CurrentCentenePolicy CP PMN.125

Clinical Policy: Milnacipran (Savella)

Policy governing medical necessity and prior authorization criteria for milnacipran (Savella) for management of fibromyalgia and certain off-label depression uses for Centene lines of business (Commercial, HIM, Medicaid). Affects prescribers and providers submitting PA requests to Centene-affiliated plans.

Policy Summary

PayerCentene

PolicyClinical Policy: Milnacipran (Savella)

Policy CodePolicy CP PMN.125

Change TypeNo material change

Effective DateAug 1, 2012

Next Review DateN/A

Key ActionProvider must submit documentation (office chart notes, lab results, or other clinical information) supporting that the member meets all approval criteria.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

200 mg/dayMax dose

12 monthsApproval duration

>18Age limit

Duloxetine trialStep therapy

Suicide riskBoxed warning

Coverage and Medical Necessity Criteria

inv-01: Initial Therapy - Fibromyalgia

Covered when ALL of the following are met:

Initial fibromyalgia criteria: 1) Diagnosis of fibromyalgia; 2) Age > 18 years; 3) Member meets ONE of the following branches: (a) Failure of a 30-day trial of duloxetine at up to maximally indicated doses in the last 180 days; for patients <65 years, failure of any tricyclic antidepressant (TCA) or cyclobenzaprine at up to maximally indicated doses is also required; OR (b) Member has a contraindication or intolerance to duloxetine, and failure of a 30-day trial of one alternative agent in the last 180 days (examples include gabapentin up to 1,800 mg/day) unless clinically significant adverse effects or contraindications exist; 4) Requested dose does not exceed 200 mg per day and adheres to tablet/quantity limits (2 tablets/day).dose <= 200 mg/day

For Illinois HIM requests, step therapy requirements do not apply as of 1/1/2026 per IL HB 5395.

inv-02: Continued Therapy

Covered when ALL of the following are met:

Continued therapy: 1) Member is currently receiving Savella via the Centene benefit or documentation supports current receipt of Savella for a covered indication for at least 30 days; 2) Member is responding positively to therapy; 3) If a dose increase is requested, the new dose does not exceed 200 mg per day (and does not exceed 2 tablets per day).dose <= 200 mg/day

Approval durations: Medicaid/HIM 12 months; Commercial 12 months or duration of request, whichever is less.

inv-03: Depression (Off-label) Criteria

Off-label depression requests must meet ALL of the following when applicable:

Depression (off-label): 1) Diagnosis of depression; 2) Member meets one of the following branches: (a) For treatment in a State with limitations on redirection/step therapy (see Appendix E), failure of a >=4-week trial of one SSRI at up to maximally indicated doses unless contraindicated or intolerant; OR (b) For all other requests, failure of a >=4-week trial of one SSRI AND failure of a >=4-week trial of another generic antidepressant (e.g., bupropion, TCA, mirtazapine) AND failure of two SNRIs each used for >=4 weeks unless contraindicated or clinically significant adverse effects occur; 3) Requested dose does not exceed 200 mg per day.each trial >=4 weeks; dose <= 200 mg/day

See Appendix E for state-specific redirection/step therapy limitations; trial durations shortened to 4 weeks per 2Q2023 update.

inv-04: Dosing, Warnings, and Interaction Restrictions

Key clinical/coverage-relevant criteria and constraints present in this portion of the policy

Dosing and max dose: Initial titration schedule for fibromyalgia and maintenance dosing as listed; maximum dose 200 mg/day.max 200 mg/day

Titration schedule: Day 1: 12.5 mg once; Days 2-3: 25 mg/day (12.5 mg twice daily); Days 4-7: 50 mg/day (25 mg twice daily); After Day 7: 100 mg/day (50 mg twice daily). Dose may be titrated based on response up to 200 mg/day.

Boxed warning: Increased risk of suicidal ideation, thinking, and behavior in children, adolescents, and young adults taking antidepressants.

Apply standard suicide risk monitoring per boxed warning.

MAOI and serotonergic interaction constraints: Concomitant use with MAOIs is contraindicated; allow at least 14 days after stopping an MAOI before starting Savella and allow at least 5 days after stopping Savella before starting an MAOI.14 days/5 days

Non‑FDA approved indications that are not specifically addressed in this policy are not authorized unless the provider submits sufficient documentation of efficacy and safety in accordance with the referenced off‑label use policies: CP.CPA.09 for Commercial, HIM.PA.154 for Health Insurance Marketplace, and CP PMN.53, or unless an applicable evidence of coverage document provides authorization.

Milnacipran (Savella) must not be used concomitantly with a monoamine oxidase inhibitor (MAOI). Allow at least 14 days after stopping an MAOI before initiating Savella, and allow at least 5 days after stopping Savella before initiating an MAOI due to the risk of serious, potentially fatal serotonergic interactions.

Savella should not be initiated in patients currently receiving linezolid or intravenous methylene blue. If Savella is stopped to permit administration of linezolid or IV methylene blue, monitor the patient for signs of serotonin syndrome for up to 24 hours after the last dose of linezolid or IV methylene blue; therapy with Savella may be resumed 24 hours after the last dose when appropriate.

