptable intake limit for nitrosamine impurities.
Accordingly, the Agency will continue to list ZANTAC (ranitidine
HCl) injection, EQ 25 mg base/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. FDA will not begin procedures to withdraw approval of
approved ANDAs that refer to this drug product. Additional ANDAs for
this drug product may be approved by the Agency as long as they meet
all other legal and regulatory requirements for the approval of ANDAs,
including satisfying any applicable acceptable intake limit for
nitrosamine impurities.
[[Page 57767]]
If FDA determines that labeling for this drug product should be revised
to meet current standards, the Agency will advise ANDA applicants to
submit such labeling.
Lowell M. Zeta,
Acting Deputy Commissioner for Policy, Legislation, and International
Affairs.
[FR Doc. 2025-22676 Filed 12-11-25; 8:45 am]
BILLING CODE 4164-01-P