Hereditary angioedema (HAE) is a disorder characterized by recurrent episodes of non-allergic, severe swelling (angioedema) in the absence of urticaria or hives. Individuals experience swelling episodes that resolve within 2 to 5 days without treatment; however laryngeal swelling can be fatal. The most common areas of the body to develop swelling are the limbs, face, intestinal tract, and airway. Minor trauma or stress may trigger an attack, but swelling often occurs without a known trigger. Episodes involving the intestinal tract cause severe abdominal pain, nausea, and vomiting. Swelling in the airway can restrict breathing and lead to life-threatening obstruction of the airway.

Bradykinin is a vasodilator that results in the swelling that is associated with angioedema. Since the angioedema is non-allergic, histamines are not involved and antihistamines are not effective. HAE can also occur because of a deficiency (missing or low levels of the protein C1 esterase inhibitor [C1-INH]) or malfunction of the C1 inhibitor in the body which regulates the coagulation pathway. Lack of adequate amounts of C1-INH impacts vascular permeability, causing fluid leakage in blood vessels and capillaries.

There are three types of hereditary angioedema: type I (low C1-INH levels), accounting for roughly 85% of cases; type II (poorly functioning C1-INH levels), accounting for roughly 15% of cases; and type III (normal functioning C1-INH), considered to be very rare, occurring predominantly in women. The different types have similar signs and symptoms, but are distinguished based on the underlying causes and levels of C1-INH protein. Treatment options consist of on-demand therapy for acute HAE attacks in order to reduce the severity and duration of attacks and ongoing preventive or prophylactic therapy to prevent attacks in individuals who experience frequent or severe attacks, with dramatic lifestyle impairment. Treatment options consist of various mechanisms of action, including C1 esterase inhibitors, plasma kallikrein inhibitors and bradykinin B2 receptor antagonists.

Prophylaxis Therapy

HAE Type I and II

C1 Esterase Inhibitor [Human] (Cinryze® or Haegarda®) or lanadelumab-flyo (Takhzyro™) may be considered medically necessary when ALL of the following criteria are met:

• The individual meets the following age requirements:
  • C1 Esterase Inhibitor [Human] (Cinryzeor Haegarda): greater than or equal to six (6) years of age; or
  • Lanadelumab (Takhzyro): greater than or equal to two (2) years of age; or
• Administration is for routine prophylaxis against hereditary angioedema (HAE) attacks; and  
• The individual must have a diagnosis of HAE where diagnosis is based on evidence of a low C4 level and ONE of the laboratory tests listed in Table 1*; and

• History of severe attack(s) with swelling of hands, feet, limbs, face, intestinal tract or airway; and
• Medication is prescribed by either an immunologist, allergist or rheumatologist; and
• Medications known to cause angioedema (i.e. ACE inhibitors, estrogens, angiotensin II receptor blockers) have been evaluated and discontinued when appropriate ;and
• For C1 Esterase Inhibitor [Human] (Haegarda) ONLY: documentation of individual’s weight; and
• No dual therapy with other medications for the prevention of HAE attacks; and
• Initial authorization will be for a period of 12 months

The use of C1 Esterase Inhibitor [Human] (Cinryze, Haegarda) or lanadelumab (Takhzyro) for all other indications is considered not medically necessary.

HAE Type III

C1 esterase inhibitor [human] (Cinryze or Haegarda) or lanadelumab (Takhzyro) may be considered medically necessary when ALL of the following criteria are met:

