DraftPremera BluecrossPolicy N/A

CGRP Inhibitors for Migraine Prophylaxis

Medical necessity and site-of-service criteria for CGRP-targeting preventive therapies for migraine, including administration site review for IV/injectable agents; affects providers submitting medical or pharmacy benefit requests for Premera members.

Policy Summary

PayerPremera Bluecross

PolicyCGRP Inhibitors for Migraine Prophylaxis

Policy CodePolicy N/A

Change TypeCriteria revisions, site-of-service addition, coding updates

Effective DateNov. 1, 2025

Next Review DateN/A

Key ActionObtain prior authorization and document average monthly migraine days, trial/failure of two prophylactic medications, and site-of-service justification for IV agents.

SourceLink

POLICY UPDATE CHANGES

Added Ajovy criteria to include coverage for preventive treatment of episodic migraine in children aged 6-17 years.

Added Vyepti (eptinezumab-jjmr) IV formulation and site-of-service review for Vyepti.

For preventive use, requirement changed to trial and failure of 2 prophylactic medications and no requirement to try a triptan first.

Non-formulary exception review authorizations for all drugs listed in this policy may be approved up to 12 months.

Added HCPC C9399 for Aimovig.

4+prophylactic eligibility threshold

12 momax non-formulary approval

10/03/2025

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6–17Ajovy pediatric age

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Coverage and Medical Necessity Criteria

General medical necessity criteria for CGRP inhibitors

Agents may be considered medically necessary when ALL of the following are met

Age: Member meets age requirement per product labeling (typically age >=18 years for adult indications; some agents have pediatric indications—see agent-specific criteria)age criteria as specified

Ajovy (fremanezumab) has pediatric criteria for ages 6-17 with a weight requirement

Migraine frequency: Member has an average of 4 or more migraine days per month (agent-specific: Ajovy pediatric episodic 4 to 14 migraine days/month; Nurtec episodic preventive 4 to 14 MMD)>=4 per month or 4-14 for episodic indications as specified

Agent-specific variations apply

Prior prophylactic therapy trials: Member has trialed and failed two different categories of prophylactic migraine therapies listed in the Appendix2 categories tried and failed

Appendix defines acceptable prophylactic medication categories

Site of Service criteria (IV/admin)

Site-of-service medical necessity for IV agents (Vyepti/eptinezumab)

Medically necessary sites: Preferred medically necessary sites of service for IV infusion/injection are physician's office, infusion center, or home infusionsite meets criteria

These are the preferred sites for specified drugs (including Vyepti)

Hospital-based outpatient exceptions: Hospital-based outpatient IV infusion department or hospital-based outpatient clinical level of care is considered medically necessary only under specific exceptionsfirst 90 days for initial course or re-initiation after >=6 months OR when no outpatient infusion center within 50 miles/no contracted home infusion agency will travel OR clinical risk factors present

Clinical condition examples: known symptomatic cardiac or significant pulmonary disease, unstable renal function, difficult/unstable vascular access, acute mental status changes; hospital site is medically necessary for the first 90 days for initial infusion or re-initiation after >=6 months

Investigational / not recommended uses

Use limitations and investigational statements

Combination use: Use of the named CGRP agents in combination with each other is considered investigational and not coveredno combination therapy

All other uses not outlined in this policy or Policy 5.01.503 (for example, hemiplegic migraines and vestibular migraines) are considered investigational

Erenumab efficacy

Erenumab (Aimovig) — efficacy evidence summaries

Erenumab episodic migraine evidence: STRIVE RCT (n=955) observed reductions of 3.2 (70 mg) and 3.7 (140 mg) monthly migraine days versus 1.8 for placebo; 50% responder rates were 43.3% (70 mg) and 50% (140 mg)

Open-label extension data demonstrate maintained efficacy up to one year

Erenumab chronic migraine evidence: Phase II RCT (n=656) showed mean reductions in monthly migraine days of 6.6 (70 mg and 140 mg) versus 4.2 for placebo

Efficacy demonstrated in both episodic and chronic migraine populations

Fremanezumab efficacy

Fremanezumab (Ajovy) — efficacy evidence summaries

Fremanezumab chronic migraine evidence: HALO CM (n=1130) observed reductions of 4.9 (quarterly) and 5.0 (monthly) headache days/month versus 3.2 for placebo; ~38-41% achieved >=50% reduction vs 18% for placebo

Also demonstrated efficacy in high-frequency episodic migraine trials

Fremanezumab pediatric episodic migraine evidence: Pediatric randomized trial (ages 6-17, n=235) showed mean reduction in monthly migraine days -2.5 versus -1.4 for placebo (p=0.021); safety profile consistent with adults