Requests for treatment of non‑FDA approved conditions (off‑label uses) are not authorized under this policy unless the request includes documentation meeting the referenced off‑label use policies or evidence of coverage that supports the requested use. Absent that supporting documentation, coverage for off‑label indications will be denied.

Authorization durations and program rules are subject to periodic review and adjustment. Current standard approval durations are identified by line of business (for example, Medicaid/HIM and Commercial approval durations noted in the policy), and programmatic edits described in annual reviews may shorten trial durations or add state‑specific redirection/bypass options.

Recent program updates include shortening antidepressant trial durations to 4 weeks (2Q2023) and adding state‑specific redirection/bypass provisions (see Appendix E). Approval durations and trial length requirements stated in the policy should be applied as written and may be adjusted by future program reviews.

Initial Therapy Requirements

inv-21: Initial Therapy - Fibromyalgia

Initial therapy criteria for fibromyalgia

Initial Therapy Nodes: 1) Diagnosis of fibromyalgia; 2) Age > 18 years; 3) Required trials: failure of a 30-day trial of duloxetine at up to maximally indicated doses within the last 180 days OR if duloxetine is contraindicated/intolerant, failure of a 30-day trial of an alternate agent (e.g., gabapentin up to 1,800 mg/day) within the last 180 days unless adverse effects or contraindications; 4) Dose not to exceed 200 mg/day and quantity limits (2 tablets/day).dose <= 200 mg/day

IL HIM requests: step therapy requirements do not apply as of 1/1/2026 per IL HB 5395.

inv-22: Initial Dosing

Initial titration schedule for fibromyalgia

Titration schedule: Day 1: 12.5 mg once; Days 2-3: 25 mg/day (12.5 mg twice daily); Days 4-7: 50 mg/day (25 mg twice daily); After Day 7: 100 mg/day (50 mg twice daily).

Titrate based on efficacy and tolerability; maximum dose 200 mg/day.

Continuation / Renewal Criteria

inv-23: Continuation Therapy

Criteria for continued coverage

Continued Therapy Nodes: 1) Member currently receiving Savella via Centene benefit or documentation supports at least 30 days of therapy; 2) Member is responding positively to therapy; 3) Dose limits maintained (<=200 mg/day; 2 tablets/day).dose <= 200 mg/day

Approval duration: Medicaid/HIM 12 months; Commercial 12 months or duration of request, whichever is less.

inv-24: Continued Therapy Updates

Policy-level continuation/renewal edits noted in periodic reviews

Continuity of care in antidepressants: Revised continued therapy criteria to allow continuity of care in antidepressants for all indications (2Q2024 update).

Programmatic updates include shortened antidepressant trial durations to 4 weeks (2Q2023) and state-specific redirection/bypass provisions (Appendix E).

Step Therapy Requirements

Required prior trials / documentation	Minimum trial duration / lookback	Notes / exceptions
Failure of a 30‑day trial of duloxetine at up to maximally indicated doses in the last 180 days	30 days (within last 180 days)	For age <65 years, failure of any TCA or cyclobenzaprine at up to maximally indicated doses is also required; members with contraindication or intolerance to duloxetine may instead have failure of a 30‑day trial of an alternate agent (e.g., gabapentin up to 1,800 mg/day).

Step therapy modification	Minimum trial duration applied	State redirection / bypass notes
Antidepressant trial durations shortened per 2Q2023 annual review	4 weeks per antidepressant agent (each)	Policy adds redirection/bypass options for members in states with limitations on step therapy in certain mental health settings (see Appendix E). Example: Texas — single‑drug redirection applies for HIM requests. Illinois HIM: step therapy requirements do not apply as of 1/1/2026 per IL HB 5395.

Actions, Authorization, and Documentation Requirements

Prior Authorization

Prior authorization required

Prior authorization is required for initial and continued therapy. Initial and continuation approvals are subject to the clinical criteria and documentation requirements below; failure to meet or to document these requirements may result in denial.

Initial and continued therapy prior authorization required

Documentation Required

Documentation requirement

Provider must submit documentation (such as office chart notes, medication administration records, and relevant lab or imaging results) supporting that the member meets all approval criteria. Failure to submit sufficient documentation demonstrating the member meets the criteria may result in denial of the request.

Examples: office visit notes, medication history, prior trial dates/doses, adverse reaction documentation, lab results as applicable

Documentation Required

Post-exposure monitoring documentation

If a member is exposed to linezolid or intravenous methylene blue while on therapy, the provider must document monitoring for signs and symptoms of serotonin syndrome for up to 24 hours after the last dose of linezolid or IV methylene blue; therapy may be resumed 24 hours after the last dose when clinically appropriate. Document the exposure, monitoring duration, findings, and the rationale for resuming or discontinuing therapy.

