ModifiedmhnPolicy CP.PHAR.600

Trofinetide (Daybue, Daybue Stix) coverage for Rett syndrome

Defines medical necessity criteria, dosing limits, and prior authorization requirements for trofinetide (Daybue and Daybue Stix) for treatment of Rett syndrome in members of Centene-affiliated health plans.

Policy Summary

Payermhn

PolicyTrofinetide (Daybue, Daybue Stix) coverage for Rett syndrome

Policy CodePolicy CP.PHAR.600

Change TypeFormulation addedcriteria revised

Effective DateMar 10, 2023

Next Review Date

Key ActionSubmit prior authorization with documentation showing diagnosis, MECP2 genetic confirmation, specialist involvement, age/weight thresholds, baseline assessment (RSBQ or CGI-S ≥ 4), and dosing within weight-based limits.

SourceLink

POLICY UPDATE CHANGES

Added new Daybue Stix formulation.

Initial approval CGI-I requirement was updated to CGI-S with a minimum score of 4.

For continued therapy, added requirement for documentation of response via specific RSBQ or CGI-I score improvements.

≥2 yrsminimum age for FDA-approved indication

24,000 mg/daymaximum daily dose

≥9 kgminimum weight for coverage

MECP2genetic confirmation required

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12 moapproval duration

Coverage Criteria for Trofinetide (Daybue, Daybue Stix)

Initial Therapy Criteria

Covered when ALL of the following are met.

Initial Approval for RTT: 1. Diagnosis of Rett syndrome with both: (a) classic/typical RTT and (b) MECP2 gene mutation confirmed by genetic testing.

Prescriber: 2. Prescribed by or in consultation with a pediatric neurologist, geneticist, or developmental pediatrician.

Age and Weight: 3. Age ≥ 2 years.

Age and Weight: 4. Weight ≥ 9 kg.

Seizure status: 5. Member has had no seizures or has a stable pattern of seizures (e.g., no changes in seizure frequency, antiepileptic drugs, or behavioral treatments).

Baseline assessment: 6. Documentation of one of the following baseline assessment scores: (a) Rett Syndrome Behavior Questionnaire (RSBQ) baseline score, or (b) Clinical Global Impression–Severity (CGI-S) score ≥ 4.

Exclusions at time of request: 7. At the time of request, member does not have either of the following: (a) Long QT syndrome or baseline QTcF interval > 450 msec, and (b) current treatment with insulin.

Dosing limits: 8. Dose does not exceed weight-based limits (maximum 24,000 mg/day). For Daybue oral solution, dose limits by weight are: (i) 9 to <12 kg: 10,000 mg (50 mL)/day; (ii) 12 to <20 kg: 12,000 mg (60 mL)/day; (iii) 20 to <35 kg: 16,000 mg (80 mL)/day; (iv) 35 to <50 kg: 20,000 mg (100 mL)/day; (v) ≥50 kg: 24,000 mg (120 mL)/day. For Daybue Stix packets, per-day dosing and packet counts by weight are: (i) 9 to <12 kg: 10,000 mg = two 5,000 mg packets; (ii) 12 to <20 kg: 12,000 mg = two 6,000 mg packets; (iii) 20 to <35 kg: 16,000 mg = two 8,000 mg packets; (iv) 35 to <50 kg: 20,000 mg = four 5,000 mg packets; (v) ≥50 kg: 24,000 mg = four 6,000 mg packets.

Documentation requirement: Note: Provider must submit documentation (e.g., office chart notes, labs, or other clinical information) supporting that member has met all approval criteria.

See Appendix D for definition of classic RTT and Appendices E/F for scoring instruments.

Continuation Therapy Criteria

Covered when ALL of the following are met.

Eligibility for continuation: 1. Member meets one of the following: (a) currently receiving medication via Centene benefit or previously met initial approval criteria; or (b) currently receiving medication and is enrolled in a state/product with continuity of care regulations.

Documented response: 2. Member is responding positively to therapy, evidenced by one of: (a) ≥ 3-point reduction in overall RSBQ total score from baseline; (b) if on drug ≤ 6 months, a CGI‑I score between 1–4; (c) if on drug > 6 months, a CGI‑I score between 1–3.

