FDA LABELED INDICATIONS AND DOSAGE
Agent(s) |
FDA Indication(s) |
Notes |
Ref# |
Leucovorin calcium Tablet |
To diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists |
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1 |
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL
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Module |
Clinical Criteria for Approval |
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Initial Evaluation Target Agent(s) will be approved when ALL of the following are met: 1. ONE of the following: A. The requested agent is eligible for continuation of therapy AND ONE of the following:
1. The patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days OR 2. The prescriber states the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days AND is at risk if therapy is changed OR B. The patient has a medication history of use in the past 180 days to methotrexate or another folic acid antagonist OR C. The patient has a diagnosis of cerebral folate deficiency (CFD) confirmed by ONE of the following: (medical records required) 1. Lumbar puncture (spinal tap) OR 2. Genetic testing (e.g., FOLR1) OR 3. Folate receptor alpha autoantibodies OR D. The patient has an FDA labeled indication for the requested agent and route of administration OR E. The patient has another indication that is supported in compendia for the requested agent and route of administration AND 2. If the patient has a diagnosis of CFD, then the prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND 3. The patient does NOT have any FDA labeled contraindications to the requested agent Compendia Allowed: AHFS, DrugDex 1 or 2a level of evidence, or NCCN 1 or 2a recommended use Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.
Renewal Evaluation Target Agent(s) will be approved when ALL of the following are met: 1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process (Note: patients not previously approved for the requested agent will require initial evaluation review) AND 2. ONE of the following: A. The patient has a medication history of use in the past 180 days to methotrexate or another folic acid antagonist OR B. The patient has had clinical benefit with the requested agent AND 3. If the patient has a diagnosis of cerebral folate deficiency (CFD), then the prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND 4. The patient does NOT have any FDA labeled contraindications to the requested agent Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. |
PRIOR AUTHORIZATION CLINICAL CRITERIA OPERATIONAL LEVEL OF EVIDENCE REQUIREMENTS
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Module |
Ops Set Up |
Validation Options |
Other Explanation |
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Documentation: Requirements as noted within the policy;Validation: Apply Baseline and go to Validation Options |
Continuation of Therapy;Diagnosis;Prerequisites |
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QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL
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Module |
Clinical Criteria for Approval |
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Universal QL |
Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met: 1. The requested quantity (dose) does NOT exceed the program quantity limit OR 2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following: A. BOTH of the following: 1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND 2. There is support for therapy with a higher dose for the requested indication OR B. BOTH of the following: 1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND 2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR C. BOTH of the following: 1. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND 2. There is support for therapy with a higher dose for the requested indication Length of Approval: up to 12 months |
QUANTITY LIMIT CLINICAL CRITERIA OPERATIONAL LEVEL OF EVIDENCE REQUIREMENTS
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Module |
Ops Set Up |
Validation Options |
Other Explanation |
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Universal QL |
Validation: Apply Baseline and go to Validation Options |
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Cerebral folate deficiency |
Folate (vitamin B-9) is an essential vitamin to nervous system development. In human embryo development, it is essential for neural tube formation and closure. Folate plays a role throughout fetal brain development as well as maturation and maintenance of the nervous system during infancy and childhood.(2) Cerebral folate deficiency (CFD) is defined as any neuropsychiatric or developmental disorder characterized by decreased cerebrospinal fluid (CSF) folate levels in the presence of normal folate status outside of the nervous system.(3,4) CFD occurs due to the impaired transport of folates across the blood-brain barrier, typically due to dysfunction of the folate receptor alpha. Folate receptor alpha is a receptor with a high affinity for 5-methyltetrahydrofolate (5-MTHF) which is the active folate metabolite in CSF. 5-MTHF functions to mediate transport of folates across the blood-brain barrier through adenosine triphosphate dependent receptor-mediated endocytosis. Dysfunction of the folate receptor alpha can occur through a number of mechanisms (genetic mutations [e.g., FOLR1], autoantibodies, mitochondrial dysfunction), with the most common cause being autoantibodies.(3) CFD has been associated with autism spectrum disorder (ASD) as a number of studies have reported a commonality with folate receptor dysfunction caused by autoantibodies. ASD is a spectrum of neurodevelopmental disorders, which involve difficulties interacting and communicating with others. The etiology of ASD is complex involving a variety of factors, including maternal, environmental, nutritional, and genetic influences.(5) The Centers for Disease Control (CDC) estimates the prevalence of ASD in the United States to be 1 in 31 (3.2%) children aged 8 years.(6) Several studies have suggested a link between the prevalence of ASD and CFD (pooled prevalence of ASD in individuals with CFD was 44%, while the pooled prevalence of CFD in ASD was 38%).