Premera Bluecross folate antimetabolite Coverage

Coverage Criteria

Pemetrexed (Alimta and equivalents)

Pemetrexed (Alimta and multiple branded/unbranded formulations) is considered medically necessary when ANY one of the following is met:

pemetrexed_indications: In combination with pembrolizumab (Keytruda) and platinum chemotherapy for initial treatment of metastatic non-squamous non–small cell lung cancer (NSCLC) with no EGFR/ALK/ROS1 genomic tumor aberrations (or while awaiting results); in combination with pembrolizumab and platinum chemotherapy for treatment of metastatic non-squamous NSCLC after progression on FDA‑approved targeted therapy for EGFR/ALK/ROS1 mutations; in combination with platinum chemotherapy for initial treatment of locally advanced or metastatic non‑squamous NSCLC; single‑agent maintenance therapy for locally advanced/metastatic non‑squamous NSCLC not progressed after four cycles of platinum‑based first‑line chemotherapy; single‑agent treatment for recurrent, metastatic non‑squamous NSCLC after prior chemotherapy; initial chemotherapy with cisplatin for unresectable malignant pleural mesothelioma; in combination with osimertinib and platinum‑based chemotherapy for first‑line treatment of locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.

Pralatrexate (Folotyn)

Folotyn (pralatrexate) is considered medically necessary when:

pralatrexate_PTCL: Treatment of relapsed or refractory peripheral T‑cell lymphoma (PTCL).

Methotrexate (Rasuvo, Xatmep) criteria

Methotrexate formulations (Rasuvo SC, Xatmep oral) are considered medically necessary when ALL listed conditions are met:

methotrexate_RA_pJIA_psoriasis: For Rasuvo (methotrexate SC): treatment of rheumatoid arthritis OR polyarticular juvenile idiopathic arthritis (pJIA) intolerant of or with inadequate response to one prior therapy OR treatment of psoriasis in adults intolerant of or with inadequate response to two prior therapies; the individual has tried generic methotrexate tablets with documentation of either inadequate response after 3 months OR intolerance, AND has tried generic injectable methotrexate with documentation of either 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 challenges); not used in combination with another methotrexate product.

xatmep_pediatric_ALL_pJIA: For Xatmep (methotrexate oral solution): for individuals <18 years, treatment of acute lymphoblastic leukemia (ALL) as a component of a maintenance combination chemotherapy regimen prescribed by or in consultation with an oncologist/hematologist OR treatment of pJIA intolerant of or with inadequate response to one prior therapy; must meet prior therapy and prescriber requirements; quantity limited to 2 bottles every 28 days; not used in combination with another methotrexate product.

Medical necessity criteria for oral liquid methotrexate

Covered when ALL of the following are met

Primary coverage conditions: Prescribed by or in consultation with a rheumatologist; not used in combination with another methotrexate product; quantity limited to 2 bottles every 28 days; AND one of: documented inability to swallow solid oral dosage forms OR prior trial of generic methotrexate tablets with documentation of inadequate response after 3 months OR intolerance to generic methotrexate.

Initial coverage criteria

Covered when ALL of the following are met

Overall: Coverage is allowed when all below conditions are met

Primary eligibility: Either documented inability to swallow solid oral dosage forms OR prior trial of generic methotrexate tablets with inadequate response after 3 months OR intolerance to generic methotrexate

Documented inability to swallow solids supports use of liquid; otherwise require trial of tablets.

Quantity and combination: Not used in combination with another methotrexate product AND quantity limited to 2 bottles every 28 days2 bottles/28 days

Requests exceeding this quantity may be denied.

Prescriber requirement:

Initial therapy / coverage criteria

Covered when ANY of the following are met:

Primary coverage pathways: 1) Documented inability to swallow solid oral dosage forms AND not used in combination with another methotrexate product AND quantity limited to 2 bottles every 28 days.

Supports members who cannot take tablets; requires no combination therapy and enforces quantity limit.

Rheumatology-managed pathway with prior trial: 2) Prescribed by or in consultation with a rheumatologist AND the individual has tried generic methotrexate tablets with documentation of either inadequate response after 3 months OR intolerance to generic methotrexate.3 months trial

Requires rheumatology involvement and prior trial of oral tablet methotrexate unless inability to swallow is documented.

Initial coverage criteria

Covered when ONE of the following sets of conditions is met:

Coverage pathways: Pathway A: Documented inability to swallow solid oral dosage forms AND not used in combination with another methotrexate product AND quantity limited to 2 bottles every 28 days.

Supports patients unable to take tablets.

