CurrentAetnaPolicy 0782

Hereditary Angioedema

Defines Aetna's medical necessity, precertification, and coverage criteria for prophylactic and acute pharmacologic treatments for hereditary angioedema (HAE) for commercial medical plans and specifies site-of-care considerations for certain agents.

Policy Summary

PayerAetna

PolicyHereditary Angioedema

Policy CodePolicy 0782

Change TypeNo material change

Effective DateApr 10, 2009

Next Review DateJun 27, 2024

Key ActionPrecertification is required for hereditary angioedema agents; call (866) 752-7021 or fax (888) 267-3277 and use Specialty Pharmacy precertification/SMN forms.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

Multipledistinct agents with individual criteria

Requiredrequires precertification

50%continuation threshold example

20 IU/kgBerinert acute dose

2 yrsTakhzyro pediatric min age

Coverage Criteria for Hereditary Angioedema Therapies

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Cinryze — Initial Approval (prophylaxis)

Covered when EITHER of the following diagnostic pathways is met and prescribed by or in consultation with an HAE specialist, and not used in combination with other prophylactic HAE medications:

Diagnostic pathway A: Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing

AND one of: C1-INH antigenic level below laboratory lower limit OR normal antigenic level with C1-INH functional level <50% or below laboratory lower limit

Diagnostic pathway B: Member has normal C1 inhibitor as confirmed by laboratory testing

AND one of: pathogenic mutation in F12, angiopoietin-1, plasminogen, KNG1, HS3ST6, or MYOF confirmed by genetic testing OR documented family history and refractory to a trial of high‑dose antihistamine (eg, cetirizine 40 mg/day or equivalent) for ≥1 month

Cinryze — Continuation of Therapy (prophylaxis)

Covered when ALL of the following are met:

Continuation criteria: Member meets the criteria for initial approval; and member has experienced a significant reduction in frequency of attacks; and member has reduced use of medications to treat acute attacks since starting treatment; and medication is prescribed by or in consultation with a prescriber who specializes in the management of HAEsignificant reduction e.g., >= 50%

Haegarda — Initial Approval (prophylaxis)

Covered when EITHER of the following diagnostic pathways is met and prescribed by or in consultation with an HAE specialist, and not used in combination with other prophylactic HAE medications:

Diagnostic pathway A: Member has C1 inhibitor deficiency or dysfunction confirmed by laboratory testing

Same laboratory criteria as other prophylactic agents: C1-INH antigenic level below lab lower limit OR normal antigenic with functional C1-INH <50% or below lab lower limit

Diagnostic pathway B: Member has normal C1 inhibitor as confirmed by laboratory testing

Same genetic or family-history + antihistamine‑refractory criteria as Cinryze (F12, ANGPT1, plasminogen, KNG1, HS3ST6, MYOF mutation OR documented family history and refractory to ≥1 month high‑dose antihistamine)

Haegarda — Continuation of Therapy (prophylaxis)

Covered when ALL of the following are met:

Takhzyro — Initial Approval (prophylaxis)

Covered when EITHER of the following diagnostic pathways is met and prescribed by or in consultation with an HAE specialist, and not used in combination with other prophylactic HAE medications:

Diagnostic pathway A: Member has C1 inhibitor deficiency or dysfunction confirmed by laboratory testing

Same laboratory criteria as other prophylactic agents

Diagnostic pathway B: Member has normal C1 inhibitor as confirmed by laboratory testing

AND one of: pathogenic mutation in F12, angiopoietin-1, plasminogen, KNG1, HS3ST6, or MYOF confirmed by genetic testing OR documented family history and refractory to ≥1 month trial of high‑dose antihistamine (eg, cetirizine 40 mg/day or equivalent)

Takhzyro — Continuation of Therapy (prophylaxis)

Covered when ALL of the following are met:

Continuation criteria: Member meets the criteria for initial approval; member has experienced a significant reduction in frequency of attacks (e.g., >=50%); member has reduced use of medications to treat acute attacks since starting treatment; the requested drug is being dosed every 4 weeks or dosing every 4 weeks has been considered if the member is well‑controlled on therapy for more than 6 months; and medication is prescribed by or in consultation with a prescriber who specializes in the management of HAE

Berinert — Initial Approval (short-term preprocedural prophylaxis)

Covered for short-term preprocedural prophylaxis when prescribed by or in consultation with an HAE specialist and EITHER diagnostic pathway is met:

Diagnostic pathway A: Member has C1 inhibitor deficiency or dysfunction confirmed by laboratory testing

Same laboratory criteria as prophylactic agents

Diagnostic pathway B: Member has normal C1 inhibitor as confirmed by laboratory testing

AND one of: specified gene mutation confirmed by genetic testing OR documented family history and refractory to ≥1 month high‑dose antihistamine trial

Berinert — Initial Approval (acute attacks)

Covered for treatment of acute HAE attacks when prescribed by or in consultation with an HAE specialist, not used in combination with other acute agents, and EITHER diagnostic pathway is met:

Diagnostic pathway A: Member has C1 inhibitor deficiency or dysfunction confirmed by laboratory testing

Same laboratory criteria as above

Diagnostic pathway B: Member has normal C1 inhibitor as confirmed by laboratory testing

AND one of: pathogenic mutation in F12, angiopoietin-1, plasminogen, KNG1, HS3ST6, or MYOF OR documented family history and refractory to ≥1 month high‑dose antihistamine

Berinert — Continuation of Therapy (acute attacks)

Covered when ALL of the following are met:

Continuation criteria: Member meets the criteria for initial approval; member has experienced reduction in severity and/or duration of acute attacks; medication is prescribed by or in consultation with a prescriber who specializes in the management of HAE; and prophylaxis should be considered based on attack frequency/severity, comorbid conditions, and the member's quality of life

Kalbitor — Initial Approval (acute attacks)

Covered for treatment of acute HAE attacks when prescribed by or in consultation with an HAE specialist, not used in combination with other acute agents, and EITHER diagnostic pathway is met:

Diagnostic pathway A: Member has C1 inhibitor deficiency or dysfunction confirmed by laboratory testing

Same laboratory criteria

Diagnostic pathway B: Member has normal C1 inhibitor as confirmed by laboratory testing

AND one of: specified gene mutation confirmed by genetic testing OR documented family history and refractory to ≥1 month high‑dose antihistamine

Kalbitor — Continuation of Therapy (acute attacks)

Covered when ALL of the following are met:

Continuation criteria: Member meets the criteria for initial approval; member has experienced reduction in severity and/or duration of acute attacks; prophylaxis should be considered based on attack frequency/severity, comorbid conditions, and the member's quality of life; and medication is prescribed by or in consultation with a prescriber who specializes in the management of HAE

Ruconest — Initial Approval and Continuation (acute attacks)

Covered for treatment of acute HAE attacks when prescribed by or in consultation with an HAE specialist, not used in combination with other acute agents, and diagnostic criteria mirrored to other acute agents:

Diagnostic pathway A: Member has C1 inhibitor deficiency or dysfunction confirmed by laboratory testing

Diagnostic pathway B: Member has normal C1 inhibitor as confirmed by laboratory testing

AND one of: specified gene mutation confirmed by genetic testing OR documented family history and refractory to ≥1 month high‑dose antihistamine

Continuation: Member meets initial approval criteria; member has experienced reduction in severity and/or duration of acute attacks; prophylaxis should be considered based on attack frequency/severity, comorbid conditions, and the member's quality of life; and medication is prescribed by or in consultation with an HAE specialist

Icatibant — Initial Approval and Continuation (acute attacks)

Covered for treatment of acute HAE attacks when prescribed by or in consultation with an HAE specialist, not used in combination with other acute agents, and diagnostic criteria are met:

Diagnostic pathway A: Member has C1 inhibitor deficiency or dysfunction confirmed by laboratory testing

Diagnostic pathway B: Member has normal C1 inhibitor as confirmed by laboratory testing

AND one of: specified gene mutation confirmed by genetic testing OR documented family history and refractory to ≥1 month high‑dose antihistamine

Medication dosing and administration

Dosing and administration recommendations (per manufacturers) — implied coverage when clinical policy criteria are met

Takhzyro dosing: Adults and pediatrics ≥12 years: start 300 mg SC q2w; may consider 300 mg q4w if well‑controlled >6 months. Pediatrics 6–11 years: start 150 mg SC q2w; may consider 150 mg q4w if well‑controlled >6 months. Pediatrics 2–5 years: 150 mg SC q4w.age strata

SC administration; intended for healthcare provider but may be self‑administered by trained persons.

Berinert dosing: 20 IU/kg IV for acute HAE attacks; doses lower than 20 IU/kg should not be administered. Administer at room temperature within 8 hours of reconstitution; inject ≈4 mL/min.weight based

IV only; trained persons may self‑administer upon recognition of an HAE attack.