(7) The typical onset of CFD is early childhood, and common symptoms include developmental delays, seizures, and movement disorders. CFD is diagnosed by measuring 5-MTHF concentration in the CSF, which is done with a lumbar puncture (spinal tap). Blood folate and metabolite status do not reflect central nervous system (CNS) folate deficiency, so a lumbar puncture is necessary to accurately diagnose CFD. Molecular genetic testing for mutations (e.g., FOLR1) gene is also available to confirm the diagnosis. Serum testing of folate receptor alpha autoantibody of the blocking and binding type can be performed to determine if autoantibodies are responsible for CFD.(3,4) There are no established clinical practice guidelines for the treatment of CFD. Oral treatment with folinic acid (d,l-leucovorin); the active form of folate, has been shown to improve symptoms in CFD and ASD. Folinic acid enters the CNS through a different folate transporter (reduced folate carrier [RFC]) and has been reported to normalize 5-MTHF levels in CSF for individuals with CFD. Clinical response to leucovorin is dramatic in some cases, especially if this treatment is started early in life, but notable response has also been seen in adults. Data for the use of leucovorin is derived mainly from case reports and case series, and there have been no randomized placebo-controlled clinical trials that have been conducted on the use of leucovorin in the treatment of CFD.(3,5,7) While leucovorin has a generally favorable safety profile, its safety for the treatment of CFD and ASD has not been established. Some studies have reported significant adverse effects such as aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%).(7) Future studies are needed to evaluate the long-term efficacy and safety of leucovorin in the treatment of CFD and ASD. |
Efficacy |
"The FDA has conducted a systematic analysis of literature published between 2009-2024, including published case reports with patient-level information, as well as mechanistic data, and has determined that the information supports a finding that leucovorin calcium can help individuals suffering from CFD. Analysis across 23 publications from 2009-2024 demonstrated the effectiveness for CFD. Overall, 85% of patients experienced some type of clinical benefit including improved speech/communication capabilities. The FDA has announced that they are requesting from the innovator company updated prescribing information (PI) to include the new indication of CFD, a condition often associated with autistic symptoms. The PI of generic leucovorin products will be updated accordingly."(8,9) |
Safety |
Leucovorin is contraindicated in patients with pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B12. A hematologic remission may occur while neurologic manifestations continue to progress.(1) |
Number |
Reference |
1 |
Leucovorin prescribing information. Hikma Pharmaceuticals USA Inc. June 2023. |
2 |
Balashova OA, Visina O, Borodinsky LN. Folate action in nervous system development and disease. Developmental neurobiology. 2018;78(4):391-402. doi:10.1002/dneu.22579 |
3 |
Ramaekers VTh, Quadros EV. Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies. Nutrients. 2022;14(15):3096. doi:10.3390/nu14153096 |
4 |
National Organization for Rare Disorders (NORD) Cerebral Folate Deficiency. Last updated August 22,2019. https://rarediseases.org/rare-diseases/cerebral-folate-deficiency/ |
5 |
Frye RE, Rossignol DA, Scahill L, McDougle CJ, Huberman H, Quadros EV. Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder. Seminars in Pediatric Neurology. 2020;35:100835. doi:10.1016/j.spen.2020.100835 |
6 |
CDC. Data and Statistics on Autism Spectrum Disorder. Autism Spectrum Disorder (ASD). Published April 15, 2025. https://www.cdc.gov/autism/data-research/index.html |
7 |
Rossignol DA, Frye RE. Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis. Journal of Personalized Medicine. 2021;11(11):1141. doi:10.3390/jpm11111141 |
8 |
Autism Announcement Fact Sheet. HHS.gov. Published September 22, 2025. https://www.hhs.gov/press-room/autism-announcement-fact-sheet.html |
9 |
FDA Takes Action to Make a Treatment Available for Autism Symptoms. U.S. Food and Drug Administration. Published 2025. https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms |
POLICY AGENT SUMMARY PRIOR AUTHORIZATION
Final Module |
Target Agent GPI |
Target Brand Agent(s) |
Target Generic Agent(s) |
Strength |
Targeted MSC |
Targeted NDCs When Exclusions Exist |
Final Age Limit |
Preferred Status |
Effective Date |
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217550401003 |
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leucovorin calcium tab |
10 MG ; 15 MG ; 25 MG ; 5 MG |
M ; N ; O ; Y |
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POLICY AGENT SUMMARY QUANTITY LIMIT
Target Agent GPI |
Target Brand Name(s) |
Target Generic Name(s) |
Strength |
QL Amount |
Dose Form |
Days Supply |
Duration |
Targeted NDCs When Exclusions Exist |
Age Limit |
Effective Date |
Term Date |
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21755040100325 |
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Leucovorin Calcium Tab 10 MG |
10 MG |
60 |
Tablets |
30 |
DAYS |
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21755040100335 |
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Leucovorin Calcium Tab 15 MG |
15 MG |
30 |
Tablets |
30 |
DAYS |
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21755040100345 |
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Leucovorin Calcium Tab 25 MG |
25 MG |
30 |
Tablets |
30 |
DAYS |
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21755040100310 |
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Leucovorin Calcium Tab 5 MG |
5 MG |
120 |
Tablets |
30 |
DAYS |
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CLIENT SUMMARY – PRIOR AUTHORIZATION
Target Brand Agent(s) |
Target Generic Agent(s) |
Strength |
Client Formulary |
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leucovorin calcium tab |
10 MG ; 15 MG ; 25 MG ; 5 MG |
Commercial ; HIM ; WY NetR-Commercial Custom |
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
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Leucovorin Calcium Tab 10 MG |
10 MG |
Commercial ; HIM ; WY NetR-Commercial Custom |
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Leucovorin Calcium Tab 15 MG |
15 MG |
Commercial ; HIM ; WY NetR-Commercial Custom |
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Leucovorin Calcium Tab 25 MG |
25 MG |
Commercial ; HIM ; WY NetR-Commercial Custom |
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Leucovorin Calcium Tab 5 MG |
5 MG |
Commercial ; HIM ; WY NetR-Commercial Custom |