• The individual meets the following age requirements:
  • C1 esterase inhibitor [Human] (Cinryze or Haegarda): greater than or equal to six (6) years of age; or
  • Lanadelumab (Takhzyro): greater than or equal to two (2) years of age; and
• Documented normal* or near normal C4, C1INH antigen, and C1INH function; and ONE of the following:
  • Demonstration of a F12 mutation that is associated with the disease; or
  • A positive family history of angioedema; and
• History of severe attack(s)  in the absence of concomitant hives with swelling of hands, feet, limbs, face, intestinal tract or airway; and
• Medication is prescribed by either an immunologist, allergist or rheumatologist; and
• Medications known to cause angioedema (i.e. ACE inhibitors, estrogens, angiotensin II receptor blockers) have been evaluated and discontinued when appropriate; and
• Trial and failure of second generation antihistamines (e.g. cetirizine, desloratadine, fexofenadine, levocetirizine, or loratadine);and
• For C1 Esterase Inhibitor [Human] (Haegarda) ONLY: documentation of individual’s weight; and
• No dual therapy with other medications for the prevention of HAE attacks; and
• Initial autorization will be for a period of 12 months

*Values defined by the laboratory performing the test.

The use of C1 Esterase Inhibitor [Human] (Cinryze or Haegarda) or lanadelumab (Takhzyro) for all other indications is considered not medically necessary.

Acute Attacks

HAE Type I and II

Icatibant (Firazyr®), ecallantide (Kalbitor®), C-1 esterase inhibitor [human] (Berinert®) or C1 esterase inhibitor [recombinant] (Ruconest®) may be considered medically necessary for the treatment of acute angioedema attacks when the following criteria are met: 

• The individual meets the following age requirement:
  • Icatibant (Firazyr): greater than or equal to 18 years of age; or
  • Ecallantide (Kalbitor): greater than or equal to 12 years of age; or
  • C-1 esterase inhibitor [human] (Berinert): greater than or equal to five (5) years of age; or  
  • C1 esterase inhibitor [recombinant] (Ruconest): greater than 13 years of age; and
• The individual must have a diagnosis of HAE where diagnosis is based on evidence of a low C4 level and ONE of the laboratory tests listed in Table 1*; and

• The individual must be experiencing at least one (1) symptom of the moderate or severe attack (e.g., airway swelling, severe abdominal pain, facial swelling, nausea and vomiting, painful facial distortion); and
• Medication is prescribed by either an immunologist, allergist or rheumatologist; and
• Medications known to cause angioedema (i.e. ACE inhibitors, estrogens, angiotensin II receptor blockers) have been evaluated and discontinued when appropriate; and
• Individual not self-administering two acute medications on the same day; and
• For C-1 esterase inhibitor [human] (Berinert) or C1 esterase inhibitor [recombinant] (Ruconest) ONLY: documentation of individual’s weight; and
• Not used in combination with other approved treatments for acute HAE attacks (e.g. C-1 esterase inhibitor [human] (Berinert), icatibant (Firazyr), ecallantide (Kalbitor) or C1 esterase inhibitor [recombinant] (Ruconest); and
• Initial authoization will be for a periord of 12 months.

The use of Icatibant (Firazyr), ecallantide (Kalbitor), C-1 esterase inhibitor [human] (Berinert) or C1 esterase inhibitor [recombinant] (Ruconest) for all other indications is considered not medically necessary.

HAE Type III

Icatibant (Firazyr), Ecallantide (Kalbitor), C-1 esterase inhibitor [human] (Berinert), or C1 esterase inhibitor [recombinant] (Ruconest) may be considered medically necessary in an individual who experiences attacks associated with HAE when the following criteria are met:

• The individual meets the following age requirements:
  • Icatibant (Firazyr): greater than or equal to 18 years of age; or
  • Ecallantide (Kalbitor): or greater than or equal to12 years of age; or
  • C-1 esterase inhibitor [human] (Berinert): greater than or equal to five (5) years of age; or
  • C1 esterase inhibitor [recombinant] (Ruconest): greater than 13 years of age; and
• Documented normal or near normal C4, C1INH antigen, and C1INH function; and ONE of the following:
  • Demonstration of a F12 mutation that is associated with the disease; or
  • A positive family history of angioedema; and
• History of severe attack(s) in the absences of concomitant hives with swelling of hands, feet, limbs, face, intestinal tract or airway; and
• Medication is prescribed by either an immunologist, allergist or rheumatologist; and
• Medications known to cause angioedema (i.e. ACE inhibitors, estrogens, angiotensin II receptor blockers) have been evaluated and discontinued when appropriate; and
• Trial and failure of second generation antihistamines (e.g. cetirizine, desloratadine, fexofenadine, levocetirizine, or loratadine); and
• For C-1 esterase inhibitor [human] (Berinert) or C1 esterase inhibitor [recombinant] (Ruconest) ONLY: documentation of individual’s weight; and
• Not used in combination with other approved treatments for acute HAE attacks (e.g. C-1 Esterase Inhibitor [Human] (Berinert), icatibant (Firazyr), ecallantide (Kalbitor) or C1 esterase inhibitor [recombinant] (Ruconest).

