ModifiedPremera BluecrossPolicy N/A

Hereditary Angioedema (HAE) drug therapy and site-of-service review

Defines medical necessity, site-of-service, and authorization criteria for pharmacy and medical benefit drugs used to treat hereditary angioedema (HAE) for Premera members, and documents required for review.

Policy Summary

PayerPremera Bluecross

PolicyHereditary Angioedema (HAE) drug therapy and site-of-service review

Policy CodePolicy N/A

Change TypeMaterial coverage and age/step updates

Effective DateJun 1, 2026

Next Review DateN/A

Key ActionSubmit prior authorization supporting medical records and requests may be approved for up to 12 months when criteria are met.

SourceLink

POLICY UPDATE CHANGES

Updated Orladeyo (berotralstat) coverage criteria age requirement from aged 12 years or older to 2 years or older.

Updated coverage criteria for Orladeyo to clarify dose limits (150 mg/day for individuals ≥12 years; weight‑based dosing for ages 2–11) and quantity limited to 30 capsules or packets per 30 days.

Removed requirement to try danazol or another androgen for adult males from multiple C1‑INH and kallikrein pathway agents.

Clarified that generic icatibant step therapy requirement applies to individuals aged 18 years or older who are not currently pregnant.

Added coverage for Andembry (garadacimab‑gxii) and Dawnzera (donidalorsen) for long‑term prophylaxis and Ekterly (sebetralstat) for acute attacks; added HCPCS J3590 for Andembry and Dawnzera.

12 monthsUpdated initial approval length for all drugs

30/moOrladeyo quantity limit

age 2+Orladeyo minimum covered age (updated)

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

300 mg q2wkLanadelumab dosing

52%Laryngeal attack risk (est.)

Coverage Criteria for HAE Therapies

Agent-specific medical necessity general criteria

Covered when ALL of the following are met for listed agent-specific indications (examples below reflect repeated structured criteria across agents):

Diagnostic confirmation: HAE type I or II established by documented laboratory values (e.g., low C4 and low C1‑INH antigenic levels for type I; low C4, normal/high C1‑INH antigenic, and low functional C1‑INH for type II).laboratory confirmation per agent

'Low' defined by lab reference range

Clinical features: Has two or more clinical features such as recurrent angioedema without wheals/urticaria, recurrent abdominal attacks, positive family history, or failure to respond to antihistamines/glucocorticoids/epinephrine.2+ features

Additional qualifying conditions: One of: history of ≥1 HAE attacks/month over a 6‑month period requiring acute treatment with listed acute therapies; documentation of pregnancy; or documentation of a laryngeal HAE attack within the last 5 years.1 of listed

Agent-specific

Concomitant therapy restriction: Treatment is not used concomitantly with other targeted HAE‑specific therapies for prophylactic (or acute where specified) treatment.no concomitant targeted HAE therapy

Ekterly dosing criteria

Ekterly (sebetralstat) acute-treatment dosing restrictions:

Age and diagnosis: Individuals aged ≥12 years with HAE (type I or II) or acquired angioedema where applicable; diagnostic laboratory confirmation per policy.age ≥12

Dose limits: Dose prescribed is limited to a maximum of 1,200 mg in any 24‑hour period (per attack) and 2,400 mg every 30 days.1,200 mg/24h; 2,400 mg/30d

Takhzyro (lanadelumab-flyo)

Takhzyro (lanadelumab-flyo) prophylaxis criteria and dosing:

Age and diagnosis: Individuals aged ≥2 years with type I or II HAE established by documented laboratory values per policy.age ≥2

Dose limit: Dose prescribed is limited to 300 mg subcutaneously every 2 weeks.300 mg q2w

Ruconest (rhC1-INH)

Ruconest (rhC1‑INH) acute treatment criteria and quantity/dose limits:

Age and diagnosis: Individuals aged ≥13 years with type I HAE established by documented laboratory values per policy.age ≥13

