Folate Antimetabolites

Coverage Summary

This coverage policy for folate antimetabolites (effective May 1, 2026; last reviewed April 14, 2026) defines medical necessity criteria and management for pemetrexed, pralatrexate, and methotrexate products. It specifies which products/indications are covered with criteria (for example multiple branded and generic pemetrexed products for defined NSCLC and mesothelioma uses, Folotyn/brand/generic pralatrexate for relapsed/refractory PTCL, and methotrexate formulations including Rasuvo and Xatmep for certain rheumatologic, dermatologic, and pediatric oncology indications), notes whether drugs are managed under the medical or pharmacy benefit, and describes authorization lengths and reauthorization conditions per the policy (initial approvals and reauthorizations as specified).

Product-specific Medical Necessity Criteria

Pemetrexed products

Pemetrexed products (e.g., Alimta, Axtle, Pemfexy, Pemrydi RTU, and branded/unbranded pemetrexed formulations) may be considered medically necessary when ANY of the following indications are met:

In combination with pembrolizumab (Keytruda) and platinum chemotherapy (e.g., cisplatin, carboplatin, oxaliplatin) for the initial treatment of metastatic non-squamous non-small cell lung cancer (NSCLC) in individuals with no EGFR or ALK/ROS1 genomic tumor aberrations or while awaiting results of such genomic testing

In combination with pembrolizumab (Keytruda) and platinum chemotherapy for treatment of metastatic non-squamous NSCLC with EGFR or ALK/ROS1 genomic mutations who have disease progression on FDA‑approved therapy for these mutations (e.g., EGFR or ALK/ROS1 inhibitors)

In combination with platinum chemotherapy (e.g., cisplatin, carboplatin, oxaliplatin) for the initial chemotherapy treatment of locally advanced or metastatic, non-squamous NSCLC

As a single agent for maintenance treatment of locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy

As a single agent for treatment of recurrent, metastatic non-squamous NSCLC after prior chemotherapy

Initial chemotherapy treatment in combination with cisplatin for malignant pleural mesothelioma that is unresectable or when the individual is not a candidate for curative surgery

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

Pralatrexate (Folotyn)

Pralatrexate (Folotyn) and equivalent branded/generic pralatrexate formulations may be considered medically necessary when ALL of the following are met:

ALL of the following

The request is for pralatrexate (Folotyn) or an equivalent brand/generic pralatrexate formulation
The individual has relapsed or refractory peripheral T‑cell lymphoma (PTCL)

Rasuvo (methotrexate) subcutaneous

Rasuvo (subcutaneous methotrexate) may be considered medically necessary when ALL of the following criteria are met:

ALL of the following

The individual is diagnosed with one of the following: Rheumatoid arthritis (RA); OR polyarticular juvenile idiopathic arthritis (pJIA) who are 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
The individual has tried generic methotrexate tablets with documented either inadequate response after 3 months of treatment OR intolerance to generic methotrexate tablets
The individual has tried generic injectable methotrexate with documented either inadequate response after 3 months of treatment OR intolerance to generic injectable methotrexate OR a documented reason for requiring a special injection device (e.g., lack of dexterity or visual acuity challenges)
Rasuvo is not used in combination with another methotrexate product

Xatmep (oral solution)

Xatmep (oral methotrexate solution) may be considered medically necessary when ALL of the following are met:

ALL of the following

The individual is an infant or child for whom an oral liquid formulation is clinically required (age‑appropriate dosing/administration)
The individual has a diagnosis for which methotrexate is indicated (e.g., juvenile idiopathic arthritis, or other approved indication per product labeling) with documentation of clinical need specific to the diagnosis
The individual has tried (or has documented intolerance to) appropriate prior therapies when applicable per indication (for example, prior therapies for pJIA or psoriasis as outlined in other criteria)
Xatmep will not be used in combination with another methotrexate product

Other methotrexate branded products

Other branded methotrexate oral or injectable products (e.g., Jylamvo, Jylamvo branded formulations, and other brand-name methotrexate products) may be considered medically necessary when ALL of the following are met:

