ModifiedmhnPolicy CP.PMN.193

Hydroxyurea (Siklos, Xromi)

Coverage and medical necessity criteria for Siklos and Xromi (hydroxyurea) for sickle cell disease and selected oncology/off-label indications across commercial, HIM/ICHRA, and Medicaid lines of business.

Policy Summary

Payermhn

PolicyHydroxyurea (Siklos, Xromi)

Policy CodePolicy CP.PMN.193

Change TypeMaterial updates to age, products, specialist and step-therapy rules

Effective DateFeb 19, 2019

Next Review Date

Key ActionSubmit prior authorization with documentation showing diagnosis, age criteria, dosing within allowed limits, and trial of generic hydroxyurea when required.

SourceLink

POLICY UPDATE CHANGES

For oncology off-label indications, added specialist requirement for an oncologist or hematologist.

Added newly approved Xromi formulation and clarified pediatric extension up to 18 years per updated prescribing information.

Revised age criterion to age ≥ 9 months and clarified that generic hydroxyurea trial applies to members age ≥ 2 years.

Added step therapy bypass for Illinois HIM per IL HB 5395.

35 mg/kg/dayMax dose (SCD)

80 mg/kg/dayMax dose (Oncology)

≥9 monthsMinimum age (Siklos)

≥2 years

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12 monthsApproval duration

Coverage and Medical Necessity Criteria

Initial Therapy — Sickle Cell Disease

Initial Approval Criteria — Sickle Cell Disease (must meet all):

SCD Initial: 1. Diagnosis of sickle cell disease (SCD).

Age Criterion: 2. Age meets product-specific criteria:

Siklos age: - For Siklos: age ≥ 9 months.

Xromi age: - For Xromi: age ≥ 6 months and < 18 years.

Step therapy: 3. For members aged ≥ 2 years: member must use generic hydroxyurea unless contraindicated or clinically significant adverse effects are experienced; for Illinois HIM requests, the step therapy requirement does not apply as of 1/1/2026 per IL HB 5395.

Dose limit: 4. Dose does not exceed 35 mg/kg per day based on weight.<= 35 mg/kg/day

Initial Therapy — Oncology/Off-label

Initial Approval Criteria — Oncology Indications (off-label) (must meet all):

Oncology Initial: 1. Diagnosis of one of the following malignancies: acute myeloid leukemia; chronic myeloid leukemia; head and neck cancer; myeloproliferative neoplasms (myelofibrosis, polycythemia vera, essential thrombocythemia); myelodysplastic syndromes; or Langerhans cell histiocytosis.

Langerhans cell histiocytosis added per NCCN-supported recommendation (2Q 2022).

Product: 2. Request is for Siklos.

Specialist involvement: 3. Prescribed by or in consultation with an oncologist or hematologist.

Added requirement in 2Q 2026.

Age: 4. Age ≥ 2 years.

Continuation Therapy

Continuation/Renewal Criteria — All Indications in Section I (must meet all):

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

Refer to state-specific continuity of care addendums.

Response: 2. Member is responding positively to therapy.

Dose increase: 3. If request is for a dose increase, request meets one of the following based on indication:

Prescribed regimen must be FDA-approved or recommended by NCCN.

SCD dose increase: - a. For SCD: new dose does not exceed 35 mg/kg per day based on weight.

Oncology off-label criteria

Policy updates and coverage-related criteria noted

Oncology off-label requests: 1. For oncology off‑label indications, requests must be for Siklos and the prescribed regimen must be FDA‑approved or recommended by NCCN; request must include specialist (oncologist or hematologist) involvement.

Specialist requirement added in 2Q 2026; Langerhans cell histiocytosis added in 2Q 2022.

Requests for hydroxyurea for non‑FDA approved indications that are not specifically addressed in this policy are not authorized unless the provider submits sufficient documentation demonstrating efficacy and safety in accordance with the applicable off‑label use policies (e.g., CP.CPA.09 for commercial, HIM.PA.154 for marketplace/ICHRA, or CP.PMN.53 for Medicaid).

Within the portion of the document reviewed there are no explicit exclusions listed beyond the general statement regarding non‑FDA approved indications; specific exclusions are not detailed in this policy excerpt.

This section does not define additional not‑medically‑necessary categories or other unspecified coverage exclusions in the provided document portion.