Ajovy is approved for preventive treatment of episodic migraine in ages 6-17 who meet weight and frequency criteria

Galcanezumab efficacy

Galcanezumab (Emgality) — efficacy evidence summaries

Episodic migraine evidence (EVOLVE-1/2): EVOLVE-1 and EVOLVE-2 Phase 3 RCTs showed reductions in monthly MHDs of approximately 4.3-4.7 for galcanezumab (120/240 mg) versus 2.3-2.8 for placebo (p<0.001)

Improvements also observed in acute medication use and quality-of-life measures

Chronic migraine evidence (REGAIN): REGAIN (Phase 3) reported reductions of ~4.62-4.83 monthly MHDs for galcanezumab versus 2.47 for placebo (p<0.001) with significant 50% and 75% responder improvements

Galcanezumab was also studied in episodic cluster headache (300 mg monthly) with a consistent safety profile

Eptinezumab efficacy

Eptinezumab (Vyepti) — efficacy and safety summaries

Eptinezumab PROMISE trials: PROMISE-1 and PROMISE-2 demonstrated that eptinezumab 100 mg and 300 mg significantly reduced monthly migraine days over months 1-3 versus placebo and produced significant >=50% and >=75% reductions in MMD in evaluated windows; infusion produced reduced incidence of migraine on day 1 after infusion

Safety database included 2076 exposed individuals; common adverse reactions included nasopharyngitis and hypersensitivity

Rimegepant efficacy

Rimegepant (Nurtec ODT) — preventive efficacy

Rimegepant preventive trial: A randomized, double-blind, placebo-controlled trial of rimegepant 75 mg every other day for 12 weeks in adults (baseline ~10.2 migraine days per 28 days) showed statistically significant reductions in mean monthly migraine days versus placebo; concomitant CGRP pathway agents were not permitted in the trial

Approximately 10% of participants were taking one preventive medication at baseline

Atogepant efficacy

Atogepant (Qulipta) — efficacy summaries

Atogepant ADVANCE (episodic): The ADVANCE 12-week Phase 3 trial in adults with 4-14 MMD (n=902) showed all doses (10, 30, 60 mg QD) significantly decreased MMD vs placebo with differences of -1.21 to -1.72 days; 50% responder rates ranged 56-61% vs 29% for placebo

Individuals with CVD were included; some trials excluded those with inadequate response to >4 prior medications

Atogepant chronic and other trials: Phase 2b/3 and a chronic migraine randomized study (Qulipta 60 mg QD) showed significant reductions in MMD versus placebo (treatment mean change ~-6.x vs -5.1 for placebo; p<0.001)

Various dosing regimens studied including BID schedules in phase 2b/3 trials

Key updated coverage criteria (excerpt)

Selected explicit coverage statements and requirement changes shown in document excerpts

Preventive CGRP agents prior therapy: For preventive use, members must have trial and failure of two prophylactic medications (updated requirement); there is no requirement to try a triptan firsttrial/failure of 2 prophylactic medications

Policy updated 10/01/23 and prior updates removed triptan requirement

Non-formulary exception duration: Non-formulary exception review authorizations for drugs in this policy may be approved up to 12 months<=12 months when granted

Administrative clarification added in 03/01/25 update

Investigational indications: Use of drugs in this policy for hemiplegic migraines and vestibular migraines is considered investigational and not covered

General preventive therapy coverage criteria (summary)

Covered when ALL of the following general conditions are met (summarized from policy history):

Migraine frequency: Individual has an average of more than 4 migraine days per month for preventive CGRP agents>4 days/month

This average MMD threshold has been used and reinforced across policy updates

Prior medication trials: Documented trial and failure of two prophylactic medications is required for preventive CGRP use (policy updated 10/01/23)2 prior prophylactic medications

Earlier versions required different numbers/types of trials; triptan requirement removed

Age indication: Agent is being used consistent with product labeling for age (most agents for adults ≥18 years; Ajovy has pediatric episodic approval for ages 6-17 with weight >=45 kg)

Use of the named CGRP pathway agents in combination with one another is considered investigational and is excluded from coverage under this policy. The policy further states that other uses not specifically outlined in this policy or in policy 5.01.503 are investigational.

Relevant clinical trials prohibited concomitant use of other CGRP‑pathway agents; for example, the rimegepant preventive trial did not permit use of a medication acting on the CGRP pathway. Trials also commonly excluded individuals with inadequate responses to multiple prior preventive medications (e.g., failure of ≥3 agents), which informs the policy expectation that prior preventive therapy history be documented when assessing coverage.

