Hereditary angioedema (HAE) is a disorder characterized by recurrent episodes of non-allergic, severe swelling (angioedema) in the absence of urticaria or hives. Patients 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 or malfunction of the C1 inhibitor in the body which regulates the coagulation pathway. Missing or low levels of the protein C1 esterase inhibitor (C1-INH). Lack of adequate amounts of C1-INH impact 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

Hereditary Angioedema Type I and II

C1 Esterase Inhibitor [Human] (Cinryze®) 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] (Cinryze): greater than or equal to six (6) years of age; or
  • Lanadelumab-flyo (TAKHZYRO): greater than or equal to twelve (12) years of age; and
• 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 (C4 less than 14 mg/dL; normal range 14 to 40 mg/dL, or C4 below the lower limit of normal as defined by the laboratory performing the test) and ONE of the following laboratory tests:*
  • A low C1 inhibitor (C1INH) antigenic level (C1INH less than 19 mg/dL; normal range 19 to 37 mg/dL, or C1INH antigenic level below the lower limit of normal as defined by the laboratory performing the test); or
  • A normal C1INH antigenic level (C1INH normal range to 19 to 37 mg/dL) and a low C1INH functional level (functional C1INH less than 50%); or below the lower limit of normal as defined by the laboratory performing the test); 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.

*Values defined by the laboratory performing the test.

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

Hereditary Angioedema Type III

C1 Esterase Inhibitor [Human] (Cinryze) may be considered medically necessary when ALL of the following criteria are met:

• Administration is for routine prophylaxis against HAE attacks in adolescents (greater than or equal to six (6) years of age) and adult patients diagnosed with HAE; 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).

*Values defined by the laboratory performing the test. The use of C1 Esterase Inhibitor [Human] (Cinryze) for all other indications is considered not medically necessary.

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

Acute Attacks

Hereditary Angioedema 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 (C4 less than 14 mg/dL; normal range 14 to 40 mg/dL, or C4 below the lower limit of normal as defined by the laboratory performing the test); and
  • A low C1 inhibitor (C1INH) antigenic level (C1INH less than 19 mg/dL; normal range 19 to 37 mg/dL, or C1INH antigenic level below the lower limit of normal as defined by the laboratory performing the test); or
  • A normal C1INH antigenic level (C1INH normal range to 19 to 37 mg/dL) and a low C1INH functional level (functional C1INH less than 50 %); or
  • Below the lower limit of normal as defined by the laboratory performing the test); 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
• Patient not self-administering two acute medications on the same day ; 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).

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.

Hereditary Angioedema 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
• 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.

Note: Product specific dosage and/or frequency limits may apply in accordance with the U.S. Food and Drug Administration (FDA)-approved product prescribing information, national compendia, Centers for Medicare and Medicaid Services (CMS) and other peer reviewed resources or evidence-based guidelines.