ModifiedCentenePolicy CP.PMN.125

Clinical Policy: Milnacipran (Savella)

Policy governing prior authorization and coverage criteria for milnacipran (Savella) for fibromyalgia and certain off-label depression uses for Centene lines of business (Commercial, HIM/ICHRA, Medicaid). Affects providers seeking coverage for these indications.

Policy Summary

PayerCentene

PolicyClinical Policy: Milnacipran (Savella)

Policy CodePolicy CP.PMN.125

Change TypeTemplate updatesstep-duration revisionredirection additions

Effective DateAug 1, 2012

Next Review Date

Key ActionProvider must submit documentation (e.g., office chart notes, lab results) demonstrating the member meets indication-specific prior authorization criteria, including required prior medication trials or contraindications.

SourceLink

POLICY UPDATE CHANGES

Added redirection to generic Savella and added ICHRA line of business.

Shortened the trial durations of antidepressant agents from 8 weeks to 4 weeks.

Added gabapentin redirection option to fibromyalgia criteria.

≥18Minimum age for coverage

200 mg/dayMaximum daily dose

12 moApproval duration

FibromyalgiaPrimary approved indication

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14 daysMAOI washout (to start)

Coverage Criteria

inv-01: Initial Therapy - Fibromyalgia

Covered when ALL of the following are met

Fibromyalgia initial criteria: 1) Diagnosis of fibromyalgia; 2) Age ≥ 18 years; 3) For Savella requests, member must use milnacipran unless contraindicated or clinically significant adverse effects are experienced; 4) Member meets one of the following: (a) failure of a 30-day trial of duloxetine at up to maximally indicated doses in the last 180 days; OR (b) contraindication or intolerance to duloxetine AND failure of a 30-day trial of one of the following in the last 180 days unless clinically significant adverse effects are experienced or all agents are contraindicated: (i) for age <65 years: any TCA or cyclobenzaprine at up to maximally indicated doses; (ii) gabapentin at ≥ 1,800 mg/day; 5) Dose does not exceed both: a) 200 mg per day; b) 2 tablets per day.

Illinois HIM exceptions to step therapy per IL HB 5395 effective 1/1/2026 noted in policy

inv-02: Initial Therapy - Depression (off-label)

Covered when ALL of the following are met

Depression initial criteria: 1) Diagnosis of depression; 2) Age ≥ 18 years; 3) Member meets one of the following: (a) request is for treatment in a State with limitations on step therapy in certain mental health settings (see Appendix E); OR (b) for all other requests, failure of: (i) ≥4-week trial of one SSRI at up to maximally indicated doses unless contraindicated/intolerant; (ii) failure of two SNRIs at up to maximally indicated doses, each used for ≥4 weeks unless contraindicated/intolerant; (iii) failure of a ≥4-week trial of another generic antidepressant (e.g., bupropion, TCA, mirtazapine) at up to maximally indicated doses unless contraindicated/intolerant; 4) For Savella requests, member must use milnacipran unless contraindicated or clinically significant adverse effects are experienced; 5) Dose does not exceed both: a) 200 mg per day; b) 2 tablets per day.

Appendix E lists states with limitations; trial durations for antidepressants were shortened to 4 weeks per template changes

inv-03: Continuation Therapy

Continuation therapy (renewal) covered when ALL of the following are met

Continuation criteria: 1) Currently receiving medication via Centene benefit, or documentation supports that member has received Savella for at least 30 days; 2) Member is responding positively to therapy; 3) For Savella requests, member must use milnacipran unless contraindicated or clinically significant adverse effects are experienced; 4) If request is for a dose increase, new dose does not exceed both: a) 200 mg per day; b) 2 tablets per day.

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

Non–FDA–approved indications that are not specifically addressed in this policy are not authorized unless the provider supplies sufficient clinical documentation of efficacy and safety in accordance with the applicable off‑label use policies: CP.CPA.09 for Commercial, HIM.PA.154 for Health Insurance Marketplace/ICHRA, or CP.PMN.53 for Medicaid, or unless the member’s evidence of coverage permits the use. Documentation should demonstrate how the requested off‑label use meets those off‑label policy standards.

Concomitant use of monoamine oxidase inhibitors (MAOIs) with milnacipran (Savella) is contraindicated because of the risk of severe, sometimes fatal, interactions. Providers must allow at least a 14‑day washout after discontinuing an MAOI before initiating milnacipran. Conversely, allow at least a 5‑day washout after stopping milnacipran before starting an MAOI.

Milnacipran is an SNRI and, like other serotonergic agents, can contribute to serotonin syndrome when used with other serotonergic drugs. Concomitant use of serotonergic medications (including linezolid or IV methylene blue) is not recommended without careful monitoring; if serotonin syndrome is suspected, discontinue Savella promptly and manage per clinical guidance. Patients given linezolid or IV methylene blue while on Savella should be monitored for signs of serotonin syndrome for up to 5 days or until 24 hours after the last dose of the interacting agent, and therapy may be resumed 24 hours after the last dose of the interacting agent when clinically appropriate.