Use of drugs listed in this policy for the prevention or treatment of hemiplegic migraines and vestibular migraines is explicitly stated to be investigational and not covered.

Consistent with the investigational exclusions above, the policy reiterates that medications named in the document are subject to FDA dosing and administration and that any uses not described in this policy (including those specifically listed as investigational) are considered investigational and excluded from coverage.

When site‑of‑service criteria are not met, use of a hospital‑based outpatient infusion setting for administration of IV or injectable therapies addressed by this policy is not medically necessary. The policy specifies preferred medically necessary sites (physician office, infusion center, or home infusion) and limits hospital‑based outpatient medical necessity to the initial 90 days of an infusion course, re‑initiation after ≥6 months, or when specified geographic or clinical risk exceptions apply.

If a requested use is not described in this policy or in policy 5.01.503 (including hemiplegic or vestibular migraine, or combinations of CGRP agents), the policy designates those uses as investigational and they will not meet medical‑necessity coverage criteria.

The policy clarifies that combinations of the listed CGRP agents or other indications not outlined in this policy are considered investigational. Requests for such combinations or off‑policy indications should be expected to be denied as not meeting coverage criteria.

Billing and Coding

HCPCS codes for CGRP agentsHCPCS

C9399	Unclassified drugs or biologicals (used to report Aimovig)
J3031	Injection, fremanezumab-vfrm, (Ajovy) 1 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered)
J3032	Injection, eptinezumab-jjmr, (Vyepti) 1 mg
J3590	Unclassified biologics (use to report Aimovig and Emgality)

Policy-related HCPCS codes mentionedHCPCS

J3031	HCPCS code added to policy (as listed in document)
J3032	HCPCS code added to policy (as listed in document)
J3590	HCPCS code added to policy (historically added/removed as noted)

Prophylactic therapy HCPCS codes (added/updated over time)HCPCS

J3590	Unclassified biologics (historically added/removed as noted)
J3032	HCPCS code added (specific description not provided in this chunk)
J3031	HCPCS code added
C9399	Added for Aimovig

Migraine days per month — 4+ (general and episodic ranges)

Policy threshold (most CGRP preventive agents)Average of 4 or more migraine days per month

Episodic migraine (agent-specific)4 to 14 migraine days per month for episodic indications (e.g., Ajovy, Nurtec)

Use in adultsMost agents require adult age criteria (age ≥18) paired with the 4+ MMD threshold

Pediatric weight threshold (Ajovy)

Pediatric weight requirement (Ajovy)Patient must weigh ≥45 kg (99 lbs.)

Pediatric age range (Ajovy)Ages 6 to 17 years

Provider Requirements, Prior Authorization, and Documentation

Documentation Required

Document MMD and diagnostic subtype

Document the baseline Monthly Migraine Days (MMD) and migraine diagnostic subtype in the medical record. Clinical trial entry criteria commonly required specific MMD ranges (e.g., 4–14 MMD for episodic migraine or ≥15 MMD for chronic migraine); include duration of migraine history and prior acute and preventive medication use.

Include baseline MMD (monthly migraine days) and specify episodic vs chronic vs other migraine subtype.
Document duration of migraine history (e.g., ≥1 year when required by trial inclusion).
Record prior acute and preventive medication use and responses.

Prior Authorization

Prior authorization and coding

Prior authorization is required per medical or pharmacy benefit rules. Submit requests with the applicable HCPCS/biologic and unclassified codes as applicable; charges billed without prior authorization may be denied.

Background and Clinical Context

Migraine is a disabling neurologic disorder characterized by severe, recurrent headaches often accompanied by nausea, photophobia, and phonophobia. Preventive (prophylactic) therapy is used for individuals with frequent migraine days to reduce headache frequency and severity; CGRP‑pathway agents were developed to address limitations of existing preventive treatments.

Key Definitions

Chronic migraine definition

Chronic migraine definitionGreater than 15 headache days per month, of which at least 8 are migraine days

Indication for preventive therapyChronic migraine (per definition) is an indication for preventive treatment

Contrast with episodic migraineEpisodic migraine defined as 4–14 migraine days per month (guides treatment approach)

Episodic cluster headache (Emgality indication)

Episodic cluster headache (Emgality) core definitionAt least two cluster periods lasting 7 days to 1 year (when untreated) separated by pain‑free remission ≥3 months

Allowed frequencyOccurs with frequency between one every other day and 8 per day

Policy Changes and Revision History

2025-11-01policy_updateLatest

Ajovy (fremanezumab-vfrm) criteria expanded to include coverage for preventive treatment of episodic migraine in children aged 6–17 years.

