ModifiedPremera BluecrossPolicy PHARMACY / MEDICAL POLICY -5.01.617

Folate Antimetabolites

Coverage rules for folate antimetabolite drugs (medical and pharmacy benefit) including pemetrexed products, pralatrexate, methotrexate formulations (Rasuvo, Xatmep) for oncology and select rheumatologic/dermatologic indications, and when use is investigational.

Policy Summary

PayerPremera Bluecross

PolicyFolate Antimetabolites

Policy CodePolicy PHARMACY / MEDICAL POLICY -5.01.617

Change TypeMultiple material additions and revisions (brands and indications)

Effective DateMay 1, 2026

Next Review Date

Key ActionObtain prior authorization and submit office visit notes documenting diagnosis, relevant history, physical evaluation, medication history, and trials of generic methotrexate when required.

SourceLink

POLICY UPDATE CHANGES

Added generic pralatrexate to the policy with the same criteria as Folotyn (pralatrexate) and brand pralatrexate.

Updated criteria to include pemetrexed products in combination with osimertinib and platinum-based chemotherapy for first-line treatment of EGFR-mutated NSCLC (exon 19 deletions or exon 21 L858R).

Updated Pemfexy (pemetrexed) criteria to include use in combination with pembrolizumab and platinum chemotherapy for metastatic non-squamous NSCLC without EGFR or ALK/ROS1 aberrations.

Added coverage criteria for Pemrydi RTU (pemetrexed).

Removed coverage criteria for several methotrexate products (RediTrex, Jylamvo, Otrexup) as withdrawn or removed.

Clarified that non-formulary exception review authorizations may be approved up to 12 months and that medications are subject to FDA dosing/administration.

Updated initial authorization durations for certain methotrexate products (Xatmep, Rasuvo) from 6 months to 12 months and other oral drugs from 3 to 6 months.

May 1, 2026Effective date

Apr. 14, 2026Last revised

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1new generic pralatrexate added

≤18Xatmep pediatric limit

12 moMax exception auth

Coverage Criteria

Covered indications and agent-specific criteria

Agents (pemetrexed products, pralatrexate, Rasuvo, Xatmep) are considered medically necessary when the specific agent-specific criteria below are met.

Pemetrexed products (Alimta, Pemfexy, Pemrydi RTU and listed biosimilars/brands): Covered when ONE of: in combination with pembrolizumab (Keytruda) and platinum chemotherapy for initial treatment of metastatic non-squamous non-small cell lung cancer (NSCLC) with no EGFR or ALK/ROS1 genomic tumor aberrations or while awaiting results; in combination with platinum chemotherapy for initial treatment of locally advanced or metastatic non-squamous NSCLC; as single-agent maintenance when disease has not progressed after four cycles of platinum-based first-line chemotherapy; as single-agent for recurrent/metastatic non-squamous NSCLC after prior chemotherapy; initial treatment with cisplatin for unresectable malignant pleural mesothelioma; or in combination with osimertinib and platinum-based chemotherapy for first-line treatment of adult individuals with locally advanced or metastatic non-squamous NSCLC with documented EGFR exon 19 deletions or exon 21 L858R mutations.FDA indication/non-squamous histology where specified

Applies to multiple branded and unbranded pemetrexed products listed in policy.

Pralatrexate (Folotyn and generic pralatrexate): Covered when used for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) per FDA-approved indication.FDA indication

Includes brand and generic pralatrexate.

Rasuvo (methotrexate) subcutaneous injection: Covered when ALL of the following are met: the individual has a diagnosis of rheumatoid arthritis (RA) OR polyarticular juvenile idiopathic arthritis (pJIA) who is intolerant of or had an inadequate response to one prior therapy OR psoriasis in adults who are intolerant of or had an inadequate response to two prior therapies; AND the individual has tried generic methotrexate tablets with documentation of either inadequate response after 3 months of treatment or intolerance; AND the individual has tried generic injectable methotrexate with documentation of inadequate response after 3 months or intolerance OR has a documented reason for requiring a special injection device (e.g., lack of dexterity or visual acuity); AND the product is not being used in combination with another methotrexate product.3 months trial durations for generics noted

Managed under medical and pharmacy benefit.

