Hereditary Angioedema

Number: 0782

Brand Selection for Medically Necessary Indications

As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Berinert (human C1 esterase inhibitor) brand is more costly to Aetna than other hereditary angioedema agents for acute attacks of hereditary angioedema. There is a lack of reliable evidence that Berinert is superior to the lower cost hereditary angioedema agent, Ruconest (recombinant C1 esterase inhibitor), for acute attacks of hereditary angioedema. Therefore, Aetna considers Berinert to be medically necessary only for members who have a contraindication, intolerance or ineffective response to the available equivalent alternative hereditary angioedema agent (one-month trial): Ruconest.

Policy

Note: Requires Precertification. 

Precertification of hereditary angioedema agents is required of all Aetna participating providers and members in applicable plan designs.  For precertification of hereditary angioedema agents, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277. 

Note: Site of Care Utilization Management Policy applies to Cinryze. For information on site of service for Cinryze, please see Utilization Management Policy on Site of Care for Specialty Drug Administration.

Prophylactic Hereditary Angioedema Agents

1. Cinryze Criteria for Initial Approval

   Aetna considers human C1 esterase inhibitor (Cinryze) medically necessary for prevention of hereditary angioedema attacks when the requested medication will not be used in combination with any other medication used for the prophylaxis of HAE attacks and either of the following criteria is met:

   1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets both of the following criteria:
      
      
      1. Member has a C4 level below the lower limit of normal as defined by the laboratory performing the test; and
      2. Member meets one of the following criteria:
         
         
         1. C1 inhibitor (C1-INH) antigenic level is below the lower limit of normal as defined by the laboratory performing the test; or
         2. Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test); or
            
   2. Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:
      
      
      1. Member has an F12, angiopoietin-1, plasminogen, or kininogen-1 (KNG1) gene mutation as confirmed by genetic testing, or
      2. Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy for Cinryze

   Aetna considers continued use of Cinryze medically necessary when all of the following criteria are met:

   1. Member meets the criteria for initial approval; and
   2. Member has experienced reduction in frequency of attacks by 50% or more since starting treatment; and
   3. Member has reduced the use of medications to treat acute attacks.

3. Haegarda Criteria for Initial Approval 

   Aetna considers human C1 esterase inhibitor (Haegarda) medically necessary for prevention of hereditary angioedema attacks when the requested medication will not be used in combination with any other medication used for the prophylaxis of HAE attacks and either of the following criteria is met:

   1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets both of the following criteria:

      1. Member has a C4 level below the lower limit of normal as defined by the laboratory performing the test, and
      2. Member meets one of the following criteria:
         
         
         1. C1 inhibitor (C1-INH) antigenic level is below the lower limit of normal as defined by the laboratory performing the test; or
         2. Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test); or

   2. Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:

      1. Member has an F12, angiopoietin-1, plasminogen, or kininogen-1 (KNG1) gene mutation as confirmed by genetic testing, or
      2. Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month.

   Aetna considers all other indications as experimental and investigational. 

4. Continuation of Therapy for Haegarda

   Aetna considers continued use of Haegarda medically necessary when all of the following criteria are met:

   1. Member meets the criteria for initial approval; and
   2. Member has experienced reduction in frequency of attacks by 50% or more since starting treatment; and 
   3. Member has reduced the use of medications to treat acute attacks.

5. Takhzyro Criteria for Initial Approval

   Aetna considers plasma kallikrein inhibitor (Takhzyro) medically necessary for prevention of hereditary angioedema attacks when the requested medication will not be used in combination with any other medication used for the prophylaxis of HAE attacks and either of the following criteria is met:

   1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets both of the following criteria:
      
      
      1. Member has a C4 level below the lower limit of normal as defined by the laboratory performing the test, and
      2. Member meets one of the following criteria:
         
         
         1. C1 inhibitor (C1-INH) antigenic level is below the lower limit of normal as defined by the laboratory performing the test; or
         2. Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test); or
            
   2. Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:
      
      
      1. Member has an F12, angiopoietin-1, plasminogen, or kininogen-1 (KNG1) gene mutation as confirmed by genetic testing, or
      2. Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month.