Coding, Dosing, and Age Criteria

Codes referencedmixed

N/A	No explicit CPT/HCPCS/ICD-10/NDC codes listed in this document portion

Maximum dose — Sickle cell disease

Maximum dose (Siklos and Xromi) for SCD35 mg/kg/day

Dose titration guidance (Siklos)Initial 15 mg/kg adults, 20 mg/kg children; increase by 5 mg/kg/day every ~8 weeks as tolerated

Dose details (Xromi)Initial 15 mg/kg (rounded to nearest 10 mg); maximum 35 mg/kg/day

Maximum dose — Oncology indications (Siklos)

Maximum dose for oncology indications (Siklos)80 mg/kg/day based on weight

Alternative allowanceDose >80 mg/kg/day may be allowed if supported by practice guidelines or peer-reviewed literature (prescriber must submit evidence)

Provider Requirements, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required. Provider must obtain prior authorization and submit documentation (office chart notes, laboratory results, dosing, weight calculations, and other clinical information) demonstrating the diagnosis of sickle cell disease or the requested oncology indication, member age, product-specific limits, and that dosing is within allowed limits.

Applies to Siklos and Xromi requests
Include dose calculation and weight when relevant
Include prior treatment history (see step therapy requirement)

Prior Authorization

Prior Authorization and Specialist Requirement

Prior authorization for Siklos and Xromi requires specialist involvement for oncology (off‑label) indications. Oncology/off-label requests must be prescribed by or in consultation with an oncologist or hematologist.

Oncology indications listed include AML, CML, head and neck cancer, myeloproliferative neoplasms, myelodysplastic syndromes, and Langerhans cell histiocytosis

Approved Regimens and Dosage Tables

Regimen	Indication / Limits
Siklos; dose up to 80 mg/kg/day	Oncology/off-label indications (AML, CML, head and neck cancer, myeloproliferative neoplasms, MDS, Langerhans cell histiocytosis). Dose must not exceed 80 mg/kg/day based on weight OR dosing supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence). Prescribed regimen must be FDA‑approved or recommended by NCCN.

Regimen	Coverage Note
Siklos (for oncology off‑label requests)	Off‑label oncology use supported when the prescribed regimen is FDA‑approved or recommended by NCCN; request must be for Siklos and include prescribing by or consultation with an oncologist or hematologist. Age ≥ 2 years and generic hydroxyurea trial required unless contraindicated; for Illinois HIM requests the step therapy exemption per IL HB 5395 applies as noted in policy updates.

Line-of-Therapy Considerations

salvage

Line of therapy - salvage: Prescribed by or in consultation with an oncologist or hematologist; age ≥ 2 years; product Siklos; dosing ≤ 80 mg/kg/day or dosing supported by practice guidelines or peer‑reviewed literature; generic hydroxyurea trial attempted unless contraindicated.dose <= 80 mg/kg/day or guideline-supported

This node represents salvage line‑of‑therapy criteria for oncology/off‑label use.

salvage

Line of therapy - salvage (alternate): Langerhans cell histiocytosis included as an off‑label oncology indication per NCCN‑supported category 2A recommendation; requests for off‑label oncology indications must meet the oncology initial criteria and specialist involvement requirement.

Added 2Q 2022; specialist requirement added 2Q 2026.

Definitions and Safety Warnings

Hydroxyurea — definition

DefinitionHydroxyurea is an antimetabolite medication

Examples of branded formulationsSiklos, Xromi

Primary clinical roleUsed to reduce frequency of painful crises and transfusion need in sickle cell disease (per policy background)

Safety warnings

Boxed warningsMyelosuppression and malignancies

ContraindicationHypersensitivity to hydroxyurea or any component of its formulation

Clinical implication

Background and Clinical Context

Hydroxyurea is an antimetabolite medication used in sickle cell disease to reduce the frequency of painful vaso‑occlusive events and to decrease the need for blood transfusions; product formulations referenced in this policy include Siklos and the newly added Xromi, which have differing labeled pediatric age ranges and dosing considerations.

Policy Revision History and Material Changes

2026-04-09Annual review (2Q 2026)Latest

For oncology off-label indications, added requirement that requests be prescribed by or in consultation with an oncologist or hematologist; added ICHRA line of business and updated references.

2025-09-08Administrative update

Added step therapy bypass for Illinois HIM per Illinois HB 5395.

2025-01-13RT4 — product labeling update

Policy Summary

Payermhn

PolicyHydroxyurea (Siklos, Xromi)

Policy CodePolicy CP.PMN.193

Change TypeMaterial updates to age, products, specialist and step-therapy rules

Effective DateFeb 19, 2019

Next Review Date

Key ActionSubmit prior authorization with documentation showing diagnosis, age criteria, dosing within allowed limits, and trial of generic hydroxyurea when required.

SourceLink

On This Page

Step therapy: 5. Member must use generic hydroxyurea unless contraindicated or clinically significant adverse effects are experienced; for Illinois HIM requests, the step therapy requirement does not apply as of 1/1/2026 per IL HB 5395.

Generic trial clarified to apply to members age ≥ 2 years (2Q 2024).