Kalbitor dosing: 30 mg SC given as three 10 mg injections; if attack persists an additional 30 mg may be given within 24 hours.

Experimental and investigational determinations

Aetna's experimental and investigational determinations (may lead to coverage denial for these uses)

Concomitant use of specified agents: Concomitant use of Cinryze, Haegarda, and/or Takhzyro is considered experimental and investigational for all indications because effectiveness of combination therapy has not been established.combination use

Supports denial risk for combination prophylactic therapy.

Cinryze off‑label indications: Cinryze is experimental and investigational for treatment of acute angioedema attacks and other non‑established indications (eg, cerebral ischemic injury, cytokine‑induced vascular leak syndrome, myocardial infarction, sepsis).off‑label

May be denied for these indications.

Berinert off‑label indications: Berinert is experimental and investigational for prophylaxis against angioedema attacks (except short‑term preprocedural prophylaxis when criteria met), for autoimmune cold agglutinin‑associated hemolytic anemia, and for combination use with Kalbitor, icatibant (Firazyr), or Ruconest.

Cinryze (C1-INH) prophylaxis

Covered when product-specific FDA indications and supporting clinical documentation are met

Cinryze routine prophylaxis: Cinryze is indicated for routine prophylaxis against angioedema attacks in patients 6 years of age and older with HAE; clinical trial inclusion typically required history of ≥2 HAE attacks per month and confirmed diagnosis.age >= 6 years; history of attacks (trial often used >=2 per month)

FDA approval and trial data support reduced attack rate and days of swelling

Haegarda (subcutaneous C1-INH) prophylaxis

Covered when product-specific FDA indications and supporting clinical documentation are met

Haegarda routine prophylaxis: Haegarda is indicated for routine prophylaxis to prevent HAE attacks in patients 6 years of age and older; it is not indicated for treatment of acute attacks and carries warnings for severe hypersensitivity to C1‑INH preparations.age >= 6 years

Subcutaneous route allows at‑home self‑injection after training; common adverse reactions include injection site reactions, hypersensitivity, nasopharyngitis and dizziness.

Takhzyro (lanadelumab) prophylaxis

Covered when product-specific FDA indications and supporting clinical documentation are met

Takhzyro prophylaxis: Takhzyro (lanadelumab‑flyo) is indicated for prophylaxis to prevent HAE attacks in patients 2 years of age and older; clinical trials in patients ≥12 years demonstrated significant reductions in monthly attack rates and a proportion of patients remaining attack‑free over 26 weeks.age >= 2 years (product label)

Dosing regimens include 300 mg q2w with higher attack‑free rates; common adverse reactions include injection site reactions and dizziness.

FDA indications and trial-based efficacy/safety summaries

Summaries of FDA-approved indications and key clinical trial findings for prophylactic and acute HAE treatments

Lanadelumab (Takhzyro) efficacy: HELP trial: lanadelumab significantly reduced monthly attack rates versus placebo (eg, 0.26 attacks/month with 300 mg q2wks) and increased proportion of attack‑free patients over 26 weeks; common AEs included injection site reactions and dizziness.study endpoints

FDA label expanded to include pediatric patients ≥2 years based on HELP and SPRING data.

Berinert (C1 esterase inhibitor, human): Berinert is indicated for treatment of acute abdominal, facial, or laryngeal HAE attacks in adult and pediatric patients; 20 IU/kg shortened time to onset of symptom relief versus placebo in RCTs.dosing per label (20 IU/kg)

Self‑administration permitted with training; safety warnings include hypersensitivity and thromboembolic events.

Icatibant (Firazyr):

Evidence supporting acute HAE therapies

Clinical evidence supporting acute use:

Kalbitor efficacy: EDEMA3 and EDEMA4 randomized, double‑blind, placebo‑controlled trials: 30‑mg SC Kalbitor produced statistically significant improvement in TOS and MSCS at 4 and 24 hours versus placebo; fewer Kalbitor‑treated patients required medical intervention within 24 hours. Some patients received a second 30‑mg dose within 24 hours for persistent symptoms.TOS > 0 indicates improvement

Kalbitor carries anaphylaxis risk; administer in setting with anaphylaxis management available.

Ecallantide early‑phase data: Phase II ascending‑dose IV ecallantide improved symptoms within 4 hours compared with placebo (72.5% vs 25.0% reporting significant improvement).

Supports role of kallikrein inhibition in HAE pathophysiology.