   Aetna considers all other indications as experimental and investigational. 

6. Continuation of Therapy for Takhzyro

   Aetna considers continued use of Takhzyro medically necessary when all of the following criteria are met:

   1. Member meets the criteria for initial approval; and
   2. Member has experienced reduction in frequency of attacks by 50% or more since starting treatment; and 
   3. Member has reduced the use of medications to treat acute attacks; and
   4. The requested drug is being dosed every 4 weeks or dosing every 4 weeks has been considered if the member is stable on therapy

7. Berinert Criteria for Initial Approval for Short-term Preprocedural Prophylaxis

   Aetna considers Berinert (human C1 esterase inhibitor) medically necessary for short-term preprocedural prophylaxis (i.e., prior to surgical or major dental procedures) when either of the following criteria is met:

   1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets both of the following criteria:

      1. Member has a C4 level below the lower limit of normal as defined by the laboratory performing the test; and
      2. Member meets one of the following criteria:
         
         
         1. C1 inhibitor (C1-INH) antigenic level is below the lower limit of normal as defined by the laboratory performing the test; or
         2. Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test); or

   2. Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:

      1. Member has an F12, angiopoietin-1, plasminogen, or kininogen-1 (KNG-1) gene mutation as confirmed by genetic testing; or
      2. Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month.

8. Continuation of Therapy for Berinert for Short-term Preprocedural Prophylaxis

   Aetna considers continued use of Berinert medically necessary for all members (including new members) requesting authorization for continued short-term preprocedural prophylaxis (i.e., prior to surgical or major dental procedures) must meet all initial authorization criteria.

Acute Hereditary Angioedema Agents

1. Berinert Criteria for Initial Approval for Treatment of HAE Attacks

   Aetna considers Berinert (human C1 esterase inhibitor) medically necessary for treatment of treatment of acute hereditary angioedema attacks when the requested medication will not be used in combination with Firazyr, Kalbitor, or Ruconest and either of the following criteria is met:

   1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets both of the following criteria:

      1. Member has a C4 level below the lower limit of normal as defined by the laboratory performing the test; and
      2. Member meets one of the following criteria:
         
         
         1. C1 inhibitor (C1-INH) antigenic level is below the lower limit of normal as defined by the laboratory performing the test; or
         2. Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test); or

   2. Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:

      1. Member has an F12, angiopoietin-1, plasminogen, or kininogen-1 (KNG1) gene mutation as confirmed by genetic testing, or
      2. Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month.

   Aetna considers all other indications as experimental and investigational [except for short-term preprocedural prophylaxis (i.e., prior to surgical or major dental procedures when criteria met)] (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy for Berinert for Treatment of HAE Attacks

   Aetna considers continued use of Berinert for acute HAE attacks medically necessary when all of the following criteria are met:

   1. Member meets the criteria for initial approval; and
   2. Member has experienced reduction in severity and/or duration of attacks when the requested medication is used to treat an acute attack; and
   3. For members who have had more than 12 severe attacks or more than 24 days of severe symptoms in the last 12 months, prophylaxis treatment should be considered.

3. Kalbitor Criteria for Initial Approval

   Aetna considers Kalbitor (ecallantide) medically necessary for treatment of acute hereditary angioedema attacks when the requested medication will not be used in combination with Berinert, Firazyr, or Ruconest and either of the following criteria is met:

   1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets both of the following criteria:

      1. Member has a C4 level below the lower limit of normal as defined by the laboratory performing the test, and
      2. Member meets one of the following criteria:
         
         
         1. C1 inhibitor (C1-INH) antigenic level is below the lower limit of normal as defined by the laboratory performing the test, or
         2. Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test); or
            

   2. Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:

      1. Member has an F12, angiopoietin-1, plasminogen, or kininogen-1 (KNG1) gene mutation as confirmed by genetic testing, or
      2. Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

4. Continuation of Therapy for Kalbitor

   Aetna considers continued use of Kalbitor medically necessary when all of the following criteria are met:

   1. Member meets the criteria for initial approval; and
   2. Member has experienced reduction in severity and/or duration of attacks when the requested medication is used to treat an acute attack; and
   3. For members who have had more than 12 severe attacks or more than 24 days of severe symptoms in the last 12 months, prophylaxis treatment should be considered.