Xatmep (methotrexate) oral solution: Covered when ALL of the following are met: the individual is aged 18 years or younger; AND diagnosis is either acute lymphoblastic leukemia (ALL) when Xatmep is a component of a combination chemotherapy maintenance regimen prescribed by or in consultation with an oncologist/hematologist OR polyarticular juvenile idiopathic arthritis (pJIA) when intolerant of or had an inadequate response to one prior therapy and prescribed by or in consultation with a rheumatologist; AND the individual has tried generic methotrexate tablets with documentation of inadequate response after 3 months of treatment or intolerance, or has a documented inability to swallow solid oral dosage forms; AND Xatmep is not used in combination with another methotrexate product; AND the quantity is limited to 2 bottles every 28 days.Age ≤18; 2 bottles every 28 days

Managed under pharmacy benefit.

Covered indications and product-specific criteria

Covered when meeting FDA-approved indication and product-specific criteria (summarized from policy updates):

Pemetrexed for non-squamous NSCLC: Covered for non-squamous locally advanced or metastatic NSCLC as initial therapy in combination with platinum chemotherapy; in combination with pembrolizumab and platinum chemotherapy for first-line metastatic non-squamous NSCLC without EGFR/ALK/ROS1 aberrations when product labeling supports the combination; and as maintenance therapy following non-pemetrexed containing platinum-based chemotherapy when disease has not progressed after four cycles, per FDA labeling.FDA-approved indications; non-squamous histology where specified

Policy updates (2022–2026) expanded pemetrexed product labeling and specified non-squamous histology for certain combinations.

Pemetrexed for malignant pleural mesothelioma: Covered when used in combination with cisplatin for initial chemotherapy treatment of unresectable malignant pleural mesothelioma or when individuals are not candidates for curative surgery, per FDA-approved indication.FDA indication

Added to multiple pemetrexed product criteria in 2026 updates.

All other uses of the medications listed in this policy that are not specifically enumerated as medically necessary in the policy are considered investigational. The policy states that the listed drugs are subject to the product's FDA dosing and administration information, and that uses not described as medically necessary within this policy should be treated as investigational for coverage decisions.

When Pemfexy (a pemetrexed product) was first added to the policy it was noted that Pemfexy was NOT approved for use in combination with pembrolizumab and platinum chemotherapy for initial treatment of metastatic non-squamous NSCLC without EGFR or ALK genomic aberrations. Subsequent updates to the policy and product labeling have expanded pemetrexed product criteria to include pembrolizumab-plus-platinum combinations where the specific product's FDA approval supports that combination.

Coverage for Folotyn (pralatrexate) is limited to the FDA-approved indication for relapsed or refractory peripheral T‑cell lymphoma (PTCL). The pivotal single‑arm trial that supported approval reported an overall response rate but did not demonstrate a benefit in progression‑free survival or overall survival; as a result, coverage remains tied to the FDA‑approved indication and the limitations of the trial evidence are noted in the policy.

Initial Therapy Criteria

Initial therapy — rules for pemetrexed and methotrexate products

Initial therapy rules for pemetrexed and methotrexate products

Pemetrexed initial therapy (combination regimens): Pemetrexed products are covered for initial treatment when used in combination with platinum chemotherapy for locally advanced or metastatic non-squamous NSCLC and when used in combination with pembrolizumab and platinum chemotherapy for first-line metastatic non-squamous NSCLC without EGFR/ALK/ROS1 aberrations or while awaiting genomic testing, provided product labeling supports the combination.no EGFR/ALK/ROS1 aberrations for pembrolizumab combination; non-squamous histology

Applies across listed pemetrexed brands.

Xatmep initial criteria (pJIA/ALL): Xatmep oral solution is covered for initial therapy when the individual is ≤18 years and has ALL as part of a combination maintenance chemotherapy regimen prescribed by or in consultation with an oncologist/hematologist, or has pJIA after intolerance or inadequate response to one prior therapy and prescribed by or in consultation with a rheumatologist; additionally, prior trial of generic methotrexate tablets (or inability to swallow) is required and quantity limits apply.Age ≤18; prior 3-month trial of generics where applicable

Re-authorization and Maintenance Criteria

Re-authorization criteria

Re-authorization

Re-authorization may be approved for up to 12 months as long as the drug-specific coverage criteria are met and chart notes demonstrate continued positive clinical response to therapy.Up to 12 months

Applies broadly to drugs listed in the policy; see product-specific initial authorization durations.