Dose/quantity limits: For individuals aged ≥12 years dose limited to 150 mg per day; for ages 2–11 dose is weight‑based as specified (72 mg for 12–<24 kg; 96 mg for 24–<32 kg; 108 mg for 32–<40 kg; 132 mg for ≥40 kg). Quantity limited to 30 capsules/packets per 30 days.age/weight-based per table; qty ≤30/30 days

Icatibant and related acute therapies

Icatibant (Firazyr, Sajazir, generic) and other acute agents general criteria:

Age and diagnosis: Icatibant products: individuals aged ≥18 years with HAE (type I or II) or acquired angioedema where applicable; diagnostic laboratory confirmation required per policy.age ≥18

Prior therapy requirement (where specified): If aged ≥18 and not currently pregnant, must have tried and had inadequate response or intolerance to generic icatibant when specified for certain agents (per policy step‑therapy nodes).trial of generic icatibant where specified

Applies to adults not pregnant

Concomitant therapy restriction: Icatibant and other acute agents are not to be used concomitantly with other targeted HAE‑specific therapies for acute treatment when policy specifies.no concomitant targeted HAE therapy

Benefit-specific coverage assignment

Coverage and benefit assignment by product and guideline‑preferred therapy:

Benefit assignment: Ekterly and Orladeyo are managed through the pharmacy benefit; Andembry, Dawnzera, Firazyr, generic icatibant, Haegarda, Kalbitor, Sajazir, and Takhzyro are managed through both pharmacy and medical benefits; Berinert, Cinryze, and Ruconest are managed through the medical benefit.

Supports prior authorization and billing route determination.

Guideline-preferred therapy

Guideline-based preferred therapy ordering for long‑term prophylaxis and acute treatment:

Long-term prophylaxis: First‑line: C1‑INH, lanadelumab, and berotralstat; Second‑line: androgens (avoid in pregnancy and children when possible due to side effects).

Derived from WAO/EAACI 2021 guideline.

Acute attack treatment: Recommended agents for acute HAE attacks: intravenous C1‑INH, ecallantide, or icatibant; individuals should have medication for at least two attacks and carry on‑demand medication at all times.

Guideline recommendation for on‑demand therapy.

Orladeyo coverage (updated)

Policy coverage statements updated or clarified in these sections include age indications, step therapy requirements, dose/quantity limits, and approval duration.

Orladeyo (berotralstat) coverage update: Covered for individuals aged 2 years and older when other policy criteria are met; dose limited to 150 mg/day for individuals ≥12 years and weight‑based dosing for ages 2–11; quantity limited to 30 capsules/packets per 30 days.age>=2; dose<=150 mg/day or weight‑based for 2–11; qty<=30/30 days

Initial approval length 12 months

Step therapy and age/pregnancy exceptions

Step therapy requirements and exceptions

Generic icatibant step: Generic icatibant (or Sajazir when listed historically) is required before brand icatibant (Firazyr) for individuals aged ≥18 years who are not currently pregnant when acute treatment criteria apply.age>=18 and not pregnant

Applies to acute treatment pathways for multiple agents

The policy's Site of Service (SOS) Medical Necessity review applies to medical-benefit IV and injectable HAE therapies for individuals aged 13 years and older. Preferred medically necessary sites include the physician office, infusion center, or home infusion program. Hospital-based outpatient settings are considered not medically necessary when the SOS criteria are not met; limited exceptions (for example initial courses or re‑initiation after prolonged interruption, lack of local infusion resources, or clinically high‑risk conditions) are described in the policy's site‑of‑service section.

Traditional hypersensitivity treatments such as antihistamines, epinephrine, and corticosteroids are not effective for acute HAE attacks because HAE is mediated by kallikrein‑driven bradykinin formation rather than mast‑cell histamine release. These agents therefore are not appropriate therapy for HAE acute attacks.

Site‑of‑Service Medical Necessity criteria do not apply to Alaska fully‑insured members pursuant to Alaska HB 226; this exception and its adoption into the policy are documented in the 2025 updates and history.