5. Ruconest Criteria for Initial Approval

   Aetna considers Ruconest (recombinant C1 esterase inhibitor) medically necessary for treatment of acute hereditary angioedema attacks when the requested medication will not be used in combination with Berinert, Firazyr, or Kalbitor and either of the following criteria is met:

   1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets both of the following criteria: 

      1. Member has a C4 level below the lower limit of normal as defined by the laboratory performing the test; and
      2. Member meets one of the following criteria:
         
         
         1. C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test; or
         2. Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test); or

   2. Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:

      1. Member has an F12, angiopoietin-1, plasminogen, or kininogen-1 (KNG1) gene mutation as confirmed by genetic testing, or
      2. Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

6. Continuation of Therapy for Ruconest

   Aetna considers continued Ruconest therapy medically necessary when all of the following criteria are met:

   1. Member meets the criteria for initial approval; and
   2. Member has experienced reduction in severity and/or duration of attacks when the requested medication is used to treat an acute attack; and
   3. For members who have had more than 12 severe attacks or more than 24 days of severe symptoms in the last 12 months, prophylaxis treatment should be considered.

7. icatibant (e.g., Firazyr) Criteria for Initial Approval

   Aetna considers icatibant (e.g., Firazyr) injection medically necessary for the for treatment of acute hereditary angioedema attacks when the requested medication will not be used in combination with Berinert, Kalbitor, or Ruconest and either of the following criteria is met:

   1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing and meets both of the following criteria:

      1. Member has a C4 level below the lower limit of normal as defined by the laboratory performing the test; and
      2. Member meets one of the following criteria:
         
         
         1. C1 inhibitor (C1-INH) antigenic level is below the lower limit of normal as defined by the laboratory performing the test, or
         2. Normal C1-INH antigenic level and a low C1-INH functional level (functional C1-INH less than 50% or C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test); or
            

   2. Member has normal C1 inhibitor as confirmed by laboratory testing and meets one of the following criteria:

      1. Member has an F12, angiopoietin-1, plasminogen, or kininogen-1 (KNG1) gene mutation as confirmed by genetic testing, or
      2. Member has a documented family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

8. Continuation of Therapy for icatibant (e.g, Firazyr)

   Aetna considers continued use of icatibant medically necessary when all of the following criteria are met:

   1. Member meets the criteria for initial approval; and
   2. Member has experienced reduction in severity and/or duration of attacks when the requested medication is used to treat an acute attack; and
   3. For members who have had more than 12 severe attacks or more than 24 days of severe symptoms in the last 12 months, prophylaxis treatment should be considered.

Note: For berotralstat (Orladeyo), refer to the Pharmacy Clinical Policy Bulletins.

Dosage and Administration

Cinryze

Cinryze (C1 esterase inhibitor [human]) is available for injection as approximately 500 Units (lyophilized) in an 8 mL vial. For intravenous use only. 

Table: Routine Prophylaxis Dosing in Adults, Adolescents, and Children

Population	Indication	Dose	Infusion Rate
Adults and adolescents (12 years old and above)	Routine prophylaxis against HAE attacks	1,000 Units (U) Intravenous (IV) every 3 or 4 days For persons who have not responded adequately to 1,000 U of Cinryze every 3 or 4 days, doses up to 2,500 U (not to exceed 100 U/kg) every 3 or 4 days may be considered based on the individual’s response.	1 mL/min (10 min)
Pediatrics (6 to 11 years old)	Routine prophylaxis against HAE attacks	500 U, IV every 3 or 4 days The dose may be adjusted according to individual response, up to 1,000 U every 3 to 4 days.	1 mL/min (5 min)

Source: Shire ViroPharma, 2018

Haegarda

Haegarda (C1 Esterase Inhibitor Subcutaneous [Human]) is available as a white lyophilized powder supplied in single-use vials containing 2000 or 3000 International Units (IU) of C1-INH. After reconstitution, for subcutaneous use only.