Maintenance therapy — pemetrexed maintenance rules

Maintenance pemetrexed therapy

Maintenance pemetrexed after platinum chemotherapy: Pemetrexed is covered as maintenance treatment for NSCLC following first-line non-pemetrexed containing platinum-based chemotherapy when individuals did not progress after four cycles and when use is consistent with FDA labeling.No progression after four cycles of platinum-based chemotherapy

Step Therapy Requirements

Documentation Required

Documentation required

Documentation required: Include chart notes documenting diagnosis (RA, pJIA, or psoriasis), prior therapies tried, dates and outcomes of generic methotrexate tablet and generic injectable methotrexate trials, reason for intolerance or inadequate response, and any need for a special injection device (e.g., dexterity or visual impairment). If prescribing for pJIA, note rheumatologist involvement or consultation. Provide dosing details per FDA labeling and any dose adjustments.

Denial Risk

Benefit limitation/denial risk

Benefit limitation/denial risk: Requests will be denied or limited if documentation does not show a trial and inadequate response or intolerance to generic methotrexate tablets and to generic injectable methotrexate (unless a documented clinical reason prevents trial), if the medication is prescribed in combination with another methotrexate product, or if required provider consultation (e.g., rheumatologist for pJIA) is not documented.

Coding and Quantity Limits

HCPCS codes listedHCPCS

J3490	Unclassified drugs (Use to report Rasuvo)
J8612	Methotrexate (Xatmep), oral, 2.5 mg
J9292	Injection, pemetrexed dipotassium (Axtle), 10 mg
J9294	Injection, pemetrexed (Hospira) not therapeutically equivalent to J9305, 10 mg
J9296	Injection, pemetrexed (Accord) not therapeutically equivalent to J9305, 10 mg
J9297	Injection, pemetrexed (Sandoz), not therapeutically equivalent to J9305, 10 mg
J9304	Injection, pemetrexed (Pemfexy), 10 mg
J9305	Injection, pemetrexed (Alimta), 10 mg
J9307	Injection, pralatrexate (Folotyn and brand pralatrexate), 1 mg
J9314	Injection, pemetrexed (Teva) not therapeutically equivalent to J9305, 10 mg

1–10 of 12

1/2

HCPCS codes referenced in policy historyHCPCS

J9305	Alimta (pemetrexed) HCPCS code
J9307	Folotyn (pralatrexate) HCPCS code
J9314	HCPCS code added (reference in history)
J9294	HCPCS code added
J9296	HCPCS code added
J9297	HCPCS code added
J9322	HCPCS code added
J9323	HCPCS code added (later removed/discontinued)
J9255	HCPCS code (added then removed)
J8611	HCPCS code (added then removed)

1–10 of 13

1/2

inv-09: Xatmep quantity limit

Quantity limit2 bottles every 28 days

Age restrictionIndividuals aged 18 years or younger

Benefit managementManaged under the pharmacy benefit

Combination useNot to be used in combination with another methotrexate product

inv-28: Trexall (methotrexate) — moved to Drug Quantity Management 5.01.656

Policy actionTrexall (methotrexate) coverage criteria removed from this policy and quantity limit moved to Drug Quantity Management 5.01.656

Provider Actions and Documentation Requirements

Prior Authorization

Prior authorization required

Prior authorization is required per the policy's medical necessity criteria for the folate antimetabolite drugs listed in this policy (medical or pharmacy benefit). Submit requests for the applicable HCPCS/J‑codes listed in the policy for review.

Applies to pemetrexed products, pralatrexate (Folotyn/generic), Rasuvo, and Xatmep.
Relevant HCPCS codes include J9305, J9304, J9292, J9307, J8612, J9324, J9294, J9296, J9297, J9314, J9322, and J3490 (see coding table).

Prior Authorization

Authorization durations and initial approval lengths

Initial authorization lengths vary by product and review type: most oral and injectable drugs may be approved up to 6 months initially; non‑formulary exception reviews and all reviews for Rasuvo and Xatmep for PJIA may be approved up to 12 months.

Re‑authorization may be approved up to 12 months if drug‑specific criteria are met and chart notes show continued positive clinical response.
Initial authorization for Xatmep and Rasuvo for PJIA was updated from 6 months to 12 months; other oral drugs' initial authorizations changed from 3 to 6 months (see policy history).

Site of Care and Benefit Type

Billing Rule

Medical vs pharmacy benefit — site of care determines billing

Some products are managed under the medical benefit (IV/injectable oncology agents); Rasuvo and Xatmep may be billed through either the medical benefit or pharmacy benefit depending on site of care.

Manage IV pemetrexed products, pralatrexate, and Pemrydi RTU under the medical benefit.
Rasuvo and Xatmep are managed under both the medical and pharmacy benefits—site (infusion center, office, or retail pharmacy) determines billing route.