The policy history notes that Sajazir (icatibant) was removed as a preferred treatment for acute HAE attacks during the 2025 updates; contemporaneous changes clarified step‑therapy and age/pregnancy exceptions for icatibant products.

Coding and Age/Dose References

HCPCS codes listedHCPCS

J0593	Injection, lanadelumab-flyo (Takhzyro), 1 mg
J0596	Injection, C1 esterase inhibitor (recombinant), Ruconest, 10 units
J0597	Injection, C-1 esterase inhibitor (human), Berinert, 10 units
J0598	Injection, c-1 esterase inhibitor (human), Cinryze, 10 units
J0599	Injection, c-1 esterase inhibitor (human), (Haegarda), 10 units
J1290	Injection, ecallantide (Kalbitor), 1 mg
J1744	Injection, icatibant, 1 mg (used to report Firazyr, Sajazir and generic icatibant)
J3590	Unclassified biologics (use to report: Andembry and Dawnzera)

Policy history HCPCS/CPT changesHCPCS

J0593	HCPCS code added (new code effective 10/1/19) as listed in history
J0596	HCPCS code added in initial history
J0597	HCPCS code added in initial history
J0598	HCPCS code added in initial history
J0599	HCPCS code added 02/01/19
J1290	HCPCS code added in initial history
J1744	HCPCS code added in initial history
J3490	HCPCS code previously added then removed
J3590	HCPCS code added for Andembry and Dawnzera

Age thresholds for drug indications

Takhzyro (lanadelumab) age thresholdGenerally indicated for individuals ≥12 years in table; prophylactic indications elsewhere include ages ≥2 for some uses — age thresholds vary by product; confirm product labeling for specific indication.

Orladeyo (berotralstat) age thresholdCovered for individuals aged 2 years and older (policy updated 03/01/26).

Cinryze / Haegarda age thresholdExamples in policy show Cinryze/Haegarda age threshold commonly ≥6 years (varies by product).

Ruconest (rhC1‑INH) age thresholdPolicy lists Ruconest acute treatment for individuals aged ≥13 years.

Firazyr / Icatibant age thresholdIcatibant agents (Firazyr/Sajazir) approved for acute attacks in patients ≥18 years per table.

What Providers Must Do

Prior Authorization

Prior Authorization Required — Approval Length

Prior authorization is required for drugs listed in this policy. Initial authorizations may be approved for up to 12 months. Reauthorizations may be approved for up to 12 months when criteria continue to be met and the individual has shown clinical benefit (reduction in baseline frequency of attacks for long-term prophylaxis agents or reduction in duration/severity of attacks for acute treatment agents). Non-formulary exception reviews may also be approved up to 12 months.

Initial and reauthorization approvals: up to 12 months
Non-formulary exception authorizations: may be approved up to 12 months

Denial Risk

Site‑of‑Service Denial Risk

Site-of-service medical necessity criteria apply to medical-benefit reviews for IV and injectable drugs in this policy and may affect coverage decisions. Site-of-service rules do NOT apply to Alaska fully-insured members. Hospital outpatient settings may be considered medically necessary for the initial course (first 90 days) or when specific clinical or access conditions are met. Providers should verify benefit type (medical vs pharmacy) and the member's state-specific rules before scheduling a site of service.

Initial Therapy Eligibility and Preferences

Initial therapy eligibility — general eligibility

Initial therapy general eligibility

Age and diagnostic labs: Age thresholds vary by drug (see product‑specific criteria); documented labs showing low C4 and appropriate C1‑INH antigenic/functional levels per HAE type are required.age and labs per agent

Examples provided in product sections

Clinical features for initiation: Has two or more clinical features (recurrent angioedema without wheals/urticaria, recurrent abdominal attacks, positive family history, or failure to respond to antihistamines/glucocorticoids/epinephrine) and one qualifying condition (frequent attacks, pregnancy, or recent laryngeal attack) as described in policy.meets clinical and qualifying conditions

Initial therapy — product-specific roles and recommendations

Step Therapy Requirements

Requirement	Details
Prior trial required	If aged 18 years or older and not currently pregnant, must have tried and had an inadequate response or intolerance to generic icatibant when explicitly specified in an agent's criteria.
Applies to	Specified for certain acute and prophylactic agents (examples include Orladeyo and Haegarda where the policy states the adult, non‑pregnant trial requirement).