2025-10-03policy_update

Added site-of-service review for Vyepti (eptinezumab-jjmr) IV and clarified that Site of Service Medical Necessity criteria can apply to injection drugs (effective following 90-day provider notification).

2025-07-01

Policy Summary

PayerPremera Bluecross

PolicyCGRP Inhibitors for Migraine Prophylaxis

Policy CodePolicy N/A

Change TypeCriteria revisions, site-of-service addition, coding updates

Effective DateNov. 1, 2025

Next Review DateN/A

Key ActionObtain prior authorization and document average monthly migraine days, trial/failure of two prophylactic medications, and site-of-service justification for IV agents.

SourceLink

On This Page

Explicit investigational stance in policy updates

age per drug labeling

Site-of-service review applies for IV agent Vyepti; some agents have pediatric criteria

Indication in pediatricsApproved for preventive treatment of episodic migraine in children 6–17 when weight and MMD criteria met

Minimum average migraine days — historical note

Historical minimum average MMDPolicy historically referenced eligibility with an average of more than 4 migraine days per month

Past stricter requirementsEarlier versions required failure of at least three preventive therapies in some statements

Subsequent updatesThreshold maintained while prior-therapy requirements were revised over time

Average migraine days per month — policy threshold

Current policy average MMD standardPolicy uses an average of 4 or more migraine days per month as the preventive threshold for CGRP agents

Agent-specific episodic rangeSome agents (e.g., Ajovy, Nurtec) specify 4–14 migraine days/month for episodic indications

Documentation expectationProviders should document average monthly migraine days consistent with the 4+ threshold in authorization requests

HCPCS/biologic codes: J3031 (fremanezumab 1 mg), J3032 (eptinezumab 1 mg).
Unclassified drug/biologic codes: C9399, J3590 (as historically used).
Prior authorization may be required under either the medical or prescription benefit depending on product and route (IV vs SC vs oral).

Denial Risk

Concomitant CGRP agent prohibition noted in trial

Do not prescribe or request concomitant CGRP-pathway agents. Clinical trials and policy stipulate that use of multiple CGRP pathway medications together or concomitant CGRP agents for prevention and/or acute treatment is not permitted and is considered investigational.

Concurrent use of two or more agents that act on the CGRP pathway (preventive or acute) is considered investigational and may be denied.
If a patient used a CGRP agent in a prior trial, document details (agent, dates, reason for discontinuation).

Denial Risk

Requests for prophylactic therapy that do not meet prior trial/failure criteria may be denied

Requests for prophylactic therapy must demonstrate that the individual meets all medication step and trial criteria before CGRP or other specified preventive agents will be approved. Requests that do not meet the policy's prior trial/failure requirements may be denied.

For preventive CGRP agents, document trial and inadequate response or intolerance to the required number of prophylactic medications (see therapy trials required).
Non-formulary exception reviews may allow approvals up to 12 months when criteria and benefit rules are met.

Documentation Required

Required documentation

Provide complete medical records with the request. Records must include office visit notes with diagnosis, relevant history, physical exam, headache frequency and severity, and medication history.

Office visit notes should document diagnosis, history, physical, headache frequency (MMD), headache severity, and prior medication trials.
Include documentation of response, adverse effects, and reasons for discontinuation of prior preventive agents.

Documentation Required

Documentation of baseline MMD and migraine history

Document baseline MMD, migraine history duration, and prior preventive/acute medication trials. Clinical trials used these elements for enrollment and the policy requires them to assess medical necessity.

Baseline MMD (numeric) and method of measurement (headache diary preferred).
Duration of migraine history (e.g., ≥1 year when applicable).
List of prior preventive medications tried, duration, and reason for failure/intolerance.

Documentation Required

Documentation & site-of-service notes

Include site-of-service rationale when requesting IV or clinic-administered agents. Site-of-service medical necessity criteria apply for IV/injectable administration; requests without justification for hospital-based outpatient or infusion center use may be denied.

For IV administration (e.g., Vyepti), indicate preferred site (physician office, infusion center, home infusion) and justify hospital outpatient use only when criteria are met (first 90 days, lack of local infusion/home services, or clinical risk factors).
Site-of-service criteria apply to members age ≥13 for medical-benefit reviews and may be excluded for Alaska fully-insured members per benefit rules.

Prior Authorization

Authorizations are subject to FDA dosing and benefit rules

Authorizations are subject to the product's FDA dosing and administration prescribing information and to benefit-specific non-formulary exception rules. Non-formulary exception approvals may be granted up to 12 months; other authorizations are typically limited per policy.

