ModifiedmhnPolicy CP.PHAR.133

Clinical Policy: Idelalisib (Zydelig)

Coverage and medical necessity criteria for idelalisib (Zydelig) for treatment of CLL and SLL and guidance for other/off-label uses for members under Centene-affiliated health plans.

Policy Summary

Payermhn

PolicyClinical Policy: Idelalisib (Zydelig)

Policy CodePolicy CP.PHAR.133

Change TypeMaterial updates to prior therapy and approval durations

Effective DateDec 1, 2018

Next Review Date

Key ActionSubmit prior authorization with documentation showing prior therapy with a BTK inhibitor and venetoclax-based regimens when requesting coverage for CLL/SLL.

SourceLink

POLICY UPDATE CHANGES

For CLL/SLL, revised prior therapy requirement from at least one prior therapy to prior therapy with BTK inhibitor and Venclxta-based regimens per NCCN.

For CLL, added step therapy bypass for IL HIM per IL HB 5395.

Extended initial approval duration for Medicaid and HIM from 6 months to 12 months for this maintenance medication for a chronic condition.

Removed follicular lymphoma (FL) and SLL from FDA approved indications; retained criteria for SLL designated as off-label per NCCN.

12 monthsinitial approval duration (Medicaid/HIM)

300 mg/daymaximum dose

≥18minimum age

Relapsed/refractory

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Coverage and Medical Necessity Criteria

Initial Therapy — CLL

Covered when ALL of the following are met for Chronic Lymphocytic Leukemia (CLL):

CLL initial approval criteria: 1. Diagnosis of chronic lymphocytic leukemia (CLL). 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. Disease is relapsed or refractory as evidenced by prior therapy with both of the following: a) a BTK inhibitor (e.g., acalabrutinib, zanubrutinib, ibrutinib, pirtobrutinib) and b) venetoclax (Venclexta). 5. Prescribed as a single agent (off-label) or in combination with rituximab. 6. Member must use idelalisib (Zydelig) if available unless contraindicated or clinically significant adverse effects are experienced. 7. Request meets one of the following: a) Dose does not exceed i) 300 mg per day and ii) 2 tablets per day; or b) Dose is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence). Prescribed regimen must be FDA‑approved or recommended by NCCN. 8. Prior authorization may be required; prescriber must document prior therapies and provide supporting clinical documentation as requested.300 mg per day

Initial approval duration and prior authorization requirements may vary by line of business; see policy history for recent updates (prior therapy requirement revised to BTK inhibitor + venetoclax).

Initial Therapy — SLL (off-label)

Covered when ALL of the following are met for Small Lymphocytic Leukemia (SLL) (off-label):

SLL initial approval criteria (off-label): 1. Diagnosis of small lymphocytic lymphoma (SLL). 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age ≥ 18 years. 4. Disease is relapsed or refractory as evidenced by prior therapy with both of the following: a) a BTK inhibitor (e.g., acalabrutinib, zanubrutinib, ibrutinib, pirtobrutinib) and b) venetoclax (Venclexta). 5. Prescribed as a single agent or in combination with rituximab. 6. Member must use idelalisib (Zydelig) if available unless contraindicated or clinically significant adverse effects are experienced. 7. Request meets one of the following: a) Dose does not exceed i) 300 mg per day and ii) 2 tablets per day; or b) Dose is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence). Prescribed regimen must be FDA‑approved or recommended by NCCN. 8. Prior authorization may be required; note that SLL is retained as an off‑label indication per NCCN guidance.300 mg per day

Off‑label indication; prescriber must provide supporting evidence when applicable.

Continuation Therapy

Covered when ALL of the following are met for continuation/renewal:

Continuation therapy: 1. Member is currently receiving Zydelig via the Centene benefit, or documentation supports that the member has received Zydelig for a covered indication for at least 30 days. 2. Member is responding positively to therapy. 3. Member must use idelalisib (Zydelig) if available unless contraindicated or clinically significant adverse effects are experienced. 4. If request is for a dose increase, the new dose meets one of the following: a) New dose does not exceed i) 300 mg per day and ii) 2 tablets per day; or b) New dose is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence). Prescribed regimen must be FDA‑approved or recommended by NCCN.300 mg per day

Approval duration extended for Medicaid/HIM to 12 months per recent policy update; prior authorization and documentation of ongoing response required.

Other Indications

Other/off-label uses and label changes:

Other diagnoses/indications: 1. If this drug has undergone a label change within the last 6 months that is not yet reflected in this policy (e.g., new approval, age expansion, new dosing), refer to the applicable formulary/no‑coverage or non‑formulary policy for the relevant line of business as specified in the policy. 2. If the requested use (diagnosis, age, dosing) is not specifically listed under the section for non‑authorized indications and criterion 1 does not apply, refer to the off‑label use policy for the relevant line of business (CP.CPA.09 commercial, HIM.PA.154 marketplace, CP.PMN.53 Medicaid).

Requests for non‑FDA approved indications not addressed in this policy require documentation of efficacy/safety per off‑label use policies and may be denied without sufficient supporting evidence. Policy history: prior therapy requirement for CLL/SLL revised to BTK inhibitor + venetoclax; step therapy bypass added for IL HIM; approval durations updated.