ALL of the following

The individual has tried generic methotrexate tablets with documented either inadequate response after 3 months of treatment OR intolerance to generic methotrexate tablets
The individual has tried generic injectable methotrexate with documented either inadequate response after 3 months of treatment OR intolerance to generic injectable methotrexate OR has a documented need for a special device or formulation
The branded methotrexate product is not used in combination with another methotrexate product
When applicable, quantity limits apply per product labeling and plan quantity‑limit policies (requests exceeding limits require clinical justification)

Investigational / Not covered

Investigational / Not covered uses — All other indications, formulations, or uses of folate antimetabolites not expressly listed in the groups above are considered investigational and are not covered.

Any use of pemetrexed, pralatrexate, methotrexate (including branded formulations) or other folate antimetabolites for indications not listed in the specific product groups above

Compounded, experimental, or unapproved formulations and routes of administration not described in product labeling

Use of multiple methotrexate products in combination (unless specifically allowed in the criteria above) as this is not medically necessary

Coding (HCPCS)

HCPCS codes (medical billing) listed in policyHCPCS

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.

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1/2

The 2026 updates removed several discontinued product codes and products (for example HCPCS code J9323 and code J8611 were removed as discontinued) and removed coverage for discontinued formulations (e.g., brand pemetrexed ditromethamine). Providers should submit claims and bill under the appropriate benefit (medical vs pharmacy) using the HCPCS codes and billing guidance listed in the policy (see provider billing rules) so that products are billed to the correct benefit.

Provider Actions & Prior Authorization

Documentation Required

Medical record documentation required

Submission must include office visit notes with diagnosis, relevant history, physical evaluation, and medication history to demonstrate medical necessity.

Prior Authorization

Prior authorization and length of approval

Non-formulary exception reviews for Rasuvo and Xatmep for PJIA may be approved up to 12 months; all other oral and injectable drugs listed may have initial approvals up to 6 months (some reviews up to 12 months for reauthorization if criteria met and clinical response demonstrated).

Background, Evidence & Definitions

This medical policy was developed by clinical experts reviewing FDA approvals, prescribing information, guidelines, and literature to define when folate antimetabolites are medically necessary. It lists multiple brand and generic products (pemetrexed formulations including Alimta, Pemfexy, Pemrydi RTU, Axtle and several unbranded/brand pemetrexed products; pralatrexate products including Folotyn, brand and generic pralatrexate; and methotrexate formulations including Rasuvo and Xatmep) and aligns coverage with FDA-approved indications and product prescribing information.

Study / Label	Key finding
FLAURA2 (osimertinib + chemo + pemetrexed)
Median overall survival with osimertinib plus platinum-pemetrexed 47.5 months vs 38.6 months with osimertinib monotherapy
Pemfexy maintenance NSCLC trial
Median OS 13.4 vs 10.6 months; median PFS 4.0 vs 2.0 months (p=0.012 for OS, p<0.00001 for PFS)
Alimta + cisplatin MPM trial
Median overall survival 12.1 months with Alimta plus cisplatin vs 9.3 months with cisplatin alone (log-rank p=0.020)

Glossary: Non-squamous NSCLC — subtype of non-small cell lung cancer excluding squamous histology as specified in the policy; Platinum chemotherapy — includes agents such as cisplatin, carboplatin, and oxaliplatin as referenced in the policy.

Revision History

2026-04-14addedLatest

Annual Review approved April 14, 2026 (reflected in 05/01/26 update): Added generic pralatrexate to the policy with the same criteria as Folotyn and brand pralatrexate. (MATERIAL CHANGE)

2026-04-14revisedLatest

Updated multiple pemetrexed product criteria clarifying 'non-squamous' for NSCLC indications and adding/clarifying use in combination with osimertinib and platinum chemotherapy for first-line treatment of EGFR exon 19/exon 21 L858R mutated NSCLC. (MATERIAL CHANGE)

2026-04-14