Sequencing preference	Notes
First‑line therapies	C1‑INH products, lanadelumab, and berotralstat are recommended as first‑line options for long‑term prophylaxis per WAO/EAACI guideline.
Second‑line therapy	Androgens are recommended as second‑line long‑term prophylaxis due to side effects and pregnancy contraindications.

Requirement	Details
Step requirement before brand icatibant	Trial of generic icatibant (or Sajazir when historically listed) is required prior to brand icatibant (Firazyr) for individuals aged 18 years or older who are not currently pregnant.
Role as qualifying acute treatment	Generic icatibant also serves as a qualifying acute treatment in criteria for multiple prophylactic agents; policy history updates clarify the age and pregnancy exception for this requirement.

Quantity and Dose Limits

Ruconest (rhC1-INH) quantity/dose reference

Quantity limitRuconest (rhC1‑INH) quantity limited to 30 capsules or packets per 30 days.

Daily dose limits (≥12 yrs)For individuals aged 12 years and older, dose limited to 150 mg per day.

Weight‑based pediatric dosing (2–11 yrs)12–<24 kg: 72 mg once daily; 24–<32 kg: 96 mg once daily; 32–<40 kg: 108 mg once daily; ≥40 kg: 132 mg once daily.

Ekterly (sebetralstat) quantity/dose limits

24‑hour maximumEkterly (sebetralstat) maximum 1,200 mg in any 24‑hour period (per attack).

30‑day limitEkterly maximum 2,400 mg per 30 days.

Site-of-Service Medical Necessity

Note

Applicable site-of-service settings

Site-of-service settings addressed by the policy include physician office, infusion center, home infusion, and hospital-based outpatient settings; site-of-service medical necessity review applies to medical benefit IV/injectable drugs and defines preferred and conditional hospital outpatient use.

Physician office
Infusion center
Home infusion
Hospital outpatient (conditional medical necessity)

Denial Risk

Hospital outpatient: not medically necessary if criteria unmet

Hospital-based outpatient settings are considered not medically necessary when the site-of-service criteria in this policy are not met; hospital outpatient care is only considered medically necessary under the specific conditions described (e.g., initial 90 days, no outpatient infusion center within 50 miles, high‑risk clinical conditions).

Note

Reauthorization and Continuation Criteria

Reauthorization criteria

Reauthorization

Clinical response: For prophylactic drugs, continued authorization requires the individual has shown and continues to show a reduction in baseline frequency of attacks; for acute drugs, continued authorization requires reduction in duration and/or severity of attacks compared with baseline.clinical improvement vs baseline

Approvals may be issued up to 12 months when criteria are met

Lanadelumab continuation — efficacy and safety summary supporting continuation

Lanadelumab continuation — efficacy and safety summary supporting continuation:

Lanadelumab efficacy: Randomized placebo‑controlled trials (HELP) demonstrated significant reductions in mean monthly attack rate for lanadelumab regimens versus placebo in individuals ≥12 years; the 300 mg SC every 2 weeks regimen had numerically better outcomes.

Background on Hereditary Angioedema

Hereditary angioedema (HAE) is an inherited disorder characterized by unpredictable, intermittent episodes of swelling, inflammation, and pain due to deficiency or dysfunction of C1 esterase inhibitor. Attacks most commonly involve the skin and gastrointestinal tract and can be life‑threatening when the larynx is involved. Pathophysiology is driven by contact‑system activation and excessive bradykinin generation rather than histamine‑mediated mechanisms, which explains why targeted HAE therapies (C1‑INH replacement, kallikrein inhibitors, bradykinin B2 receptor antagonists, and newer targeted agents) are the appropriate treatments.