Initial Therapy

inv-19: Initial therapy — Initial authorization criteria vary by indication

Initial authorization criteria vary by indication

Initial - Fibromyalgia: See initial fibromyalgia criteria: diagnosis, age ≥ 18, step therapy (duloxetine 30-day trial in last 180 days or specified alternatives), use milnacipran unless contraindicated, and dose limits (200 mg/day, 2 tablets/day).

Initial - Depression: See initial depression (off-label) criteria: diagnosis, age ≥ 18, state-specific redirection/step therapy provisions (Appendix E) or failure of specified antidepressant trials (each ≥ 4 weeks), use milnacipran unless contraindicated, and dose limits (200 mg/day, 2 tablets/day).

inv-20: Initial therapy dosing — Initial dosing and titration schedule for fibromyalgia

Initial dosing and titration schedule for fibromyalgia

Initial dosing:

Continuation / Renewal Criteria

inv-21: Renewal — Renewal requirements

Renewal requirements

Continuation: Member must be currently receiving Savella via the Centene benefit or have documentation of at least 30 days' prior use, be responding positively to therapy, and any requested dose increase must not exceed 200 mg/day and 2 tablets per day.

Continuity of care for antidepressants: Continued therapy allowed to maintain antidepressant continuity across indications per the 06.07.24 revision (revised continued therapy criteria).

Documentation should reflect prior trials and redirection attempts where applicable

inv-22: Continuation criteria — Revised continued therapy criteria to allow continuity of care in antidepressants

Revised continued therapy criteria to allow continuity of care in antidepressants

Step Therapy and Redirection

Requirement	Details
Trials must be at up to maximally indicated doses unless contraindicated or clinically significant adverse effects are experienced.	Fibromyalgia: required prior trials (e.g., duloxetine, TCAs/cyclobenzaprine, or gabapentin) must be given at up to maximally indicated doses during the specified look‑back periods (see fibromyalgia initial criteria).
Documented failure or intolerance	Failure is defined as lack of efficacy or documented clinically significant adverse effects at up to maximally indicated doses; contraindication or intolerance to a required agent exempts the member from that specific trial.
Look‑back periods and durations	Fibromyalgia: 30‑day trial of duloxetine in the last 180 days; if duloxetine contraindicated/intolerant, 30‑day trial of alternate agent in last 180 days (TCAs/cyclobenzaprine for <65 or gabapentin ≥1,800 mg/day).

Step / Redirection Rule	Policy detail
Depression step therapy — required trials	For depression (off‑label), failure of: one SSRI ≥4 weeks at up to maximally indicated doses; two SNRIs each ≥4 weeks at up to maximally indicated doses; and one additional generic antidepressant ≥4 weeks at up to maximally indicated doses, unless contraindicated or intolerant.
Redirection bypass and state exceptions	Requests for members in States with limitations on step therapy in certain mental health settings may qualify for redirection bypass per Appendix E (example: Texas — single‑drug redirection applies to HIM requests).
Documentation requirements for trials/redirection	Provider must submit documentation reflecting trials of prior antidepressant agents consistent with revised trial durations (≥4 weeks) and any redirection attempts; state‑specific redirection rules and look‑back requirements apply.

Provider Actions and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for Savella (milnacipran). Provider must document that the member meets indication‑specific criteria and any applicable redirection/step therapy requirements. Requests without required documentation or that do not meet criteria may be denied.

Prior authorization required for all indications in Section I.
Provider must demonstrate member meets indication‑specific criteria (see Initial Approval Criteria).
Requests lacking required documentation or unmet criteria may be denied.

Documentation Required

Prior Authorization and Redirection Documentation

Prior authorization requests must include documentation of prior agent trials per the step therapy rules and any applicable redirection (for example, trials of duloxetine, SSRIs, SNRIs, other generic antidepressants, TCAs, cyclobenzaprine, or gabapentin as specified). If the member is eligible for a redirection bypass (see Appendix E/state‑specific rules), document the applicable justification.

Coding and Dosing Limits

inv-07: Maximum daily dose

Maximum daily dose200 mg/day

Quantity Limits

inv-25: Milnacipran (Savella) — 200 mg/day and 2 tablets per day

Maximum daily dose (mg/day)200 mg/day

Tablet limit2 tablets per day

Recommended daily dose for fibromyalgia100 mg/day (50 mg twice daily)

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

inv-26: Milnacipran (Savella) — Quantity limit value '200'

Quantity limit value200

Unitmg per day

Definitions

inv-17: Milnacipran (Savella) — definition and high-level properties

Drug classSelective serotonin and norepinephrine reuptake inhibitor (SNRI)

Brand/genericMilnacipran (Savella)

FDA-approved indicationManagement of fibromyalgia

AgeNot approved for use in pediatric patients; coverage applies for age ≥18 years per criteria

Key contraindicationsConcomitant use with MAOIs, linezolid, or IV methylene blue (risk of serotonin syndrome)

inv-18: Serotonin syndrome — definition and clinical note

Definition

Background

Milnacipran (Savella) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) that is FDA‑approved for the management of fibromyalgia. It is not approved for use in pediatric patients. The recommended fibromyalgia titration begins with low daily doses and advances to the typical maintenance dose of 100 mg/day (given as 50 mg twice daily) based on efficacy and tolerability; the policy also notes available tablet strengths and a maximum daily dose of 200 mg/day.