Zydelig (idelalisib) is not indicated or recommended for first-line treatment of any patient, including those with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other indolent non-Hodgkin lymphomas; requests for such use are not authorized under this policy. In addition, therapy in the disallowed combinations—specifically bendamustine plus rituximab or idelalisib plus rituximab for FL, SLL, and other indolent NHL—is not recommended and is excluded from coverage. Providers requesting coverage must document that the patient meets the relevant coverage criteria or provide sufficient evidence of efficacy and safety if pursuing a non‑FDA approved use per the off‑label use policies referenced by the plan.

The FDA-approved indications for follicular lymphoma (FL) and small lymphocytic lymphoma (SLL) were removed from the prescribing information; however, criteria for SLL are retained in this policy as an off-label indication because continued use for SLL is supported by the NCCN compendium. Providers should follow the off‑label documentation requirements referenced in the plan’s off‑label use policies when requesting coverage for SLL.

This policy explicitly disallows use of idelalisib as first-line therapy for CLL, SLL, FL, or other indolent non‑Hodgkin lymphomas. Coverage is also not authorized for idelalisib when used in the specified disallowed combinations (bendamustine plus rituximab, or idelalisib plus rituximab for FL/SLL/other indolent NHL). Requests for uses not addressed by this policy must include sufficient documentation of efficacy and safety and will be evaluated against the plan’s off‑label use policies.

Dosing and Regimens

Regimen	Dose	Tablet strengths	Coverage status
Idelalisib for Chronic Lymphocytic Leukemia (CLL)
150 mg orally twice daily (total 300 mg/day). Maximum dose 300 mg per day.
Available tablets: 100 mg, 150 mg
Covered with criteria

Coding and Dose Limits

inv-08: Maximum daily dose — 300 mg per day

Maximum daily dose300 mg per day (maximum); dosing regimen for CLL is 150 mg orally twice daily

Tablet strengths available100 mg and 150 mg tablets

Dose limit per dayDo not exceed 2 tablets per day unless supported by guidelines or literature

Provider Requirements, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for all requests for idelalisib (Zydelig) for CLL and SLL per the labeled and off‑label criteria in this policy. Providers must document that the member meets the specific prior-therapy requirements (including prior BTK inhibitor and venetoclax-based regimens for CLL/SLL per Appendix B) and all other approval criteria.

Prior authorization may be required for CLL and SLL requests
Failure to document required prior therapies may result in denial

Step Therapy

Prior Therapy / Step Therapy Requirements

For CLL and SLL, prior authorization will require documentation of prior therapy with both a BTK inhibitor (e.g., acalabrutinib, zanubrutinib, ibrutinib, pirtobrutinib) and a venetoclax-based regimen per Appendix B and NCCN recommendations. Step therapy notes: IL HIM members may be eligible for a step therapy bypass per IL HB 5395.

Prior therapy must include both a BTK inhibitor and a venetoclax‑based regimen for CLL/SLL

Therapy Line Definitions and Requirements

second-line — 1 top-level node

Coverage limited to relapsed or refractory disease after prior therapy with both a BTK inhibitor and venetoclax:

Second‑line: relapsed/refractory after BTK inhibitor and venetoclax: Coverage is limited to relapsed or refractory disease after prior therapy with both a BTK inhibitor and venetoclax (Venclexta). Zydelig is not indicated for first‑line therapy. Prescriber must document prior therapies and rationale; see Appendix B for therapeutic alternatives.

Prior therapy requirement revised in 4Q 2024 to require BTK inhibitor + venetoclax per NCCN; prior authorization documentation required.

Background and Drug Information

Idelalisib is a selective phosphoinositide 3‑kinase delta (PI3Kδ) inhibitor indicated for relapsed chronic lymphocytic leukemia in combination with rituximab when rituximab alone would be appropriate. The agent is associated with serious and potentially fatal toxicities — including hepatic injury, severe diarrhea/colitis, pneumonitis, and serious infections — which are reflected in boxed warnings in the product labeling. Because of these safety concerns and labeling changes, idelalisib is not recommended as first‑line therapy and its use is restricted to the covered indications and conditions specified in this policy.

Definitions and Abbreviations

inv-18: chronic lymphocytic leukemia (CLL) definition/key term

TermChronic lymphocytic leukemia (CLL)

AbbreviationCLL

Context in policyCoverage limited to relapsed/refractory CLL per criteria; idelalisib indicated in combination with rituximab for relapsed CLL where rituximab alone would be appropriate

inv-19: follicular B-cell non-Hodgkin lymphoma (FL) definition/key term

TermFollicular B-cell non-Hodgkin lymphoma (FL)

AbbreviationFL

Policy note

Policy Revisions and Approval History

2025-11-25annual_reviewLatest

Added step therapy bypass for IL HIM per IL HB 5395 and extended initial approval duration for Medicaid and HIM from 6 months to 12 months for this maintenance medication; references reviewed and updated.

2024-11-24annual_review

Revised prior therapy requirement for CLL/SLL to require prior therapy with a BTK inhibitor and venetoclax-based regimens per NCCN; Appendix B updated and references reviewed.

2022-11-22