Follow the FDA dosing and administration for each product when requesting authorization.
Non-formulary exception reviews for drugs in this policy may be approved up to 12 months.
Other initial authorizations may be approved for variable durations (e.g., up to 6 months) unless otherwise specified.

Step Therapy

Therapy trials required

Require that the member has tried two different categories of prophylactic migraine therapies (from the Appendix) and document trials/failures before approval of CGRP or other preventive agents. Historically the requirement evolved from three agents to two for preventive use.

Document trial and failure (or intolerance) of two different prophylactic medication classes before initiating CGRP preventive therapy.
There is no longer a requirement to try triptans prior to preventive CGRP therapy.
Appendix lists acceptable prophylactic medication categories—ensure trials meet timing and dosing adequacy.

Step Therapy

Prior preventive medication trials expected

Prior preventive medication trials are expected and should be clearly documented. Some clinical trials excluded individuals with failures of multiple prior medications; the policy aligns trial expectations with step therapy requirements.

Document number and classes of prior preventive medications tried and reasons for inadequate response.
When applicable, note if prior trials were limited by intolerance vs lack of efficacy.

Step Therapy

Prophylactic medication trials required

The policy requires trial and failure of two prophylactic medications prior to coverage of CGRP or other preventive agents (updated from earlier requirements). Ensure documentation shows adequate trials (dose and duration) and reasons for failure.

Two adequate trials of prophylactic medications (different classes) are required before coverage of preventive CGRP agents.
Adequacy: document dose, duration, and clinical response or adverse effects leading to discontinuation.

Trial/dosing contextGalcanezumab 300 mg monthly was studied for episodic cluster headache (see trial data)

CGRP pathway therapies — agents and routes

Monoclonal antibody agentsErenumab, fremanezumab (Ajovy), galcanezumab (Emgality), eptinezumab (Vyepti) — parenteral monoclonal antibodies targeting CGRP ligand or receptor

Small‑molecule gepantsRimegepant (Nurtec ODT) and atogepant (Qulipta) — orally administered CGRP receptor antagonists

Administration routesMonoclonal antibodies are administered subcutaneously or intravenously (e.g., Vyepti IV); gepants are oral

Episodic cluster headache — galcanezumab 300 mg monthly study

Galcanezumab episodic cluster dosing studied300 mg monthly for up to 2 months in a placebo‑controlled trial

Study population size106 individuals studied in the episodic cluster trial (49 on galcanezumab, 57 on placebo)

Safety contextSafety profile for galcanezumab 300 mg monthly in episodic cluster headache consistent with migraine safety data

Prophylactic therapy — definition and role

Prophylactic therapy definitionPreventive treatment of migraine — therapies given to reduce frequency/severity of migraine attacks

Clinical roleUsed for episodic (4–14 MMD) and chronic (>15 headache days/month) migraine to decrease attack frequency and disability

Examples of prophylacticsIncludes beta‑blockers, antiepileptics, antidepressants, and CGRP‑targeting agents when criteria met

Clarified non-formulary exception review authorizations may be approved up to 12 months and that medications are subject to FDA dosing and administration; reiterated investigational status for hemiplegic and vestibular migraine uses; added HCPC C9399 for Aimovig.

2024-09-01annual_review

Annual review conducted with no changes to policy statements.

2024-01-01interim_review

Removed requirement for trial with a triptan for preventive treatment criteria for Aimovig, Ajovy, Emgality, Nurtec, Qulipta, and Vyepti.

2023-10-01interim_review

Updated existing preventive CGRP criteria to require trial and failure of two prophylactic medications and removed the triptan prerequisite for preventive use.

2023-06-01annual_review

Updated Qulipta (atogepant) criteria to include expanded FDA indication for preventive treatment of chronic migraine.

2020-04-01annual_review

Added Vyepti (eptinezumab-jjmr) IV formulation to the policy for preventive treatment of migraines and added HCPCS code J3590; also added Emgality criteria for episodic cluster headache.

2018-06-01new_policy

Policy established covering prophylactic therapy with Aimovig (erenumab) for individuals with more than 4 migraine days per month and prior preventive therapy failures; subsequent additions included Ajovy and Emgality criteria later in 2018.

Material changes clarified that non‑formulary exception review authorizations for drugs listed in this policy may be approved for up to 12 months. The update also added and clarified a site‑of‑service review for IV eptinezumab (Vyepti) effective 10/03/2025 and noted that site‑of‑service medical necessity criteria can apply to injection drugs. The effective date for the site‑of‑service review and other edits is documented in the policy change history.