According to an International Consensus Statement on Hereditary Angioedema testing must be performed more than once to confirm the diagnosis.

The use of icatibant (Firazyr), ecallantide (Kalbitor), C-1 esterase inhibitor [Human] (Berinert) or C1 esterase inhibitor [recombinant] (Ruconest) for all other indications is considered not medically necessary.

Reauthorization Criteria

Continuation of therapy may be considered medically necessary treatment of HAE (Berinert, Cinryze, Firazyr, Kalbitor, Ruconest, Takhzyro) when ALL the following criteria are met:

• Individual meets criteria for initial approval for the specified therapy; and
• Prescriber attestation that the individual has experienced positive clinical response from therapy (i.e decrease in frequency of HAE attacks from baseline, decrease in severity or duration of HAE attacks); and
• For Takhzyro, the prescriber has assessed clinical appropriateness for dose de-escalation to 4-week intervals if individual is attack free for more than six (6) months; and
• Reauthorization will be for a period of 12 months

C-1 esterase inhibitor [human] (Berinert, Cinryze) and C-1 esterase inhibitor [recombinant] (Ruconest) may be considered medically necessary in individuals 18 years of age and older when applicable clinical criteria for individual medication policies are met and when administered in a physician’s office not affiliated with a hospital, specialized infusion centers not affiliated with a hospital or in the home.

Outpatient facility (Outpatient Hospital IV Infusion Department or Hospital-based Outpatient Clinical Level of Care) administration may be considered medically necessary if ANY of the following criteria are present to indicate the member is medically unstable for infusions in other than an outpatient facility setting:

• Member’s home is considered unsuitable for care by the home infusion provider; or
• Individual’s medical status requires enhanced monitoring beyond that which would routinely be needed for infusion therapy; or
• Previous severe adverse reaction (including but not limited to anaphylaxis, seizure, thromboembolism, myocardial infarction, renal failure) during or following administration of prescribed medication despite standard pre-medication; or
• Individual is receiving other medications that require close monitoring with a higher level of care (e.g., cytotoxic chemotherapy or blood products); or
• Individual is at high risk for complications due to medication administration (e.g., at risk for post-transplant complications, increased risk of infusion reactions due to presence of circulating antibodies, unstable vascular access, cardiopulmonary condition at risk for severe adverse reactions, unstable renal function with inability to safely tolerate IV volume loads, etc.); or 
• Individual is initiating therapy or re-initiating therapy after a period of at least 6 months with no therapy; or
• Physically and/or cognitively impaired AND a home caregiver is not available to comply with the required treatment regimen and schedule.

Home health services may be considered medically necessary when utilized for the administration of home infusion therapy and when provided by licensed eligible provider. Each case will be addressed on an individual basis.

The medications identified in this policy will be considered not medically necessary if administered in an unapproved hospital outpatient setting when an approved site of care is a viable option for treatment.

Evidence-based guidelines support the administration of injectable medications in alternative sites of care such as the non-hospital physician’s office, non-hospital infusion center or in the home.  Administration of the injectable medications subject to this policy at alternate sites of care is based upon the professional judgment of the provider, and takes into account the clinical appropriateness for each individual member. Requests for administration of any dose of the drugs listed in this policy received from a hospital-based facility, physician’s office or specialized infusion center will be assessed for meeting the policy exception criteria based on the clinical documentation provided by the requesting practitioner.