Ruconest efficacy and safety: Ruconest was approved based on a multicenter controlled trial in 44 patients for acute attacks; common adverse reactions included headache, nausea, and diarrhea. IgE testing to rabbit epithelium is required prior to first exposure in naïve patients.

Aetna covers hereditary angioedema (HAE) agents only for the specific prophylactic, short‑term preprocedural prophylaxis, and acute‑attack indications described in this policy. All other indications not expressly listed are considered experimental and investigational and are subject to denial. Providers must document that requested use aligns with the diagnostic, prescriber specialty, and usage criteria in this policy (e.g., specialist prescribing or consultation) before coverage will be approved.

Certain ICD‑10 diagnoses are explicitly noted as not covered when used to support HAE therapy requests in this policy. Examples called out in the coding section include A41.9 (sepsis, unspecified) and a range of cerebrovascular and myocardial infarction codes (e.g., transient ischemic attack and stroke codes G45.x; I21.x–I22.x). These ICD‑10 examples are not an all‑inclusive list but illustrate non‑covered acute systemic or vascular indications outside the approved HAE uses.

Human C1‑INH products and other HAE agents should not be used in patients with a reported hypersensitivity to the product or any component. Haegarda carries a labelled warning for severe hypersensitivity and is contraindicated in individuals with prior life‑threatening hypersensitivity to C1‑INH. Plasma‑derived products (e.g., Berinert, Haegarda) also carry theoretical infectious‑agent transmission risks and have specific labeled warnings regarding thromboembolic events.

Berinert is not established for routine long‑term prophylaxis. Aetna considers Berinert experimental and investigational for prophylactic use except for short‑term preprocedural prophylaxis when the policy’s specific criteria for that indication are met.

Ruconest is approved for treatment of acute HAE attacks, but the label includes a limitation of use: effectiveness has not been established for HAE patients with laryngeal attacks. This limitation should be considered when selecting acute‑attack therapy and documenting treatment rationale.

Per Aetna brand‑selection guidance, use of the higher‑cost product Berinert for acute HAE attacks is considered medically necessary only after a one‑month trial of the lower‑cost equivalent Ruconest unless there is documented contraindication, intolerance, or ineffective response to Ruconest.

Concomitant use of multiple prophylactic agents (e.g., Cinryze, Haegarda, Takhzyro) or combinations of acute agents is considered experimental and investigational. Aetna may deny requests for uses or combinations that the policy specifically lists as investigational because effectiveness for those uses has not been established.

For HAE with normal C1‑INH (formerly HAE type III), there are no randomized controlled trials establishing efficacy of the available therapies. Evidence is limited to case reports and small series, and treatment recommendations cannot be firmly established; therefore use of HAE agents in this population should be considered with caution and may be unsupported by high‑quality trial data.

Coding and Dosing References

HCPCS/CPT/ICD codes referencedmixed

86160	Complement; antigen, each component [C4 level]
96365-96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96374-96376	Therapeutic, prophylactic, or diagnostic injection; intravenous push
96372	Therapeutic, prophylactic, or diagnostic injection; subcutaneous or intramuscular
96379	Unlisted therapeutic, prophylactic, or diagnostic IV or intra-arterial injection or infusion
J0598	Injection, C1 esterase inhibitor (human) cinryze, 10 units
J0599	Injection, C-1 esterase inhibitor (human), (haegarda), 10 units
J0593	Injection, lanadelumab-flyo, 1 mg
J0597	Injection, C-1 esterase inhibitor (human), berinert, 10 units
J0596	Injection, c1 esterase inhibitor (recombinant), ruconest, 10 units

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Significant reduction in attack frequency

DefinitionSignificant reduction in attack frequency is exemplified as 50% or more reduction in frequency of HAE attacks since starting treatment.

Use in continuation criteriaRequired as part of continuation of prophylactic therapies (Cinryze, Haegarda, Takhzyro) — member must have experienced this reduction since starting treatment.

DocumentationProviders should document baseline and on-treatment attack frequency to demonstrate the ≥50% reduction (or equivalent significant reduction).

Cinryze pediatric/adult dosing cap

Maximum per-weight capCinryze dosing may be increased up to 2,000 IU every 3 or 4 days but should not exceed 80 IU/kg.

Routine adult dosingStandard routine prophylaxis dose in adults and adolescents (≥12 years) is 1,000 IU IV every 3 or 4 days; doses up to 2,000 IU may be considered based on response.