Haegarda is intended for self-administration after reconstitution at a dose of 60 International Units (IU) per kg body weight by subcutaneous (SC) injection twice weekly (every 3 or 4 days). The individual or caregiver should be trained on how to administer Haegarda.

Source: CSL Behring, 2017

Takhzyro

Takhzyro (lanadelumab-flyo) is available for injection as 300 mg/2 mL (150 mg/mL) solution in a single-dose vial. Takhzyro is administered subcutaneously (SC) only. Persons may self-administer.

The recommended starting dose is 300 mg SC every 2 weeks. A dosing interval of 300 mg every 4 weeks is also effective and may be considered if the individual is well-controlled (e.g., attack free) for more than 6 months.

Source: Dyax Corp., 2018

Berinert 

Berinert (C1 esterase inhibitor [human]) is available for injection as 500 International Units (IU) lyophilized concentrate in a single-use vial for reconstitution with 10 mL of Sterile Water for Injection, USP. For intravenous use only. 

The recommended dose of Berinert is 20 International Units (IU) per kg body weight by intravenous injection. Doses lower than 20 IU/kg body weight should not be administered. 

Administer at room temperature within 8 hours of reconstitution. Inject at a rate of approximately 4 mL per minute. Do not mix Berinert with other medicinal products or solutions. Appropriately trained persons may self-administer upon recognition of an HAE attack. 

Source: CSL Behring, 2019

Kalbitor

Kalbitor (ecallantide) is available as a single use glass vial containing 10 mg/mL of ecallantide as a solution for injection. Kalbitor should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.

The recommended dose of Kalbitor is 30 mg (3 mL), administered subcutaneously in three 10 mg (1 mL) injections. If the attack persists, an additional dose of 30 mg may be administered within a 24-hour period.

Source: Dyax Corp, 2018

Ruconest

Ruconest (recombinant C1 esterase inhibitor) is available as 2100 U lyophilized powder for reconstitution for injection in a single use vial. For intravenous use only after reconstitution.

The recommended dose of Ruconest is 50 U per kg with a maximum of 4200 U to be administered as a slow intravenous injection over approximately 5 minutes. If the attack symptoms persist, an additional (second) dose can be administered at the recommended dose level. Do not exceed 4200 U per dose. No more than two doses should be administered within a 24-hour period.

Table: Recommended Dose of Ruconest for an Acute HAE Attack

Body Weight	Ruconest Dose for Intravenous Injection	Volume (mL) of Reconstituted Solution (150 U/mL) to be Administered
Less than 84 kg	50 U per kg	body weight in kg divided by 3
84 kg or more	4200 U (2 vials)	28 mL

Source: Pharming Healthcare, 2019

Firazyr

Firazyr (icatibant) is available for injection as 10 mg per mL.

The recommended dose of Firazyr is 30 mg administered by subcutaneous (SC) injection in the abdominal area. Additional doses may be administered at intervals of at least 6 hours if response is inadequate or if symptoms recur.

No more than 3 doses may be administered in any 24-hour period. Persons may self-administer upon recognition of an HAE attack.

Source: Shire Orphan Therapies, 2020

Note: Generic icatibant is available for the same indication and dosing recommendations as the brand, Firazyr, Shire Orphan Therapies. (Leucadia, 2019).

Experimental and Investigational

Aetna considers concomitant use of Cinryze, Haegarda, and/ or Takhzyro experimental and investigation for all indications (e.g., HAE type III) because their effectiveness for combination use for HAE has not been established.

Cinryze (not an all-inclusive list)

Aetna considers Cinryze experimental and investigational for the treatment of acute angioedema attacks, cerebral ischemic injury, cytokine-induced vascular leak syndrome, myocardial infarction, sepsis, and all other indications because its effectiveness for these indications has not been established.