Coverage pathways: Pathway B: Prescribed by or in consultation with a rheumatologist AND the individual has tried generic methotrexate tablets with documentation of either inadequate response after 3 months OR intolerance to generic methotrexate; quantity limited to 2 bottles every 28 days.3 months trial

Step therapy requirement prior to liquid formulation except for swallowing inability pathway.

Medical necessity criteria

Covered when ANY of the following are met

Main coverage pathways: 1) Documented inability to swallow solid oral dosage forms AND not used in combination with another methotrexate product AND quantity limited to 2 bottles every 28 days.quantity 2 bottles/28 days

The document repeatedly indicates this standard pathway.

Rheumatologist-prescribed pathway: 2) Prescribed by or in consultation with a rheumatologist AND the individual has tried generic methotrexate tablets with documentation of either inadequate response after 3 months of treatment OR intolerance to generic methotrexate.trial 3 months

Applies in addition to quantity limit and combination restrictions.

Initial therapy / coverage criteria

Covered when ANY of the following pathways are met:

Coverage pathways

Pathway A: Inability to swallow: Documented inability to swallow solid oral dosage forms AND not used in combination with another methotrexate product AND quantity limited to 2 bottles every 28 days
Must not be combined with other methotrexate products
Pathway B: Rheumatology + prior tablet trial: Prescribed by or in consultation with a rheumatologist AND patient has tried generic methotrexate tablets with documentation of either inadequate response after 3 months OR intolerance to generic methotrexate3 months for inadequate response
Also subject to the 2-bottle/28-day quantity limit

Initial coverage criteria

Covered when ANY of the following are met:

Coverage pathways: 1) Documented inability to swallow solid oral dosage forms AND not used in combination with another methotrexate product AND quantity limited to 2 bottles every 28 days; OR 2) Prescribed by or in consultation with a rheumatologist AND the individual has tried generic methotrexate tablets with documentation of either inadequate response after 3 months OR intolerance to generic methotrexate.

Prescriber specialty and prior trial requirements apply as alternate pathways; quantity limit applies to all pathways.

Initial coverage criteria

Covered when ANY of the following are met

Eligibility pathways: Pathway A: Documented inability to swallow solid oral dosage forms AND not used in combination with another methotrexate product AND quantity limited to 2 bottles every 28 days.2 bottles/28 days

Supports members who cannot take tablets

Step therapy pathway: Pathway B: Prescribed by or in consultation with a rheumatologist AND the individual has tried generic methotrexate tablets with documentation of either inadequate response after 3 months OR intolerance to generic methotrexate; quantity limited to 2 bottles every 28 days.3-month trial

Requires prior trial of tablet formulation

Initial coverage criteria

Covered when ANY one of the following is met

Coverage branches: Branch A: Documented inability to swallow solid oral dosage forms AND not used in combination with another methotrexate product AND quantity limited to 2 bottles every 28 days.quantity: 2 bottles/28 days

Supports immediate access without prior failure of tablets if swallowing impairment documented

Branch B: Prescribed by or in consultation with a rheumatologist AND patient has tried generic methotrexate tablets with documentation of either inadequate response after 3 months of treatment OR intolerance to generic methotrexate; quantity limited to 2 bottles every 28 days.trial: 3 months

Rheumatologist involvement required for this branch

Initial coverage criteria

Covered when ALL of the following are met:

Main coverage criteria: 1) Documented inability to swallow solid oral dosage forms OR prior trial of generic methotrexate tablets with inadequate response after 3 months or intolerance; 2) Not used in combination with another methotrexate product; 3) Prescribed by or in consultation with a rheumatologist; 4) Quantity limited to 2 bottles every 28 days.

The document repeatedly emphasizes the 2 bottles/28 days limit and prior trial requirements.

Initial coverage criteria

Covered when ALL of the following are met:

Main coverage conditions: Member has documented inability to swallow solid oral dosage forms; product is not used in combination with another methotrexate product; quantity is limited to 2 bottles every 28 days; prescribed by or in consultation with a rheumatologist; patient has tried generic methotrexate tablets with documentation of either inadequate response after 3 months or intolerance.

Uses not listed in the specific medical necessity indications for pemetrexed, pralatrexate, or methotrexate formulations are not supported by this coverage section. Requests for indications outside those enumerated in the policy may be denied as not medically necessary.

The policy explicitly prohibits use of the requested product in combination with another methotrexate product. Combination therapy with another methotrexate formulation is not permitted for coverage.

Coverage is not provided when the liquid or alternative methotrexate formulation is used together with another methotrexate product; combination use is not allowed under this policy.