Pediatric dosing (6–11 years)Pediatric routine prophylaxis dose is 500 IU IV every 3 or 4 days; may be adjusted up to 1,000 IU every 3 to 4 days based on individual response.

Berinert dosing

Recommended dose (acute attacks)Berinert recommended dose is 20 IU/kg IV for treatment of acute HAE attacks; doses lower than 20 IU/kg should not be administered.

Administration detailsAdminister at room temperature within 8 hours of reconstitution; inject at approximately 4 mL per minute; IV only; trained persons may self‑administer upon recognition of an HAE attack.

Continuation documentationFor continuation, document reduction in severity/duration of attacks and timing of dose relative to attack onset and patient weight for units/kg dosing.

Weight‑based dosing

Berinert weight-based doseBerinert: 20 IU/kg IV (doses lower than 20 IU/kg should not be administered).

Ruconest weight-based doseRuconest: 50 U/kg IV with a maximum of 4200 U per dose; if symptoms persist a second dose may be given (no more than two doses in 24 hours).

Documentation requiredProviders should document patient weight when weight‑based dosing applies and verify adherence to maximum per‑dose limits.

Provider Actions, Prior Authorization, and Safety Requirements

Prior Authorization

Precertification Required

Precertification of hereditary angioedema (HAE) agents is required for all Aetna participating providers and members in applicable plan designs. For precertification of HAE agents, call (866) 752-7021 or fax (888) 267-3277. Statement of Medical Necessity (SMN) precertification forms are available via Aetna Specialty Pharmacy Precertification resources. Failure to obtain required precertification may result in denial of the request.

Precertification contact: (866) 752-7021; fax (888) 267-3277
SMN precertification forms: Specialty Pharmacy Precertification

Denial Risk

Brand Selection and Step to Lower-Cost Alternative Before Berinert

Berinert is a more costly acute HAE agent compared with alternatives (e.g., Ruconest). Per Aetna brand-selection policy, Berinert is considered medically necessary for acute attacks only when the member has a documented contraindication, intolerance, or ineffective response to the available equivalent lower-cost alternative (one-month trial): Ruconest. Requests for Berinert should include documentation supporting that Ruconest was tried and failed, was not tolerated, or is contraindicated.

Berinert considered medically necessary only after contraindication/intolerance/ineffective response to Ruconest (one-month trial)
Document trial dates, dosing, response, and reason Ruconest not appropriate

Documentation Required

Documentation of Dosing, Route, and Patient Weight

Providers must document key clinical and dosing information with any request: the specific product requested (brand), indication, dosing (dose and dose per kg when applicable), route of administration, frequency, and the patient’s weight (for weight-based dosing). For Berinert and Ruconest, include the calculated IU dose based on patient weight and any prior doses given.

Document patient weight and show dose calculation (e.g., Berinert 20 IU/kg; Ruconest 50 U/kg, max 4200 U)
Specify route (IV vs SC), dosing frequency, and actual administered dose(s) with dates

Documentation Required

Prescriber Specialty Documentation Requirement

Prescriber specialty: prophylactic C1-INH agents (e.g., Cinryze, Haegarda) should be prescribed by or in consultation with a clinician who specializes in the management of HAE. Include specialty and consultation notes as applicable.

Prescriber specialty or consult note required for prophylactic C1-INH requests
Site-of-care utilization management may apply to certain products (e.g., Cinryze)

Prior Authorization

Requests for the More Costly Agent Berinert

For Berinert requests, include clinical documentation of the acute attack severity, prior treatments used during the attack (and response), and any rescue medication administered. For prophylactic or acute use, document contraindications or intolerance to lower-cost alternatives when claiming medical necessity for a more costly agent.

Attack severity, timing, and treatment response (including rescue medications)
If requesting Berinert without prior Ruconest trial, document contraindication/intolerance/clinical rationale

Documentation Required

IgE Testing Prior to Ruconest

Before initiating Ruconest in patients who have not previously received it, providers should document IgE testing for rabbit epithelium (dander) to assess for potential hypersensitivity. Only patients with negative IgE testing should be treated with Ruconest. Repeat IgE testing annually or after every 10 treatments, whichever comes first.

IgE antibody testing to rabbit epithelium required prior to first Ruconest dose
Repeat testing: once a year or after 10 treatments, whichever occurs first

Denial Risk

Concomitant Prophylactic Agent Use Is Experimental/Investigational

Concomitant use of multiple prophylactic HAE agents (e.g., Cinryze, Haegarda, Takhzyro) is considered experimental and investigational; such combinations are not supported by established evidence. Requests proposing combination prophylactic therapy should include rationale and supporting evidence but may be denied as investigational.

