Notice2025-15786
Determination That RIFADIN (Rifampin) Capsules, 150 Milligrams and 300 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness
Primary source
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Published
August 19, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or Agency) has determined that RIFADIN (rifampin) capsules, 150 milligrams (mg) and 300 mg, were not withdrawn from sale for reasons of safety or effectiveness to the extent that the drugs can be manufactured or formulated in a manner that satisfies any applicable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 these drug products, and it will allow FDA to continue to approve ANDAs that refer to the products as long as they meet relevant legal and regulatory requirements, including satisfying any applicable acceptable intake limit for nitrosamine impurities.
Full Text
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<title>Federal Register, Volume 90 Issue 158 (Tuesday, August 19, 2025)</title>
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[Federal Register Volume 90, Number 158 (Tuesday, August 19, 2025)]
[Notices]
[Pages 40373-40374]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-15786]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2024-P-5470]
Determination That RIFADIN (Rifampin) Capsules, 150 Milligrams
and 300 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety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 Agency) has
determined that RIFADIN (rifampin) capsules, 150 milligrams (mg) and
300 mg, were not withdrawn from sale for reasons of safety or
effectiveness to the extent that the drugs 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 these drug products, and it will
allow FDA to continue to approve ANDAs that refer to the products 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, <a href="/cdn-cgi/l/email-protection#077568656e6929616674736269667247616366296f6f7429606871"><span class="__cf_email__" data-cfemail="7f0d101d161151191e0c0b1a111e0a3f191b1e5117170c51181009">[email protected]</span></a>.
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 it must be made prior to approval of 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.
RIFADIN (rifampin) capsules, 150 mg and 300 mg, are the subject of
NDA 050420, held by Sanofi Aventis US LLC, and initially approved on
May 21, 1971. RIFADIN (rifampin) capsules, 150 mg and 300 mg, are
indicated for the treatment of all forms of tuberculosis and for the
treatment of asymptomatic carriers of Neisseria meningitidis to
eliminate meningococci from the nasopharynx.
RIFADIN (rifampin) capsules, 150 mg and 300 mg, have not been
marketed in the United States since their voluntary discontinuation
from sale in November 2020.
Novitium Pharma LLC submitted a citizen petition dated November 21,
2024 (Docket No. FDA-2024-P-5470), under 21 CFR 10.30, requesting that
the Agency determine whether RIFADIN (rifampin) capsules, 150 mg and
300 mg, were withdrawn from sale for reasons of safety or
effectiveness.
FDA has identified a number of active pharmaceutical ingredients
(APIs) that
[[Page 40374]]
have secondary or tertiary amines and are therefore at risk for forming
nitrosamine drug substance related impurities (NDSRIs). Hypothetically,
under certain conditions related to the formulation and manufacturing
process for the drug product, such as residual nitrites in excipients
used to formulate the drug product, these APIs could form NDSRIs.
Rifampin is one such API at risk of forming 1-methyl-4-
nitrosopiperazine (MNP). FDA has tested certain rifampin products for
MNP and detected MNP in all such tested rifampin products.\1\ FDA has
announced recommended acceptable intake limits for MNP in all rifampin
products, including a recommended interim acceptable intake limit.
Rifadin (rifampin) 150 mg and 300 mg capsules are 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 <a href="https://www.fda.gov/media/141720/download">https://www.fda.gov/media/141720/download</a>) (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 considering the citizen petition and reviewing Agency records
and based on the information we have at this time, FDA has determined
under Sec. 314.161 that RIFADIN (rifampin) capsules, 150 mg and 300
mg, were not withdrawn for reasons of safety or effectiveness to the
extent that the drugs can be manufactured or formulated in a manner
that satisfies any applicable acceptable intake limit for nitrosamine
impurities. The petitioner has identified no data or other information
suggesting that RIFADIN (rifampin) capsules, 150 mg and 300 mg, were
withdrawn for reasons of safety or effectiveness. We have carefully
reviewed our files for records concerning the withdrawal of RIFADIN
(rifampin) capsules, 150 mg and 300 mg, from sale. We have also
independently evaluated relevant literature and data for possible
postmarketing adverse events. We have reviewed the available evidence
and determined that these drug products were not withdrawn from sale
for reasons of safety or effectiveness to the extent that the drugs 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 RIFADIN (rifampin)
capsules, 150 mg and 300 mg, 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 these drug products. Additional ANDAs for
these drug products may also 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. 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: August 14, 2025.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-15786 Filed 8-18-25; 8:45 am]
BILLING CODE 4164-01-P
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