Dose/regimen: 6. Request meets one of the following:

Prescribed regimen must be FDA-approved or recommended by NCCN; prescriber must submit supporting evidence for guideline-supported dosing.

Dose option A: - a. Dose does not exceed 80 mg/kg per day based on weight.<= 80 mg/kg/day

Dose option B: - b. Dose is supported by practice guidelines or peer‑reviewed literature for the relevant off‑label use (prescriber must submit supporting evidence).

Oncology dose increase: - b. For Siklos in oncology indications, one of the following must be met:

Oncology option i: -- i. New dose does not exceed 80 mg/kg per day based on weight.<= 80 mg/kg/day

Oncology option ii: -- ii. New dose is supported by practice guidelines or peer‑reviewed literature for the relevant off‑label use (prescriber must submit supporting evidence).

Approval duration: 4. Approval durations are typically 12 months when continued therapy criteria are met.

Prescribed regimen requirementPrescribed regimen must be FDA‑approved or recommended by NCCN

Minimum age for use

Minimum age for hydroxyurea use (policy-wide)>= 9 months

Product-specific note — SiklosSiklos minimum age listed as ≥ 9 months in policy notes

Rationale for revisionRevised to ≥ 9 months based on guideline support and formulation availability (2Q 2024 update)

Generic hydroxyurea trial — applicability

Generic hydroxyurea trial applies to>= 2 years

Step therapy exception (Illinois HIM)For Illinois HIM requests, the generic trial requirement does not apply as of 1/1/2026 per IL HB 5395

Requirement contextMember must use generic hydroxyurea prior to Siklos or Xromi unless contraindicated or clinically significant adverse effects

For oncology uses, request must be for Siklos and prescriber must submit supporting evidence if dose exceeds standard limits

Step Therapy

Step Therapy Requirement and IL Bypass

Step therapy with generic hydroxyurea is required prior to approval for Siklos or Xromi for members aged ≥ 2 years unless contraindicated or the member experienced clinically significant adverse effects. For Illinois HIM requests, the step therapy requirement is bypassed per IL HB 5395 effective 1/1/2026.

Step therapy trial applies to members age ≥ 2 years
If contraindication or intolerance documented, include supporting clinical evidence
Illinois HIM: bypass applies beginning 2026-01-01

Documentation Required

Missing Documentation May Lead to Denial

Missing or incomplete documentation may result in denial. If requested supporting documentation (office notes, labs, dosing rationale, weight) is not provided, prior authorization cannot be completed and the request may be denied.

Ensure inclusion of age, diagnosis, prior hydroxyurea use or reason for bypass, and specialist consultation for oncology requests
For dose increases, provide evidence the new dose meets policy dose limits or is supported by guidelines or literature

Denial Risk

Age- and Trial-Related Denials

Requests may be denied if the member does not meet age criteria or the required trial of generic hydroxyurea (where applicable). For pediatric criteria: Siklos minimum age is ≥ 9 months; Xromi is for ages ≥ 6 months and < 18 years. Failure to meet the age thresholds or the generic trial requirement (for members ≥ 2 years) may result in denial.

Siklos: age ≥ 9 months
Xromi: age ≥ 6 months and < 18 years
Generic hydroxyurea trial required for members ≥ 2 years unless contraindicated

Note

Supporting Clinical References

Supporting clinical references that should be considered and can be cited with authorization requests include the Siklos and Xromi prescribing information, Lexicomp, and the NCCN Drugs & Biologics Compendium. For off‑label oncology dosing that exceeds standard limits, prescribers must submit practice guidelines or peer‑reviewed literature supporting the regimen.

Siklos Prescribing Information (Medunik) — see most recent PI
Xromi Prescribing Information (Nova Laboratories) — see most recent PI
Lexicomp Online and NCCN Drug Compendium for dosing and guideline support

Monitor blood counts due to risk of severe myelosuppression

Recommended references

Primary reference — compendiumNCCN Drugs and Biologics Compendium

Product prescribing informationSiklos and Xromi prescribing information (latest PI cited in references)

Other clinical resourcesLexicomp and select guideline publications (e.g., ASH, NHLBI) referenced in policy

Revised Xromi pediatric indication to extend use up to 18 years per updated prescribing information.

2024-05-20RT4 — product addition and criteria clarification

Added newly approved Xromi formulation and clarified that off-label oncology requests are for Siklos with prescribed regimens required to be FDA-approved or recommended by NCCN.

2024-03-05Annual review (2Q 2024)

Revised age criterion to age ≥ 9 months and clarified that the generic hydroxyurea trial applies to members age ≥ 2 years; references reviewed and updated.

2022-02-06Annual review (2Q 2022)

Added Langerhans Cell Histiocytosis as an off-label oncology indication per NCCN-supported category 2A recommendation; references reviewed and updated.