Concomitant use of Cinryze, Haegarda, and/or Takhzyro considered experimental/investigational
Provide evidence if combination therapy is being requested; expect higher denial risk

Documentation Required

Kalbitor Administration Setting and Age Requirements

Kalbitor (ecallantide) carries a boxed warning for anaphylaxis and must be administered by a healthcare professional in a setting equipped to manage anaphylaxis. Document the administration setting and that appropriate medical support is available when requesting Kalbitor.

Kalbitor administration must occur where anaphylaxis can be managed; document setting and clinician availability
Age restriction: Kalbitor indicated for patients 12 years and older

Note

Therapeutic Sequencing and Rationale for Prophylaxis

For prophylactic HAE therapies (Cinryze, Haegarda, Takhzyro), document prior therapy history (including androgens and antifibrinolytics), frequency and severity of attacks, and rationale for selecting prophylaxis over on-demand therapy. Note that therapeutic sequencing (androgens vs C1-INH products) and selection should be justified in the medical record.

Document prior androgen or antifibrinolytic use and reasons for discontinuation or intolerance
Provide attack frequency, prior ED visits/hospitalizations, laryngeal history, and quality-of-life impact to support prophylaxis

Background on Hereditary Angioedema

Background: Hereditary angioedema (HAE) is a rare, potentially life‑threatening genetic disorder caused by deficiency or dysfunction of C1 esterase inhibitor (C1‑INH) that results in recurrent, non‑urticarial angioedema episodes mediated primarily by bradykinin. Type I HAE (approximately 85% of cases) is characterized by low levels of C1‑INH, and Type II by dysfunctional C1‑INH. Management includes on‑demand treatment of acute attacks, short‑term preprocedural prophylaxis, and long‑term prophylaxis. Approved therapeutic classes include C1‑INH replacement (plasma‑derived and recombinant), plasma kallikrein inhibitors (e.g., lanadelumab), and bradykinin B2 receptor antagonists (e.g., icatibant).

Definitions and Diagnostic Criteria

C1-INH deficiency or dysfunction

DefinitionC1‑INH deficiency or dysfunction is established by laboratory testing showing C1‑INH antigenic level below the laboratory lower limit of normal or normal antigenic level with low functional C1‑INH (functional level <50% or below lab lower limit).

Supporting lab findingsMost patients also have decreased serum complement protein C4 levels; confirmatory testing should be done on two separate determinations ≥1 month apart when applicable.

Clinical contextC1‑INH deficiency/dysfunction underlies HAE types I and II and leads to bradykinin‑mediated angioedema requiring targeted therapies (C1‑INH replacement, kallikrein inhibitors, or bradykinin receptor antagonists).

Genetic-confirmed HAE with normal C1-INH

DefinitionGenetic‑confirmed HAE with normal C1‑INH is established by presence of a pathogenic mutation (eg, F12, angiopoietin‑1/ANGPT1, plasminogen, KNG1, HS3ST6, or MYOF) on genetic testing or documented family history with angioedema refractory to a one‑month trial of high‑dose antihistamine therapy.

Clinical criteriaThese patients have normal or near‑normal C1‑INH antigen and function and often normal C4; diagnosis requires lack of response to high‑dose antihistamines and either mutation or positive family history.

Consensus noteHAE with normal C1‑INH is classified by associated genetic mutations or remains of unknown mutation; bradykinin signaling is implicated in pathophysiology.

Hereditary angioedema (HAE) definition

DefinitionHereditary angioedema (HAE) is a rare, autosomal dominant genetic disorder caused by deficiency or dysfunction of C1 esterase inhibitor leading to recurrent non‑urticarial bradykinin‑mediated angioedema attacks involving the abdomen, extremities, face, larynx, and other sites.

EpidemiologyEstimated prevalence is about 1 in 50,000 individuals; attacks are unpredictable and may cause substantial morbidity and occasional mortality due to laryngeal edema.

TypesIncludes Type I (low levels and function; ~85% of cases) and Type II (dysfunctional C1‑INH with normal/elevated levels; ~15% of cases).

Diagnostic requirement for C1‑INH disorders

Diagnostic requirementDiagnosis of C1‑INH disorders requires one clinical criterion (eg, recurrent laryngeal edema, recurrent non‑inflammatory subcutaneous angioedema lasting >12 hours, or recurrent self‑remitting abdominal pain lasting >6 hours) and one laboratory criterion (eg, decreased C4 and decreased level or function of C1‑INH).