Pemetrexed Products and Related Agents

Billing Rule

Alimta and other pemetrexed products share identical criteria — bill using appropriate HCPCS

Alimta (pemetrexed) and other pemetrexed brands/unbranded pemetrexed products are listed with the same medical necessity criteria and should be billed using the applicable HCPCS code for the brand or unbranded product.

Multiple pemetrexed brands (Alimta, Pemfexy, Pemrydi RTU, Axtle, BluePoint, Sandoz, Teva, Accord, Hospira, Novaplus, etc.) have the same coverage criteria.
Use the corresponding HCPCS code (e.g., J9305 for Alimta, J9304 for Pemfexy, J9324 for Pemrydi RTU, J9292 for Axtle, etc.) as listed in the policy coding table.

Definitions

inv-19: Definitions — folate antimetabolites examples

DefinitionFolate antimetabolites: drugs that interfere with enzymes needed to create DNA by disrupting folate metabolism (examples: methotrexate, pemetrexed, pralatrexate)

MechanismImpair DNA synthesis, repair, and cellular replication by inhibiting folate-dependent enzymes

Clinical usesUsed in oncology (e.g., NSCLC, malignant pleural mesothelioma, PTCL, ALL) and immune-mediated diseases (RA, pJIA, psoriasis)

Formulations notedAvailable in multiple dosage forms and brand/generic products (oral solution, tablets, SC, IV)

inv-20: pralatrexate — antifolate analog definition

TermAntifolate analog (pralatrexate)

Background

Folate antimetabolites, including pralatrexate and other agents in this policy, act as antifolate drugs that interfere with folate‑dependent enzymes required for nucleic acid and protein synthesis. Pralatrexate specifically is an antifolate analog that inhibits dihydrofolate reductase by competing at the DHFR‑folate binding site, thereby disrupting DNA, RNA, and protein synthesis; Folotyn (pralatrexate) is FDA‑approved for treatment of relapsed or refractory peripheral T‑cell lymphoma.

Quantity Limits

inv-27: Xatmep (methotrexate) oral solution — 2 bottles

Standard quantity limit2 bottles every 28 days

Applies toXatmep (methotrexate) oral solution

Authorization notesQuantity limit included within pharmacy benefit management and prior authorization criteria

Revision History

05/01/26annual_review_approvedLatest

Annual review approved April 14, 2026; added generic pralatrexate with the same criteria as Folotyn and brand pralatrexate; expanded pemetrexed product criteria including malignant pleural mesothelioma (cisplatin combination) and clarified non-squamous NSCLC indications; updated initial authorization durations for Xatmep and Rasuvo and for other oral drugs; added/removed product-specific updates as noted.

2026-04-14approval_date

Policy annual review approved on April 14, 2026 (see May 1, 2026 effective date).

Policy Summary

PayerPremera Bluecross

PolicyFolate Antimetabolites

Policy CodePolicy PHARMACY / MEDICAL POLICY -5.01.617

Change TypeMultiple material additions and revisions (brands and indications)

Effective DateMay 1, 2026

Next Review Date

Key ActionObtain prior authorization and submit office visit notes documenting diagnosis, relevant history, physical evaluation, medication history, and trials of generic methotrexate when required.

SourceLink

On This Page

Pemetrexed with osimertinib and platinum-based chemotherapy: Covered for first-line treatment of adult individuals with locally advanced or metastatic non-squamous NSCLC whose tumors have documented EGFR exon 19 deletions or exon 21 L858R mutations, when used in combination with osimertinib and platinum-based chemotherapy and when product labeling supports the combination.Documented EGFR exon 19 or exon 21 L858R mutation

Supported by FLAURA2 trial evidence referenced in policy.

Pralatrexate for PTCL: Covered for relapsed or refractory peripheral T-cell lymphoma when used according to the FDA-approved indication; generic pralatrexate follows the same criteria as Folotyn.FDA indication

Coverage aligned with Folotyn trial data; evidence limitations noted in policy history.

Managed under pharmacy benefit; trial/failure requirements apply.

Initial therapy — pemetrexed-containing regimens

Initial therapy coverage rules for pemetrexed-containing regimens

First-line pemetrexed with pembrolizumab and platinum: Covered for initial treatment of metastatic non-squamous NSCLC without EGFR/ALK/ROS1 genomic tumor aberrations (or while awaiting results) when pemetrexed product labeling supports use in combination with pembrolizumab and platinum chemotherapy.no EGFR/ALK/ROS1 aberrations; non-squamous histology

Policy updates in 2023–2026 expanded which pemetrexed brands include this indication.