Monitor and document for serotonin syndrome up to 24 hours after last dose of linezolid or IV methylene blue
Document date/time of exposure, monitoring notes, and decision to resume Savella

Step Therapy

Step therapy for fibromyalgia

Step therapy for fibromyalgia: Prior to approval, member must have failed a 30-day trial of duloxetine at up to maximally indicated doses within the last 180 days unless there is a documented contraindication or intolerance to duloxetine. For members <65 years, failure of a trial of a tricyclic antidepressant (TCA) or cyclobenzaprine at up to maximally indicated doses may be required. If duloxetine is contraindicated/intolerant, the member must have failed a 30-day trial of an alternative such as gabapentin up to 1800 mg/day within the last 180 days, unless clinically significant adverse effects occurred or all agents are contraindicated.

Failure of a 30-day trial of duloxetine within last 180 days required unless contraindicated
If duloxetine contraindicated/intolerant, failure of 30-day trial of alternative (e.g., gabapentin ≤1800 mg/day) within last 180 days
For age <65 years: trial of a TCA or cyclobenzaprine may be required

Step Therapy

Step therapy and state redirection notes

State-specific limitations or redirection policies may modify step therapy requirements. For example, Illinois (per IL HB 5395) provides a bypass for HIM requests effective 01/01/2026 and other states listed in Appendix E may restrict redirection in certain mental health settings (see Appendix E). Providers should check applicable state appendices when submitting requests; when a state limitation applies, follow the state-directed redirection/bypass rules instead of the standard step therapy requirements.

IL HIM bypass effective 01/01/2026 per IL HB 5395 (step therapy requirements do not apply for Illinois HIM requests)
See Appendix E for states with limitations on redirections (e.g., Texas/HIM specifics)

Dosing Limits and Coding

inv-09: Maximum daily dose — 200 mg per day

Maximum daily dose200 mg per day

Tablet limitNot to exceed 2 tablets per day

Applies toInitial and continued therapy requests (dose must not exceed 200 mg/day)

Quantity Limits and Refill Rules

inv-27: Milnacipran (Savella) — quantity limit value

Quantity limit (tablets per day)2 tablets per day

Approval duration contextMedicaid/HIM: 12 months; Commercial: 12 months or duration of request, whichever is less

Related dose limitAligns with maximum daily dose of 200 mg/day (2 tablets)

Definitions and Safety Concepts

inv-19: SNRI — selective serotonin and norepinephrine reuptake inhibitor

DefinitionSelective serotonin and norepinephrine reuptake inhibitor (SNRI)

Drug class exampleMilnacipran (Savella) is an SNRI used for fibromyalgia

Clinical relevanceSNRIs increase synaptic levels of serotonin and norepinephrine and carry serotonergic risks when combined with other agents

inv-20: Serotonin syndrome — description of signs/symptoms and risk with multiple serotonergic drugs

Description / signs and symptomsSerotonin syndrome may present with tremor, myoclonus, diaphoresis, hyperthermia, rigidity, autonomic instability, seizures, agitation, delirium, or coma

Risk contextReported with SNRIs and SSRIs; risk increases with concomitant use of multiple serotonergic drugs

Management implicationAvoid initiating or combining with MAOIs, linezolid, or IV methylene blue; follow required washout periods to mitigate risk

Background and Clinical Context

Milnacipran (Savella) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated by the FDA for the management of fibromyalgia.

The policy includes the FDA‑approved fibromyalgia indication with a recommended titration schedule and dosing limits (maximum daily dose documented elsewhere in the policy). It also addresses selected off‑label use in depression under strict step therapy and documentation requirements and highlights boxed warning and serotonin syndrome risks associated with serotonergic agents.

Policy Revision History

2025-04-23annual_reviewLatest

2Q 2025 annual review: added gabapentin redirection option to fibromyalgia criteria and added step therapy bypass for Illinois HIM per IL HB 5395; references reviewed and updated.

2024-06-07criteria_update

Revised continued therapy criteria to allow continuity of care in antidepressants for all indications (applied to continuation criteria across indications).

2023-02-05annual_review

2Q 2023 annual review: shortened the trial durations of antidepressant agents to 4 weeks and added state-specific redirection bypass options (Appendix E) including Texas requirements; references reviewed and updated.

2021-01-11annual_review

2Q 2021 annual review: references updated (HIMPHAR.21 revised to HIMPA.154) and references reviewed and updated.

Policy Summary

PayerCentene

PolicyClinical Policy: Milnacipran (Savella)

Policy CodePolicy CP PMN.125

Change TypeNo material change

Effective DateAug 1, 2012

Next Review DateN/A

Key ActionProvider must submit documentation (office chart notes, lab results, or other clinical information) supporting that the member meets all approval criteria.

SourceLink

On This Page

Initiation of Savella in patients currently treated with linezolid or IV methylene blue is contraindicated due to serotonin syndrome risk.

Serotonin syndrome monitoring: If Savella is stopped to administer linezolid or IV methylene blue, monitor the patient for symptoms of serotonin syndrome for up to 24 hours after the last dose; Savella may be resumed 24 hours after the last dose.24 hours

Document monitoring and timing of resumption in the medical record.