Testing timingLaboratory criteria stipulate C1‑INH antigenic or functional levels <50% on two separate determinations at least 1 month apart (after first year of life); a pathogenic C1‑INH gene mutation can be used in infants <1 year.

Family historyA family history of recurrent angioedema supports the diagnosis but is not required, as new mutations or acquired forms can occur.

Clinical criteria for HAE

Clinical criteria listClinical criteria for HAE include: recurrent laryngeal edema; self‑limiting non‑inflammatory subcutaneous angioedema without urticaria lasting >12 hours; and recurrent self‑remitting abdominal pain without clear organic etiology lasting >6 hours.

Role of family historyA family history of recurrent angioedema, abdominal pain, or laryngeal edema supports diagnosis though not required.

Symptom courseAttacks are often unpredictable, last 2–5 days when untreated, and can cause 20–100 days of incapacitation per year in affected individuals.

Laboratory criteria for HAE

Laboratory criteria summaryLaboratory criteria: C1‑INH antigenic level <50% on two determinations ≥1 month apart (after first year of life), or C1‑INH functional level <50% on two determinations ≥1 month apart, or a pathogenic C1‑INH gene mutation (used in <1 year).

Complement testingMost cases have decreased serum complement protein C4 levels; diagnosis is confirmed by decreased C4 plus low/absent C1‑INH level or function.

Thresholds importanceThe criteria require levels below 50% — many Type I patients have levels <30% — and testing should be performed in the basal state.

HAE with normal C1-INH

DefinitionHAE with normal C1‑INH is a subtype characterized by recurrent angioedema without urticaria, with normal or near‑normal C4 and C1‑INH antigen and function, lack of response to high‑dose antihistamines, and either a known mutation (factor XII, angiopoietin‑1/ANGPT1, plasminogen, KNG1) or a family history.

Genetic associationsAssociated mutations include factor XII, angiopoietin‑1, plasminogen, and kininogen‑1; many patients remain in an unknown‑mutation category.

Diagnostic caveatConsensus criteria emphasize documented lack of response to high‑dose antihistamines (eg, second‑generation antihistamines given 4 times/day) as part of diagnosis.

HAE type 1 and type 2

Type I vs Type IIHAE Type I: low levels and reduced function of C1‑INH (accounts for ~85% of cases). Type II: dysfunctional C1‑INH with normal or elevated antigenic levels but reduced function (accounts for ~15% of cases).

PathophysiologyBoth types lead to bradykinin overproduction and increased vascular permeability resulting in angioedema; diagnosis is by decreased C4 and decreased level or function of C1‑INH.

Clinical indistinguishabilityType I and Type II are clinically indistinguishable but stem from different mutations affecting C1‑INH quantity versus function.

Icatibant definition

Mechanism and classIcatibant is a selective bradykinin B2 receptor antagonist used for treatment of acute HAE attacks in adults.

IndicationFDA‑approved for treatment of acute attacks of HAE in adults 18 years and older.

Safety noteCarries a warning for laryngeal attacks — patients treated for laryngeal attacks should seek immediate medical attention; injection site reactions were very common in trials.

Ecallantide (Kalbitor) definition

Mechanism and classEcallantide (Kalbitor) is a plasma kallikrein inhibitor indicated for treatment of acute HAE attacks in patients 12 years of age and older.

Boxed warningKalbitor carries a black box warning for risk of anaphylaxis and should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis.

Dose used in trialsClinical trials used a 30‑mg subcutaneous dose (administered as three 10‑mg injections).

Ruconest definition

Mechanism and originRuconest is a recombinant C1‑esterase inhibitor produced from transgenic rabbit milk that restores functional C1‑INH activity to treat acute HAE attacks.

Indication and limitationFDA‑approved for treatment of acute HAE attacks in adults and adolescents; limitation of use states effectiveness was not established for laryngeal attacks.

Administration and dosingRecommended dose is 50 U/kg IV (maximum 4200 U) administered as a slow IV injection; if symptoms persist a second dose may be given (no more than two doses in 24 hours).

Ecallantide (Kalbitor) trial dosing summary

Trial dosing summaryEcallantide (Kalbitor) was studied in randomized trials (EDEMA3 and EDEMA4) using a 30‑mg subcutaneous dose given as three 10‑mg injections; some patients received an additional 30‑mg dose within 24 hours for persistent symptoms.