Response metrics are quantitative and required for continuation.

Dose change: 3. If request is for a dose increase, the new dose must not exceed the same weight-based maximums as initial approval (maximum 24,000 mg/day); weight-specific limits for Daybue oral solution and Daybue Stix packets are the same as initial approval.

Non‑FDA indications that are not specifically addressed in this policy are excluded from coverage unless the request includes sufficient documentation of efficacy and safety in accordance with the applicable off‑label use policies (see CP.CPA.09 for commercial, HIM.PA.154 for Marketplace, and CP.PMN.53 for Medicaid) or other evidence of coverage documents.

When state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Refer to the applicable state Medicaid manual for specific coverage requirements that may apply to members.

Uses that are not FDA‑approved and are not specifically supported by sufficient documentation per the referenced off‑label use policies are not authorized. Providers seeking coverage for off‑label uses must supply documentation of efficacy and safety consistent with CP.CPA.09 (Commercial), HIM.PA.154 (Marketplace), or CP.PMN.53 (Medicaid) as applicable.

Coding, Dosing Thresholds, and Product Availability

Product Availability (NDCs not specified in document)NDC

NDC not listed	Trofinetide (Daybue) oral solution 200 mg/mL
NDC not listed	Trofinetide (Daybue Stix) packets: 5,000 mg, 6,000 mg, 8,000 mg

Referenced codesmixed

affected codes

placeholder referenced in policy text

inv-08: Weight-based dosing thresholds

Weight 9–<12 kgDaybue oral solution: 10,000 mg/day (50 mL); Daybue Stix: two 5,000 mg packets per day

Weight 12–<20 kgDaybue oral solution: 12,000 mg/day (60 mL); Daybue Stix: two 6,000 mg packets per day

Weight 20–<35 kgDaybue oral solution: 16,000 mg/day (80 mL); Daybue Stix: two 8,000 mg packets per day

Weight 35–<50 kgDaybue oral solution: 20,000 mg/day (100 mL); Daybue Stix: four 5,000 mg packets per day

Weight ≥50 kgDaybue oral solution: 24,000 mg/day (120 mL); Daybue Stix: four 6,000 mg packets per day

inv-09: Maximum daily dose

Provider Actions, Prior Authorization, and Documentation Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for Daybue and Daybue Stix. Prior authorization requests must demonstrate that the member meets the Initial Approval Criteria (diagnosis of Rett syndrome with genetic confirmation, prescribing provider specialty, age and weight thresholds, seizure stability, baseline assessment scores, absence of contraindications such as long QT or insulin therapy, and dosing within policy limits) or the applicable continued therapy criteria when seeking renewal.

Affected products: Daybue (oral solution) and Daybue Stix (packets)
Prior authorization must include dose and weight information to verify dosing limits

Note

Prior Authorization Guidance and Policy Conditionality

This clinical policy is a guide to medical necessity to assist coverage decisions and benefit administration; it does not guarantee coverage. Prior authorization requirements remain in effect per the member’s benefit design and applicable plan documents. Coverage decisions are subject to all terms, conditions, exclusions, limitations, state mandates, and Health Plan-level administrative policies and procedures.

Definitions and Assessment Tools

inv-20: RSBQ

DefinitionRett Syndrome Behavior Questionnaire (RSBQ): a caregiver-rated instrument used to assess characteristics of RTT

Item count45 items

ScoringEach item scored 0–2 (0 = never, 1 = sometimes, 2 = always); total score derived from item sums

UseUsed as a baseline assessment and as a quantitative response measure for continued therapy (e.g., ≥3-point reduction from baseline required)

inv-21: CGI-S / CGI-I

DefinitionClinical Global Impression scales (CGI-S and CGI-I): clinician-rated 7-point scales assessing severity (CGI-S) and improvement (CGI-I)

Background — Rett Syndrome and Trofinetide

Rett syndrome (RTT) is a rare neurodevelopmental disorder that occurs predominantly in females and is commonly associated with pathogenic variants in the MECP2 gene. Trofinetide (Daybue, Daybue Stix) is an FDA‑approved therapy for RTT in patients aged ≥ 2 years and is intended to address core features of the disorder using validated measures such as the RSBQ and CGI scales; genetic confirmation of an MECP2 mutation is required by the coverage criteria.

