CurrentmhnPolicy CP.PHAR.363

Enasidenib (Idhifa) coverage

Defines medical necessity and authorization criteria for enasidenib (Idhifa) for treatment of adult patients with relapsed or refractory AML with an IDH2 mutation, and related coverage rules for other indications and lines of business.

Policy Summary

Payermhn

PolicyEnasidenib (Idhifa) coverage

Policy CodePolicy CP.PHAR.363

Change TypeMaterial clinical updates

Effective Date09.05.17

Next Review Date

Key ActionSubmit prior authorization with documentation of AML diagnosis, IDH2 mutation, prescriber specialty, age ≥18, dosing within limits, and evidence of relapsed/refractory disease or ineligibility for intensive induction.

SourceLink

POLICY UPDATE CHANGES

Added Idhifa combination with azacitidine per NCCN.

Revised initial approval durations for all lines of business to 12 months.

Clarified use as a single agent for all AML indications per NCCN.

100 mgmaximum daily dose for AML

12 monthsstandard approval duration

≥18minimum age

IDH2required biomarker

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Coverage Criteria

inv-01: Initial Therapy

Covered when ALL of the following are met:

Initial AML criteria

Diagnosis of acute myeloid leukemia (AML).
Prescribed by or in consultation with an oncologist or hematologist.
Member is age ≥ 18 years.
Prescribed regimen
- Prescribed as single-agent therapy.
- Prescribed in combination with azacitidine.
Disease status
- Disease is relapsed or refractory.
- Member is not a suitable candidate for or declines intensive induction chemotherapy.
Presence of an IDH2 mutation.
Member must use generic enasidenib (Idhifa) if available unless contraindicated or clinically significant adverse effects are experienced.
Dosing limits
- Dose does not exceed both: (i) 100 mg per day and (ii) 1 tablet per day.
- Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).

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inv-02: Continuation Therapy

Covered for continuation when ALL of the following are met:

Continuation AML criteria

Member is currently receiving Idhifa via the Centene benefit, or documentation supports member has received Idhifa for AML for at least 30 days.
Member is responding positively to therapy.
Member must use generic enasidenib if available unless contraindicated or clinically significant adverse effects are experienced.
Dose increase requests
- New dose does not exceed both: (i) 100 mg per day and (ii) 1 tablet per day.

Requests for enasidenib (Idhifa) will be considered medically necessary and authorized only when the member meets the specific coverage criteria in this policy for the indicated use of relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation. For indications that are not FDA‑approved and not addressed by this policy, coverage will not be authorized unless the provider supplies sufficient documentation demonstrating efficacy and safety in accordance with the referenced off‑label use policies and applicable evidence‑of‑coverage documents.

Off‑label uses of Idhifa that are not explicitly covered by this policy must follow the plan’s off‑label use review process. Per the plan’s referenced policies, uses for non‑FDA approved indications are only eligible for authorization when the provider submits adequate objective documentation (for example, clinical trial data, peer‑reviewed literature, or other evidence) that demonstrates both efficacy and safety for the requested indication; otherwise such requests will be considered not authorized under the plan’s off‑label/no coverage rules.

Initial Therapy

inv-13: Initial Therapy

Initial therapy coverage conditions:

Initial therapy

Diagnosis of AML.
Prescriber is an oncologist or hematologist, or therapy is in consultation with one.
Member is age ≥ 18 years.
Regimen
- Single-agent enasidenib (Idhifa).

Continuation / Renewal Criteria

inv-14: Continuation Therapy

Renewal/continuation requirements for Idhifa (AML):

Continuation

Member has been receiving Idhifa via the Centene benefit or documentation shows member has received Idhifa for at least 30 days.
Member demonstrates a positive response to therapy.
Member must use generic enasidenib if available unless contraindicated or clinically significant adverse effects are experienced.
Dose change requests
- Requested new dose does not exceed both: (i) 100 mg per day and (ii) 1 tablet per day.

Provider Actions & Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for Idhifa (enasidenib). Requests must include documentation supporting the diagnosis of acute myeloid leukemia (AML), presence of an IDH2 mutation, prescriber specialty (oncologist or hematologist), member age ≥ 18 years, and that dosing is within policy limits or justified by guidelines/literature for off‑label dosing. Prescribed regimens must be FDA‑approved or recommended by NCCN.

Required documentation: office chart notes, pathology/lab reports confirming AML and IDH2 mutation, treatment history, and prescriber specialty.
Dose limits: ≤100 mg per day and ≤1 tablet per day unless supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence).
Approval duration: Initial and continuation approvals generally 12 months (see policy for benefit-specific details).

Documentation Required

Required Documentation

Providers must submit supporting clinical documentation (e.g., office notes, lab results, pathology reports, treatment history) demonstrating the member meets all approval criteria. Lack of adequate documentation may result in denial or delay.

Coding & Dosing

inv-05: Maximum daily dose

Maximum daily dose (AML)100 mg per day

Usual dosing regimen100 mg PO once daily (AML)

Dose units availableTablets: 50 mg, 100 mg

Quantity Limits

inv-16: Idhifa (enasidenib)

Quantity limit per dispensing1 tablet per day

Typical single-dose formTablets available in 50 mg and 100 mg strengths

Per‑day maximumDo not exceed 100 mg per day unless supported by guidelines and documented rationale

Step Therapy & Substitution

Step	Requirement
1	Member must use generic enasidenib (Idhifa) if available unless contraindicated or clinically significant adverse effects are experienced.

Definitions

inv-11: IDH2

DefinitionIsocitrate dehydrogenase-2 (IDH2): a gene encoding the IDH2 enzyme; presence of an IDH2 mutation is required for the indicated use of enasidenib in AML.

Role in therapyIDH2 mutation is the required biomarker to identify adult patients with relapsed or refractory AML who may be eligible for enasidenib therapy.

Drug classEnasidenib is an IDH2 inhibitor targeting mutant IDH2 enzymes.

inv-12: Differentiation syndrome

DefinitionDifferentiation syndrome: a potentially serious adverse event associated with enasidenib listed as a boxed warning.

Immediate management stepsIf differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

Background

Enasidenib (Idhifa) is an oral IDH2 inhibitor indicated for treatment of adult patients with relapsed or refractory AML harboring an IDH2 mutation. The drug’s approved use is limited to this biomarker‑defined population; administration for other diagnoses or without documentation of the mutation is not authorized under this policy unless supported by the off‑label evidence criteria referenced above.

Site of Care

Note

Office is the specified site of care

Site of care is the office setting; administration/dispensing is expected to occur in the office per the site‑of‑care specification in the policy.

Setting: office

Revision History

2025-07-09revisedLatest

Revised initial approval durations for all lines of business to 12 months.

2024-07-17added

Added Idhifa combination with azacitidine per NCCN (consolidated NCCN Compendium scenarios and removed age ≥60 requirement for some uses).

2023-08-09clarified