Definitions and Pathophysiology

Low lab value definition

Definition of 'Low' lab value'Low' is defined as below the lower limit of normal as defined by the laboratory test (policy note).

Usage in diagnostic criteriaUsed to interpret complement C4 and C1‑INH antigenic/functional levels when establishing HAE type I or II.

Documentation requirementLaboratory reference ranges should be provided to confirm values below the lab's lower limit of normal.

HAE Type I / II definitions

Type I HAECharacterized by insufficient production of C1 esterase inhibitor; comprises approximately 80–85% of cases.

Type II HAECharacterized by normal or high production of functionally deficient C1 esterase inhibitor.

Policy Summary

PayerPremera Bluecross

PolicyHereditary Angioedema (HAE) drug therapy and site-of-service review

Policy CodePolicy N/A

Change TypeMaterial coverage and age/step updates

Effective DateJun 1, 2026

Next Review DateN/A

Key ActionSubmit prior authorization supporting medical records and requests may be approved for up to 12 months when criteria are met.

SourceLink

On This Page

lanadelumab dosing interval

Standard dosing intervalLanadelumab (Takhzyro) dosing noted as 300 mg subcutaneously every 2 weeks (300 mg SC Q2W).

Source evidenceDose/route and indication appear in the Preferred Existing Therapy table and HELP trial safety data supporting 300 mg SC Q2W.

Clinical contextPhase 3 HELP trial data referenced (up to 26 weeks) use 300 mg SC Q2W regimen for prophylaxis in ≥12 yr population.

Orladeyo maximum quantity

Maximum monthly quantityOrladeyo (berotralstat) quantity limited to 30 capsules or packets per 30 days (policy update effective 06/01/26).

Dose limits by ageDose is 150 mg once daily for individuals ≥12 years; weight‑based dosing applies for ages 2–11 years (policy clarification).

Policy changeMinimum covered age updated from ≥12 years to ≥2 years (03/01/26 history).

SOS review applies to IV/injectable medical-benefit drugs in this policy
SOS criteria do NOT apply to Alaska fully-insured members (Alaska HB 226)
Hospital outpatient setting may be medically necessary for first 90 days or when clinical/access conditions exist

Denial Risk

Potential Grounds for Denial

Authorizations may be denied or limited when required documentation or policy rules are not met. Common grounds for denial include missing required medical record documentation, exceeding dose/quantity limits, failure to follow step-therapy (generic icatibant) where specified, concomitant use of other targeted HAE therapies when not allowed, or noncompliance with site-of-service rules for medical-benefit administration.

Missing office visit notes or applicable laboratory results may result in denial
Dose/quantity exceeding policy limits (e.g., Orladeyo dose/quantity clarifications) may be denied
Failure to trial required generic icatibant (where specified for individuals ≥18 and not pregnant) may result in denial
Use of concomitant targeted HAE therapies for acute treatment is not permitted

Step Therapy

Required Prior Trial — Generic Icatibant

When specified in the coverage criteria, individuals aged 18 years or older who are not currently pregnant must have tried and had an inadequate response or intolerance to generic icatibant prior to coverage of certain agents (for example, Berinert, Firazyr, Kalbitor, and Ruconest per policy updates). Document the trial and response in the medical record.

Applies to individuals ≥18 years and not currently pregnant where the drug-specific coverage rule requires it
Required trial options include generic icatibant (or Sajazir where noted) prior to some agents

Step Therapy

Therapy Sequencing Guidance

Follow therapy sequencing recommended by guidelines and policy: use on-demand acute therapies (IV C1‑INH, ecallantide, or icatibant) for attacks; maintain sufficient medication for at least two attacks. For prophylaxis, prefer C1‑INH, lanadelumab, or berotralstat as first-line long-term prophylaxis. Androgens are second-line and have pregnancy and pediatric limitations. Ensure sequencing rules (including prior trials) in this policy are met before approving switches or additions.