Revision History

2026-04-09annual_reviewLatest

2Q 2026 annual review: references reviewed and updated; added redirection to generic Savella and added ICHRA line of business.

2025-04-23annual_review

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

2024-06-07criteria_revision

Policy Summary

PayerCentene

PolicyClinical Policy: Milnacipran (Savella)

Policy CodePolicy CP.PMN.125

Change TypeTemplate updatesstep-duration revisionredirection additions

Effective DateAug 1, 2012

Next Review Date

SourceLink

On This Page

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). Recommended dose 100 mg/day; maximum 200 mg/day.

Titrate based on efficacy and tolerability

Continuation criteria - antidepressant continuity:

Continued therapy allowed to maintain antidepressant continuity across indications per the 06.07.24 revision; documentation should support ongoing therapy and positive response. For depression-related continuity, state-specific redirection/step therapy provisions (Appendix E) apply where noted.

Trial durations for antidepressant steps are defined as ≥4 weeks per agent (template changes).

Include dates, doses, durations, and reason for discontinuation (inefficacy, adverse effect, or contraindication) for prior therapies.
Document any state‑specific redirection exceptions (see Appendix E).
If redirection to generic milnacipran is used, document prior use or rationale as applicable.

Step Therapy

Step Therapy Requirements — Fibromyalgia

Step therapy requirements must be documented and met before approval unless a contraindication, intolerance, or applicable state redirection bypass applies. For fibromyalgia, the policy requires a 30‑day trial of duloxetine at up to maximally indicated doses within the last 180 days, unless duloxetine is contraindicated or not tolerated.

Fibromyalgia: 30‑day duloxetine trial within the last 180 days OR duloxetine contraindicated/intolerant plus trial of a TCA or cyclobenzaprine (age <65) or gabapentin ≥1,800 mg/day.
Illinois HIM: step therapy requirements do not apply for Illinois HIM requests as of 1/1/2026 per IL HB 5395 (document applicability).

Step Therapy

Step Therapy / Redirection Rules — Depression

For depression (off‑label use), document failure of specified prior antidepressant trials per the redirection/step therapy rules unless the member qualifies for a redirection bypass in a state or setting that limits step therapy. Failure is defined by lack of efficacy after trials at up to maximally indicated doses for the required durations or intolerance/contraindication.

Depression: unless redirection bypass applies, document failure of: one SSRI ≥4 weeks; two SNRIs each ≥4 weeks; and one other generic antidepressant (e.g., bupropion, TCA, mirtazapine) ≥4 weeks.
If request is in a state/setting with redirection limitations (see Appendix E), follow the bypass rules and document the applicable exception (example: Texas HIM requirements).

Documentation Required

Required Trial and Redirection Documentation

Required documentation must be provided with the prior authorization request to support that the member has met all approval criteria. Acceptable documentation includes office chart notes, medication histories, lab results, and other clinical information showing diagnosis, prior medication trials (dates, doses, duration), response to therapy, and reasons for discontinuation where applicable.

Include chart notes or medication administration records showing at least 30 days of current Savella use for continued therapy requests.
Detail prior agent trials with start/end dates, dosing, and reason for failure (inefficacy, adverse effect, contraindication).
For redirection bypasses or contraindications, include supporting clinical rationale and any state‑specific documentation (e.g., Appendix E applicability).

Denial Risk

Contraindicated Concomitant Therapy and Washout Periods

Be aware of contraindicated concomitant therapy: concomitant use of MAOIs with milnacipran is contraindicated. Allow at least 14 days after stopping an MAOI before starting milnacipran and at least 5 days after stopping milnacipran before starting an MAOI. Monitor and document management of potential serotonin syndrome if relevant.

Do not authorize if MAOI co‑therapy is present without required washout documentation.
If linezolid or intravenous methylene blue was used, document appropriate monitoring and resolution before resuming milnacipran.

Corresponding tablet limit2 tablets per day

Serotonin syndrome is a potentially life‑threatening condition associated with serotonergic drugs, characterized by agitation, autonomic instability, neuromuscular abnormalities, hyperthermia, seizures, and altered mental status.

Common signs/symptoms noted in policyTremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia, seizures, rigidity, autonomic instability, extreme agitation progressing to delirium and coma.

Clinical recommendationConcomitant use of MAOIs with Savella is contraindicated; allow at least 14 days after stopping an MAOI before starting Savella and at least 5 days after stopping Savella before starting an MAOI.

Revised continued therapy criteria to allow continuity of care in antidepressants for all indications.

2023-02-05criteria_revision

2Q 2023 annual review: shortened trial durations of antidepressant agents from 8 weeks to 4 weeks; references reviewed and updated.