First-line pemetrexed with osimertinib and platinum: Covered when used in combination with osimertinib and platinum-based chemotherapy for first-line treatment of adult individuals with locally advanced or metastatic non-squamous NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, per updated product labeling.documented EGFR exon 19 or exon 21 L858R mutation

Supported by FLAURA2 clinical trial evidence cited in policy.

Based on randomized trial evidence showing benefit in progression-free and overall survival.

Documentation Required

Documentation and dosing

Documentation and dosing: Include the specific methotrexate dosing, route (oral, SC/IM), frequency, start date, and response measures. For pJIA approvals, quantity limits (e.g., Xatmep/Rasuvo limits noted elsewhere) and duration follow FDA dosing and policy length-of-approval rules. Chart notes must support continued clinical benefit for reauthorization.

Step Therapy

Required trial of generic methotrexate

Required trial of generic methotrexate: Prior to coverage of brand or specialty methotrexate products (including oral solutions such as Jylamvo and injectable brand products like Rasuvo), the member must have tried generic methotrexate tablets with documentation of either: inadequate response after 3 months of treatment, intolerance to generic methotrexate tablets, or documented inability to swallow solid oral dosage forms. Additionally, the member must have tried generic injectable methotrexate with documentation of either inadequate response after 3 months, intolerance to the generic injectable, or a documented medical need for a special injection device (e.g., lack of dexterity or visual acuity). These step requirements were added and clarified in recent policy updates (see 2023 note regarding Jylamvo).

Step Therapy

Step therapy notes

Step therapy notes: - Product-specific step rules apply: Jylamvo (oral solution) requires prior trial/failure of generic methotrexate tablets and must not be used in combination with other methotrexate products. - Rasuvo and other injectable brands are managed under medical and/or pharmacy benefit per policy; follow quantity limits and benefit routing stated elsewhere in the policy. - Maintain documentation of intolerance, inadequate response, or clinical reason for bypassing a step. - Policy history: 2023 update introduced Jylamvo step requirement; other coding and product updates are recorded in the policy history.

Jylamvo requires trial/failure of generic methotrexate tablets and not to be used with other methotrexate products.
Document intolerance or inadequate response to both generic oral and injectable methotrexate or provide clinical rationale to bypass steps.
Quantity limits and benefit routing vary by product; check applicable sections for Rasuvo/Xatmep and others.

Change noted in 02/01/26 interim review (approved January 13, 2026)

ImplicationPrescribing and quantity limit oversight for Trexall handled under separate Drug Quantity Management policy 5.01.656

Documentation Required

Submit office visit notes and diagnosis

Office visit notes demonstrating the clinical indication must be submitted with requests; records should include the diagnosis, relevant history, physical evaluation, and medication history.

Include documentation that medical necessity criteria are met (diagnosis, history, exam, medication history).
Charts supporting non‑formulary exception reviews should include treating specialist consultation where applicable (e.g., rheumatologist for pJIA).

Documentation Required

Required clinical documentation — medication history

Include medication history and prior treatment response/intolerance documentation when requesting coverage; show trials of prior therapies and dates/outcomes of those trials.

Document prior therapies tried, duration (e.g., 3 months for tablet/injectable methotrexate), and reason for discontinuation (intolerance or inadequate response).
For PJIA, include prescriber specialty (rheumatologist) or documentation of consultation as required by the criteria.

Documentation Required

Follow FDA dosing/administration and check member benefits

Dosing and administration must follow the product's FDA labeling; consult the member benefit booklet for any applicable coverage limits or benefit rules.

Policy states medications are subject to the product's FDA dosage and administration prescribing information.
Check the member benefit booklet or contact member services to confirm benefit limits and coverage details.

Denial Risk

Benefit limitations and denial risk

Coverage decisions are subject to the member's benefit limits; services may be denied if not covered under the member's contract—consult the member benefit booklet prior to ordering or billing.

Member contracts differ in benefits; confirm coverage and any limits or exclusions with the member benefit booklet or member services.
Denials may occur if the service or drug is not covered under the member’s specific plan.

MechanismInhibits DNA, RNA, and protein synthesis by competing for the dihydrofolate reductase (DHFR)-folate binding site

FDA indicationFolotyn (pralatrexate) IV approved for treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL)

Clinical trial evidenceSingle-arm trial (115 patients) showed overall response rate but did not demonstrate progression-free survival or overall survival benefit