Drug Update · Neurology

FDA Approves Leucovorin for Cerebral Folate Transport Deficiency

July 23, 2026

Approval date

March 10, 2026

Indication

Cerebral folate transport deficiency in adult and pediatric patients with a confirmed FOLR1 variant

Label dosing ( <40 kg )

Initiate 1 to 2 mg/kg/day and adjust to maximum 8.5 mg/kg/day

Label dosing ( ≥40 kg )

Initiate 1 to 2 mg/kg/day and adjust to maximum 330 mg/day

Single dose guidance

Single doses of 25 mg or less preferred; do not administer more than 75 mg as a single dose

Clinical Perspective

Neurologists and clinicians who manage adults and pediatric patients with suspected or confirmed FOLR1-related cerebral folate transport deficiency should be aware that leucovorin calcium tablets are now FDA-approved as a treatment option for patients with a confirmed FOLR1 variant ^[1]^[2]. The approval supports using oral leucovorin in this genetically defined population and provides explicit weight-based dosing ranges and maximum daily dosages in the updated label to guide therapy ^[1]. What are the optimal long-term dosing, monitoring, and efficacy assessment strategies across different pediatric and adult age groups?

Dr. Aditi Kulkarni · Neurology

The FDA approved Wellcovorin (leucovorin calcium) tablets for the treatment of cerebral folate transport deficiency in adult and pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD) on March 10, 2026, based on a systematic review of published literature, case reports, and mechanistic data ^[2]. The agency described leucovorin as the first FDA-approved treatment for this rare genetic disorder affecting folate transport into the brain ^[2].

Clinical Context

Leucovorin calcium is a folate analog available orally as Wellcovorin (leucovorin calcium) tablets. The FDA’s approval for FOLR1-related cerebral folate transport deficiency reflects an expanded indication for a product whose NDA holder is identified as GSK in the FDA announcement; DailyMed lists Ingenus Pharmaceuticals, LLC as the packager for leucovorin calcium tablets in the updated label ^[2]^[1]. Cerebral folate transport deficiency (CFD) from FOLR1 pathogenic variants impairs folate entry into the central nervous system and is associated with developmental delay, movement disorders, and seizures; there were no previously FDA-approved therapies for FOLR1-CFTD before this action ^[2]. The approval relied on published case reports and mechanistic data rather than a randomized controlled trial ^[2].

Key Findings

The FDA approved Wellcovorin (leucovorin calcium) tablets for the treatment of cerebral folate transport deficiency in adult and pediatric patients with a confirmed FOLR1 variant; the approval was granted on March 10, 2026 and was based on a systematic review of published literature including case reports and mechanistic evidence rather than a prospective randomized trial ^[2].
The updated prescribing information provides FDA-approved dosing for FOLR1-CFTD: for patients weighing less than 40 kg initiate 1 to 2 mg/kg/day and adjust to a maximum recommended total daily dosage of 8.5 mg/kg/day; for patients 40 kg or more initiate 1 to 2 mg/kg/day and adjust to a maximum recommended total daily dosage of 330 mg/day. The label permits administering the total daily dose once daily or in divided doses up to 6 times per day and states single doses of 25 mg or less are preferred; do not administer more than 75 mg as a single dose ^[1]. Clinicians should consult current prescribing information for complete dosing guidance.
The FDA stated leucovorin is the first approved treatment specifically for CFD due to FOLR1 variants and noted the decision illustrates use of observational and mechanistic evidence to support an approval for an ultra-rare disorder ^[2].

Safety & Tolerability

Pruritus (itching) ^[1]^[2]
Rash (irritated, inflamed skin) ^[1]^[2]
Urticaria (hives) ^[1]^[2]
Dyspnea ^[1]^[2]
Rigors (sudden feeling of cold with shivering) ^[1]^[2]
Impaired thermoregulation (spontaneous changes in body temperature) ^[1]^[2]
Anaphylaxis (severe, rapid allergic reaction) has been reported and is described as a serious adverse event requiring immediate medical attention ^[1]^[2]

Study Design

This approval is an FDA regulatory decision for an expanded indication of an existing product (Wellcovorin, leucovorin calcium tablets). The FDA granted approval on March 10, 2026 for the treatment of cerebral folate transport deficiency in adult and pediatric patients with a confirmed FOLR1 variant, based on a systematic review of published literature including patient-level case reports and mechanistic data rather than on a randomized clinical trial ^[2]. The updated prescribing information and dosing guidance for FOLR1-CFTD are reflected in the DailyMed label and related labeling materials ^[1].

FAQ

Q1 What is Wellcovorin (leucovorin calcium) approved for?

Wellcovorin (leucovorin calcium) tablets are approved to treat cerebral folate transport deficiency in adult and pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD). The approval represents the first FDA-cleared therapy specifically for FOLR1-related CFD and supplements existing leucovorin indications for folic acid antagonist toxicity and methotrexate rescue described elsewhere in the labeling.

Q2 How does leucovorin work?

Leucovorin is a folate analog (leucovorin calcium) that provides reduced folate activity; in the context of FOLR1-related cerebral folate transport deficiency, oral leucovorin is intended to restore central nervous system folate availability by supplying reduced folates via alternate transport/metabolic pathways. The FDA approval was supported by mechanistic data and published case reports demonstrating clinical benefit in patients with confirmed FOLR1 variants.

Q3 What is the recommended dose for FOLR1‑CFTD?

The updated label provides weight-based dosing guidance: for patients less than 40 kg, initiate 1 to 2 mg/kg/day and titrate to a maximum recommended total daily dosage of 8.5 mg/kg/day; for patients 40 kg or more, initiate 1 to 2 mg/kg/day and titrate to a maximum recommended total daily dosage of 330 mg/day. The total daily dose may be given once daily or divided up to 6 times per day; single doses of 25 mg or less are preferred and no single dose should exceed 75 mg. Clinicians should consult current prescribing information for full dosing guidance.

Q4 What are the most common side effects to monitor?

Reported adverse events in the labeling and FDA announcement include pruritus, rash, urticaria (hives), dyspnea, rigors, and impaired thermoregulation; anaphylaxis has been reported and requires immediate treatment and discontinuation. Safety information for FOLR1-CFTD treatment is drawn from published case reports and postmarketing experience; clinicians should monitor for hypersensitivity reactions and manage them per standard emergency protocols.

Clinicians should consult current prescribing information for full dosing guidance.

FDA Approves Leucovorin for Cerebral Folate Transport Deficiency

FDA Approves Leucovorin for Cerebral Folate Transport Deficiency

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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