The policy states that the methotrexate formulation must not be used in combination with another methotrexate product. Combination therapy with other methotrexate formulations is explicitly prohibited.

Use of the liquid methotrexate product in combination with another methotrexate product is excluded from coverage. When the drug is prescribed for inability to swallow solids or other approved indications, it still must not be combined with other methotrexate products.

The policy contains an explicit prohibition: the methotrexate product must not be used in combination with any other methotrexate product for purposes of coverage under this section.

Combination use with another methotrexate product is excluded. Requests that indicate concomitant use of multiple methotrexate formulations will not meet the coverage criteria.

The policy reiterates that use in combination with another methotrexate product is not allowed; approvals require that the liquid formulation not be administered together with other methotrexate products.

As a stated requirement for coverage, the methotrexate product must not be used in combination with another methotrexate product. This exclusion is applied across the methotrexate coverage pathways.

Coverage for the liquid methotrexate formulation is conditioned on it not being used in combination with another methotrexate product; combination use is not allowed for coverage.

When considering coverage of the liquid formulation, the policy requires that it not be co‑administered with another methotrexate product. Use in combination with other methotrexate formulations is not permitted.

The policy reiterates that combination use with another methotrexate product is not permitted; requests describing combined methotrexate therapy will not satisfy coverage criteria.

Use of the liquid methotrexate product together with another methotrexate product is explicitly not allowed under this coverage policy and will not be approved.

Any use outside the enumerated medically necessary indications (for pemetrexed, pralatrexate, or methotrexate formulations) is considered not medically necessary and may be denied.

Requests that exceed the stated quantity limit are outside the coverage criteria. The policy limits bottled/oral liquid methotrexate to a maximum of 2 bottles every 28 days; requests above this quantity may be denied.

Use that exceeds the stated quantity limit (more than 2 bottles every 28 days) is not supported by the criteria and would not meet medical necessity.

Requests that exceed 2 bottles every 28 days are inconsistent with the policy's quantity limit and may be denied as not medically necessary.

Requests for the liquid formulation lacking documentation that the patient cannot swallow tablets, or lacking documentation of a prior trial and inadequate response/intolerance to generic methotrexate tablets (when required), may be considered not medically necessary.

Requests that either exceed the quantity limit of 2 bottles every 28 days or that lack required documentation (no documented trial of generic methotrexate tablets when applicable, or no documentation of inability to swallow when that is the basis for liquid use) may be denied.

Provider Actions and Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for the listed indications and formulations of methotrexate products (including Rasuvo, Xatmep, and other branded liquid methotrexate) under the payer. Requests must meet the clinical criteria and documentation requirements below; failure to provide required information or requests outside the listed indications may result in denial.

Prior authorization (PA) required to confirm patient meets a listed medical necessity indication.
PA applies to bottled/oral solution methotrexate products and certain branded/injectable formulations (e.g., Rasuvo, Xatmep).

Documentation Required

Prior Authorization Requirements and Required Documentation

Prior authorization requests must include documentation of prior therapies and prescriber specialty involvement where indicated. For liquid or special-formulation requests, the submission must document either inability to swallow solid oral dosage forms or a prior trial and inadequate response or intolerance to generic methotrexate tablets.

Step Therapy Requirements

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets and generic injectable methotrexate documented as tried with either inadequate response after 3 months or intolerance
Exceptions include documented inability to swallow solid oral dosage forms or documented need for a special injection device (e.g., lack of dexterity); product must not be used in combination with another methotrexate product

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets required with documentation of either inadequate response after 3 months or intolerance
Exception: documented inability to swallow solid oral dosage forms supports bypassing tablet trial; product must not be used in combination with another methotrexate product; quantity limit applies

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets prior to coverage of liquid formulation; documentation of inadequate response after 3 months or intolerance required
Exception: documented inability to swallow solid oral dosage forms permits liquid formulation without prior tablet trial; not to be used in combination with another methotrexate product; quantity limited to 2 bottles every 28 days

Step	Requirement	Exceptions/Notes
1
Prior trial of generic methotrexate tablets required with documentation of inadequate response after 3 months or intolerance
Exception: documented inability to swallow solid oral dosage forms allows bypassing prior tablet trial; product must not be used in combination with another methotrexate product; quantity limit applies

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets required with documentation of either inadequate response after 3 months or intolerance before coverage
If inability to swallow solid oral dosage forms is documented, the tablet trial requirement may be waived; avoid combination use with other methotrexate products; quantity limited to 2 bottles/28 days