Acute attack: IV C1‑INH, ecallantide, or icatibant recommended
Maintain on‑demand medication for at least two attacks and have it available at all times
Long‑term prophylaxis first-line: C1‑INH, lanadelumab, berotralstat; androgens second‑line with restrictions

Documentation Required

Required Documentation — Medical Records

Medical records submitted for prior authorization must document that the medical necessity criteria are met. At minimum include office visit notes with relevant history and physical and applicable laboratory testing results (e.g., C4, C1‑INH protein and functional levels, C1q where applicable). Missing documentation may delay or cause denial of the request.

Include office visit notes with relevant history and physical
Include applicable laboratory test results supporting HAE type and diagnosis (C4, C1‑INH antigenic and functional, C1q when indicated)
Documentation must show prior trials, responses, and rationale for therapy (including pregnancy status and age as applicable)

Initial therapy — product-specific roles and recommendations:

On‑demand treatment options: Intravenous C1‑INH, ecallantide, or icatibant are recommended for on‑demand treatment of acute HAE attacks; individuals should carry sufficient medication for at least two attacks.

Guideline-based

Prophylaxis options: First‑line prophylaxis options include C1‑INH products, lanadelumab, and berotralstat; product‑specific dosing and age indications are listed in the product sections of the policy.

See product tables for dosing and age

Preferred acute therapy updates (historical preference changes)

Preferred acute therapy updates (historical preference changes):

Preferred acute treatments (historical notes): Policy history documents removal of Sajazir (icatibant) from preferred acute treatments and retains step‑therapy requirements for generic icatibant in qualifying populations.

See history for dates and details

Ekterly indicated for treatment of acute attacks in individuals aged 12 years or older (when criteria met).

Orladeyo (berotralstat) maximum quantity (30)

Monthly maximum quantityOrladeyo (berotralstat) quantity limited to 30 capsules or packets per 30 days (policy clarification).

Standard adult dose150 mg orally once daily for individuals ≥12 years (dose limit noted).

Pediatric dosing noteWeight‑based dosing applies for ages 2–11 years per the policy update.

Infusion center SOS review limited to ≥13 years

Site-of-service medical necessity review for infusion centers is limited to individuals aged 13 years and older; pediatric considerations drive the age threshold for SOS review.

Billing Rule

SOS criteria may apply to infusion/injection drugs; statutory exceptions exist

Site-of-service medical necessity criteria may apply to infusion and injection drugs except where statutory exceptions exist (for example, Alaska fully‑insured members per Alaska HB 226); check policy history and local statutes for exceptions.

26‑week randomized trial evidence

Lanadelumab safety: In trials up to 26 weeks, no reported SAEs, deaths, or discontinuations due to adverse events; most common adverse events were injection‑site pain, erythema, and headache, generally mild to moderate.

Safety supports continuation in responders

Authorization duration for continuation therapy

Approval length: Initial and continuation authorizations for all drugs listed in the policy may be approved for up to 12 months when medical necessity criteria are met.

Applies across policy agents

Type III noteType III is rare (<1%) and involves normal production of functionally deficient C1 inhibitor; may be X‑linked.

Pathophysiology — bradykinin/contact system

Primary mediatorHAE attacks are primarily mediated through contact system activation and generation of bradykinin due to insufficient functional C1 esterase inhibitor.

C1‑INH roleC1 esterase inhibitor regulates complement, contact (intrinsic coagulation) and fibrinolytic systems and inhibits factor XIIa and kallikrein.

Therapeutic targetsCurrent therapies act by replacing C1‑INH, inhibiting kallikrein, or antagonizing bradykinin (B2 receptor).

lanadelumab 300 mg SC every 2 weeks (definition/reference)

Specific regimenLanadelumab 300 mg subcutaneously every 2 weeks (300 mg SC Q2W).

Context in tableListed as the prophylaxis dose/route in the Preferred Existing Therapy table (Takhzyro: 300 mg SC Q2W).

Supporting safety dataPhase 3 HELP study and phase 1b studies assessed safety at 300 mg SC Q2W (no SAEs, deaths, or discontinuations due to AEs reported).