Notice2025-18510
Approval of Previously Withdrawn New Drug Application for WELLCOVORIN (Leucovorin Calcium) Tablets
Primary source
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Published
September 24, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or Agency) is announcing approval of the previously withdrawn new drug application (NDA) for Wellcovorin (leucovorin calcium) tablets, equivalent to (EQ) 5 milligrams (mg) base and EQ 25 mg base. FDA is initiating this action on the basis of new data and is required to publish notice of approval of an NDA for which the Agency had previously withdrawn approval.
Full Text
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<title>Federal Register, Volume 90 Issue 183 (Wednesday, September 24, 2025)</title>
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[Federal Register Volume 90, Number 183 (Wednesday, September 24, 2025)]
[Notices]
[Pages 45944-45945]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-18510]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2025-N-3959]
Approval of Previously Withdrawn New Drug Application for
WELLCOVORIN (Leucovorin Calcium) Tablets
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
approval of the previously withdrawn new drug application (NDA) for
Wellcovorin (leucovorin calcium) tablets, equivalent to (EQ) 5
milligrams (mg) base and EQ 25 mg base. FDA is initiating this action
on the basis of new data and is required to publish notice of approval
of an NDA for which the Agency had previously withdrawn approval.
FOR FURTHER INFORMATION CONTACT: Harold Sano, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 4355, Silver Spring, MD 20993-0002, 301-
796-2429, <a href="/cdn-cgi/l/email-protection#6921081b06050d473a080706290f0d084701011a470e061f"><span class="__cf_email__" data-cfemail="105871627f7c743e43717e7f507674713e7878633e777f66">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION: FDA is announcing approval of the previously
withdrawn NDA 018342 for Wellcovorin (leucovorin calcium) tablets, EQ 5
mg base and EQ 25 mg base in accordance with 21 CFR 314.160, which
provides, in relevant part, that FDA may, on the basis of new data,
approve an application for which it had previously withdrawn approval.
Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and EQ 25 mg
base, are the subject of NDA 018342, initially approved on July 8,
1983, and held by GlaxoSmithKline (GSK). The most recently approved
labeling for Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and
EQ 25 mg base, stated that the drug products were indicated to diminish
the toxicity and counteract the effects of impaired methotrexate
elimination and of inadvertent overdosages of folic acid antagonists.
In the Federal Register of September 22, 1999, FDA announced that it
was withdrawing approval of NDA 018342 after GSK notified the Agency
that Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and EQ 25
mg base, were no longer marketed and requested that the approval of the
application be withdrawn under 21 CFR 314.150(c). Subsequently, in the
Federal
[[Page 45945]]
Register of April 28, 2017, FDA announced its determination that
Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and EQ 25 mg
base, were not withdrawn from sale for reasons of safety or
effectiveness under 21 CFR 314.161.
Under 21 CFR 314.160, FDA, on its own initiative or upon request of
an applicant, may, on the basis of new data, approve an application or
abbreviated application which it had previously refused, suspended, or
withdrawn approval. With respect to leucovorin calcium tablets, FDA has
conducted a systematic analysis of literature published between 2009-
2024 and has determined that the information supports a finding that
orally administered leucovorin calcium tablets improve certain symptoms
in adults and pediatric patients with cerebral folate deficiency (CFD).
Published case reports provided patient-level data on over 40 patients,
including both adults and pediatric patients, with genetically
confirmed CFD due to variants in the FOLR1 gene who were treated with
oral leucovorin. Patients had heterogenous clinical symptoms that
included global developmental delays with autistic features and
psychomotor regression, intractable epilepsy, and cerebellar ataxia. In
some patients, leucovorin dosing was titrated based on levels of 5-
methyltetrahydrofolate (5-MTHF) in the cerebrospinal fluid (CSF) or
symptoms. Clinical outcomes were compared to the known natural history
of CFD due to variants in the FOLR1 gene as historic control. The
majority of patients demonstrated substantial improvement of symptoms
of CFD that would not be expected when compared to the natural history
of CFD due to FOLR1 gene variants. In addition, we reviewed mechanistic
data that demonstrated a normalization in CSF 5-MTHF levels in 80% of
patients who had CSF samples available for analysis following
administration of leucovorin. We note that CFD has been reported in
patients with neuropsychiatric symptoms, including autistic features,
and detectable serum autoantibodies to the folate receptor alpha;
however, data on the use of leucovorin is limited in this population
and additional studies are needed.
Subsequent to the approval of NDA 018342 for Wellcovorin
(leucovorin calcium) tablets, EQ 5 mg base and EQ 25 mg base, that is
being announced in this Notice, FDA intends to request that GSK submit
a prior approval supplemental NDA to revise the prescribing information
for Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and EQ 25 mg
base, to include the essential scientific information needed for the
safe and effective use of these drug products for the treatment of CFD
in adults and pediatric patients.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-18510 Filed 9-22-25; 4:15 pm]
BILLING CODE 4164-01-P
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