Berinert (not an all-inclusive list)

Aetna considers Berinert experimental and investigational for prophylaxis against angioedema attacks [except for short-term preprocedural prophylaxis (i.e., prior to surgical or major dental procedures when criteria met], for treatment of autoimmune cold agglutinin-associated hemolytic anemia, for use in combination with Kalbitor or Firazyr or Ruconest, and for other indications because its effectiveness for these indications has not been established.

Kalbitor (not an all-inclusive list)

Aetna considers Kalbitor experimental and investigational for all other indications (e.g., reduction of blood loss during surgery, use in combination with Berinert or Firazyr or Ruconest) because its effectiveness for these indications has not been established.

Ruconest (not an all-inclusive list)

Aetna considers Ruconest experimental and investigational for use in combination with Berinert, Kalbitor or Firazyr and all other indications because its effectiveness for these indications has not been established.

icatibant (e.g., Firazyr) (not an all-inclusive list)

Aetna considers icatibant experimental and investigational for prophylaxis against angioedema attacks and other indications (e.g., acute pancreatitis, airways disease, thermal injury, use in combination with Berinert or Kalbitor or Ruconest, and refractory ascites in persons with liver cirrhosis) because its effectiveness for these indications has not been established.

Background

Hereditary angioedema (HAE) is a rare, severely debilitating, potentially life-threatening disorder caused by a deficiency of C1 inhibitor (C1-INH).  The prevalence of HAE is unclear but is estimated to be about 1 in 50,000, without known differences among ethnic groups.  This condition is the result of autosomal dominant inheritance affecting the synthesis of C1-INH, which is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins).  The primary function of C1-INH is to regulate the activation of the complement and intrinsic coagulation (contact system) pathway. It is thought that increased vascular permeability and the clinical manifestation of the HAE attacks are primarily mediated through contact system activation. Suppression of contact system activation by C1 inhibitor through the inactivation of plasma kallikrein and factor XIIa is thought to modulate this vascular permeability by preventing the generation of bradykinin. In addition, C1-INH also regulates the fibrinolytic system.  In patients with HAE, C1-INH is low or does not function properly.  These individuals experience recurrent attacks of inflammation affecting the abdomen, extremities, face, as well as laryngeal and urogenital tracts; they experience about 20 to 100 days of incapacitation per year.  These attacks, which affect an estimated 10,000 people in the United States, are often unpredictable and may be spontaneous or precipitated by trauma or psychological stress.  Estrogen has also been reported to exacerbate attacks.  In general, HAE attacks occur within a 24-hour period and then subside with 48 to 72 hours (Agostoni et al, 2004; Frank 2008; Zuraw, 2008).

There are 2 principal types of HAE. Type I accounts for 85 % of cases and is characterized by low levels and reduced functional tests of C1-INH, both of which usually range from 0 % to 30 % of normal. These abnormalities result from deficient amounts of normally-functioning inhibitor. Type II accounts for 15 % of cases and is characterized by reduced functional tests of C1 inhibitor (C1-INH) in the presence of normal or elevated C1-INH protein levels.  This is explained by a dysfunctional inhibitor, which is present in normal or elevated amounts. C1 inhibitor blocks the activity of certain proteins that promote inflammation. Without the proper levels of functional C1 inhibitor, excessive amounts of a protein fragment (peptide) called bradykinin are generated. Bradykinin promotes inflammation by increasing the leakage of fluid through the walls of blood vessels into body tissues. Most patients have decreased plasma complement protein C4 levels.  The 2 types of HAE are indistinguishable in clinical presentation but are caused by different mutations.  Diagnosis is confirmed by decreased serum levels of C4 and absence or marked decrease of the level or function of C1-INH (Gompels et al, 2005; Atkinson et al, 2008). 