Setting and monitoringBecause of anaphylaxis risk observed in trials (including ~4% anaphylaxis), Kalbitor must be administered by a healthcare professional with resources to manage anaphylaxis and monitoring documented.

Efficacy endpointsTrials demonstrated statistically significant improvement in symptom scores (TOS and MSCS) at 4 and 24 hours versus placebo and fewer patients required further medical intervention within 24 hours.

Policy Revision History

2009-04-10policy_effective

Policy effective date established for hereditary angioedema clinical policy bulletin number 0782.

2014-07-17FDA_approval_Ruconest

FDA approved Ruconest (recombinant C1 esterase inhibitor) for treatment of acute HAE attacks in adults and adolescents; policy references this approval and associated safety/testing recommendations.

2016-07-18FDA_label_expansion_Berinert_pediatric

FDA approved Berinert for pediatric patients (under 12 years) for treatment of HAE attacks; policy cites this pediatric approval and related safety information.

2017-06-27FDA_approval_Haegarda

FDA approved Haegarda for prevention of HAE attacks in patients 6 years of age and older; policy incorporates the product indication and precautions.

2018-08-23FDA_approval_Takhzyro_initial

FDA approved Takhzyro (lanadelumab-flyo) for prophylaxis to prevent HAE attacks in patients 12 years and older; policy includes trial efficacy data and prophylaxis criteria.

2018-06-10Cinryze_pediatric_approval_revision

Cinryze received supplemental FDA approval to include children 6 years and older for routine prophylaxis; policy reflects this approval and dosing considerations.

2023-02-03FDA_label_expansion_Takhzyro_pediatrics

FDA expanded Takhzyro label to include prophylaxis in pediatric patients 2 years and older; policy notes the February 2023 label expansion and corresponding prior authorization implications.

2023-09-11policy_reviewLatest

Clinical policy bulletin 0782 was last reviewed on 2023-09-11; effective date remains 2009-04-10 and next review was scheduled for 2024-06-27.

Policy Summary

PayerAetna

PolicyHereditary Angioedema

Policy CodePolicy 0782

Change TypeNo material change

Effective DateApr 10, 2009

Next Review DateJun 27, 2024

Key ActionPrecertification is required for hereditary angioedema agents; call (866) 752-7021 or fax (888) 267-3277 and use Specialty Pharmacy precertification/SMN forms.

SourceLink

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Administer only by a healthcare professional with capability to manage anaphylaxis and HAE.

Ruconest dosing: 50 U/kg IV (max 4200 U) as slow IV injection over ≈5 minutes; if symptoms persist a second dose at the recommended level may be given; do not exceed 4200 U per dose and no more than two doses in 24 hours.weight and max dose

IV only; trained persons may self‑administer upon recognition of an HAE attack.

Icatibant dosing: 30 mg SC in abdominal area; additional doses may be given at ≥6‑hour intervals if needed; maximum 3 doses in 24 hours.per 24 hours

May be self‑administered by trained persons.

May be denied for these indications.

Kalbitor off‑label indications: Kalbitor is experimental and investigational for other indications (eg, reduction of blood loss during surgery) and for combination use with Berinert, icatibant, or Ruconest.off‑label

May be denied for these indications.

Ruconest off‑label indications: Ruconest is experimental and investigational for use in combination with Berinert, Kalbitor, or icatibant and for other non‑established indications.off‑label

May be denied for these indications.

Icatibant off‑label indications: Icatibant is experimental and investigational for prophylaxis against angioedema attacks and other non‑established indications (eg, acute pancreatitis, airways disease, thermal injury, refractory ascites) and for combination use with Berinert, Kalbitor, or Ruconest.off‑label

May be denied for these indications.

Icatibant is a bradykinin B2 receptor antagonist indicated for acute HAE attacks in adults; trials showed faster symptom relief versus placebo with a 30‑mg SC dose; injection site reactions are common.

Patients treated for laryngeal attacks should seek immediate medical attention after treatment.

Ecallantide (Kalbitor): Ecallantide is a plasma kallikrein inhibitor indicated for acute HAE attacks in patients ≥12 years; randomized trials (EDEMA3/4) showed improvements in TOS and MSCS at 4 and 24 hours versus placebo.30 mg SC dose

Carries a boxed warning for anaphylaxis; must be administered where anaphylaxis can be managed.

Limitation of use: effectiveness not established for laryngeal attacks; repeat IgE testing annually or after 10 treatments.