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets required prior to coverage unless documented inability to swallow solid oral dosage forms
Documentation of inability to swallow must be provided when used as the basis for bypassing tablet trial; product must not be combined with another methotrexate product; quantity limit applies

Step	Requirement	Exceptions/Notes
1
Documentation of trial and inadequate response to generic methotrexate tablets, or documented intolerance, is required before coverage of liquid formulation
Prescriber should document rheumatology involvement when applicable; product must not be used in combination with another methotrexate product; quantity limited to 2 bottles every 28 days

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets required prior to coverage unless there is documented inability to swallow tablets or documented intolerance
When inability to swallow is documented, provide clinical documentation; avoid combination use; quantity limited to 2 bottles per 28 days; rheumatologist involvement required for non-swallowing pathway where specified

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets required prior to coverage unless intolerance or inability to swallow tablets is documented; documentation must show inadequate response after 3 months or intolerance
Product must not be used in combination with another methotrexate product; rheumatologist prescribing or consultation is required when applicable; quantity limited to 2 bottles every 28 days

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets is required prior to approval; documentation must show either inadequate response after 3 months or intolerance
If inability to swallow tablets is documented, provide clinical documentation; do not combine with other methotrexate products; quantity limited to 2 bottles per 28 days

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets required prior to coverage unless documented inability to swallow solid oral dosage forms
Documentation of inability to swallow must be provided for bypass; product must not be used in combination with another methotrexate product; quantity limited to 2 bottles every 28 days; rheumatologist consultation required when applicable

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets required prior to coverage of liquid formulation unless documented inability to swallow tablets; prescriber should be or consult with a rheumatologist
If inability to swallow is the basis, provide documentation and ensure liquid is not used with another methotrexate product; quantity limit: 2 bottles every 28 days

Step	Requirement	Exceptions/Notes
1
Trial of generic methotrexate tablets required prior to approval unless documented intolerance or inability to swallow is provided; documentation must show inadequate response after 3 months or intolerance
Prescriber must document rheumatology involvement when applicable; liquid must not be combined with other methotrexate products; quantity limited to 2 bottles per 28 days

Quantity Limits

Xatmep — quantity limit

DrugXatmep (methotrexate oral solution) and referenced methotrexate oral solution products

Quantity limitMaximum of 2 bottles every 28 days

Combination useNot used in combination with another methotrexate product

Oral liquid methotrexate — limit

ProductOral liquid methotrexate

Quantity limit2 bottles every 28 days

RequirementNot used in combination with another methotrexate product

Initial Therapy Criteria

Initial therapy — pemetrexed initial therapy coverage statements

Initial therapy coverage statements for pemetrexed products

initial_pemetrexed: Use of pemetrexed in initial therapy regimens including: in combination with pembrolizumab and platinum chemotherapy for initial treatment of metastatic non‑squamous NSCLC without EGFR/ALK/ROS1 aberrations (or while awaiting results); in combination with platinum chemotherapy for initial treatment of locally advanced or metastatic non‑squamous NSCLC; initial combination with cisplatin for malignant pleural mesothelioma; in combination with osimertinib and platinum‑based chemotherapy for first‑line treatment of EGFR‑mutated NSCLC.

Initial coverage criteria

Initial eligibility: Documented inability to swallow solid oral dosage forms OR trial of generic methotrexate tablets with inadequate response after 3 months OR intolerance to generic methotrexate; prescribed by or in consultation with a rheumatologist; not used in combination with another methotrexate product; quantity limited to 2 bottles every 28 days.

Definitions

Definition — folate antimetabolites

TermFolate antimetabolites

DefinitionDrugs that interfere with enzymes required for DNA synthesis (e.g., pemetrexed, pralatrexate, methotrexate)

Clinical useUsed in oncology and inflammatory conditions such as rheumatoid arthritis, pJIA, and psoriasis

Definition — inability to swallow (documentation)

TermDocumented inability to swallow solid oral dosage forms

DefinitionClinical documentation that the patient cannot safely or effectively swallow tablets or capsules, supporting use of liquid formulation

Evidence

Background

Folate antimetabolites inhibit enzymes required for DNA synthesis and are used to slow growth of malignant cells and to treat inflammatory conditions. Examples include pemetrexed, pralatrexate, and methotrexate; this policy defines when these agents are considered medically necessary.

OpenPayer

Folate antimetabolites (e.g., pemetrexed, pralatrexate, methotrexate) coverage criteria

Coverage Criteria

Provider Actions and Requirements

Step Therapy Requirements

Quantity Limits

Initial Therapy Criteria

Definitions

Background