Policy Revision History

2023-03-27policy update

Updated initial approval severity metric from CGI-I to CGI-S with a minimum score of 4 and added continued-therapy documentation requirements using specific RSBQ or CGI-I score improvements.

2025-12-29policy updateLatest

Added Daybue Stix formulation and revised approval durations to 12 months.

Policy Summary

Payermhn

PolicyTrofinetide (Daybue, Daybue Stix) coverage for Rett syndrome

Policy CodePolicy CP.PHAR.600

Change TypeFormulation addedcriteria revised

Effective DateMar 10, 2023

Next Review Date

SourceLink

On This Page

Maximum daily dose24,000 mg/day

ContextMaximum applies to both Daybue oral solution and Daybue Stix packets per initial and continued therapy criteria

Weight band supporting citationWeight ≥ 50 kg band specifies 24,000 mg/day (120 mL) or four 6,000 mg packets

Documentation Required

Supportive Documentation Required

Provider must submit supporting documentation (e.g., office/chart notes, genetic testing results, baseline labs, ECG/QTcF data, seizure history, and other clinical information) with the prior authorization request to verify that the approval criteria are met. Incomplete documentation may result in denial or delayed review.

Include genetic testing confirming MECP2 mutation for Rett syndrome requests
Provide ECG/QTcF and medication lists to confirm absence of long QT or insulin therapy

Documentation Required

Assessment Documentation (Baseline and Follow-up)

Baseline and follow-up assessment documentation is required: baseline RSBQ or CGI-S for initial approval and RSBQ change or CGI-I for continued therapy. Specifically, include baseline RSBQ total or CGI‑S score (≥ 4) at initiation, and for continuation provide either ≥ 3‑point reduction in RSBQ from baseline or CGI‑I scores as specified (≤ 4 if on therapy ≤ 6 months; ≤ 3 if on therapy > 6 months).

Baseline: RSBQ or CGI‑S ≥ 4
Continuation: ≥ 3‑point RSBQ improvement OR CGI‑I 1–4 (≤6 months) or 1–3 (>6 months)

Note

Provider Responsibility

Providers retain professional medical judgment and remain solely responsible for the medical advice and treatment of members. This policy does not replace clinical decision-making and is not intended to dictate treatment. Providers should document clinical rationale when deviating from policy guidance.

Note

Refer to Formulary / Off‑Label Policies

If the drug’s label has recently changed or the requested use is not listed in this policy, refer requests to the applicable formulary, non‑formulary, or off‑label use policies for the relevant line of business (see policy references below). Requests for non‑FDA approved indications require off‑label adjudication per those policies.

Formulary / no-coverage policies: CP.CPA.190 (commercial), HIM.PA.33 (marketplace), CP.PMN.255 (Medicaid)
Non-formulary policies: CP.CPA.190 (commercial), HIM.PA.103 (marketplace), CP.PMN.16 (Medicaid)
Off-label use policies: CP.CPA.09 (commercial), HIM.PA.154 (marketplace), CP.PMN.53 (Medicaid)

Step Therapy

Step therapy specifics are not provided in this policy. If applicable, step therapy requirements are defined by the member’s benefit design or separate utilization management policies; check the plan’s pharmacy benefit and prior authorization rules for any step therapy that may apply.

No step therapy requirements are specified in this document

7-point scale where higher values indicate greater severity or worse status on CGI-S; CGI-I rates improvement/worsening

Initial approval thresholdCGI-S ≥ 4 is accepted as a baseline severity measure for initial approval

Continued therapy response thresholdsCGI-I used for response: if on drug ≤6 months, CGI-I between 1–4; if on drug >6 months, CGI-I between 1–3

inv-22: Health Plan definition

DefinitionHealth Plan: a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC or its affiliates

ScopeApplies to plans that elect to adopt this clinical policy; coverage and benefit administration remain subject to plan documents and state/federal requirements

Legal notePolicy provides guidance on medical necessity and does not constitute a contract or guarantee of payment