Excessive accumulation of fluids in body tissues causes the episodes of swelling seen in individuals with hereditary angioedema type I and type II. People with hereditary angioedema can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, larynx, or trachea. If swelling closes the airways, it can be deadly. There is usually no itching or hives. Swelling of the gut can cause intestinal cramping. Attacks of swelling can become more severe in late childhood and adolescence. On average, untreated individuals have an attack every one‐to‐two weeks, and most episodes last for about three‐to‐four days.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Based on an European workshop in 2004, diagnostic criteria for C1-INH disorders were proposed.  The diagnosis of HAE is established in patients with 1 clinical criterion and 1 laboratory criterion (Agostoni et al, 2004; Atkinson et al, 2008):

Clinical Criteria

• Recurrent laryngeal edema.
• Self-limiting, non-inflammatory subcutaneous angioedema without urticaria, recurrent, and lasting more than 12 hours.
• Self-remitting abdominal pain without clear organic etiology, recurrent, and lasting more than 6 hours.

A family history of recurrent angioedema and/or abdominal pain and/or laryngeal edema, if present, supports the diagnosis of HAE, although it is not required because the patient may have a new mutation or an acquired disorder.

Laboratory Criteria

• C1-INH levels less than 50 % of the lower limit of normal at 2 separate determinations (at least 1 month apart) with the patient in their basal condition and after the first year of life.
• C1-INH function of less than 50 % of normal at 2 separate determinations (at least 1 month apart) with the patient in their basal condition and after the first year of life.
• Mutation in C1-INH gene altering protein synthesis and/or function.  This is the only laboratory criterion that can be used to make the diagnosis in patients younger than 1 year of age.

The criteria stipulate that C1-INH antigenic/functional levels must be below 50 %.  In most cases of type I HAE, the levels are below 30 %, although some patients have levels slightly higher (between 30 % and 50 %) and patients with acquired forms can have levels between 30 % and 50 % as well.

Gompels et al (2005) as well as Pedraz et al (2007) stated that diagnosis of HAE is confirmed by decreased serum levels of C4 and absence or marked decrease (less than 50 % of normal) of the level or function of C1-INH.

Management of patients with HAE entails treatment of acute attacks, short-term prophylaxis to prevent an attack, and long-term prophylaxis to minimize the frequency and severity of recurrent attacks.  Commonly employed drugs for prophylaxis and treatment of these patients include 17 alpha-alkylated androgens (e.g., danazol and stanozolol), anti-fibrinolytic agents (e.g., epsilon aminocaproic acid tranexamic acid), and infusion of C1-INH concentrate.  Moreover, fresh frozen plasma is also an option to be considered for short-term prophylaxis or treatment of acute attacks (Széplaki et al, 2005; Pedraz et al, 2007; Frank 2008; Zuraw, 2008; Epstein and Bernstein, 2008; Temiño and Peebles, 2008).

A consensus panel on hereditary angioedema with normal C1INH (HAE type III) (Zuraw, et al., 2012) found that there have been no randomized or controlled clinical trials of therapy for HAE with normal C1INH. Angioedema attacks in patients with HAE with normal C1INH do not respond to either corticosteroids or antihistamines, even at high doses. Prophylactic use of 17-alkylated androgens, the antifibrinolytic drug tranexamic acid, or progestins have shown promising results in some but not all patients. The consensus panel stated that there is relatively little experience regarding the efficacy of on-demand C1INH, icatibant, or ecallantide in HAE with normal C1INH; however, anecdotal re ports suggest that each of these agents may be beneficial. The consensus panel concluded that, until data from randomized controlled studies become available, no firm recommendations regarding the treatment of HAE with normal C1INH can be made.

The plasma derived C1-INH (pdC1NH), Cinryze, is approved for prophylaxis of HAE attack. Treatment of acute HAE attack in adult and adolescent patients include: Berinert (pdC1NH); Kalbitor (ecallantide), the recombinant inhibitor of plasma kallikrein ecallantide; and Firazyr (icatibant), the bradykinin B2 receptor antagonist.

Human C1 Inhibitors should not be utilized in the following:

• Patients that have a reported hypersensitivity to human C1 inhibitors or any component of the product
• Patients less than 12 years old
• Patients with a history of clotting disorders that have not discussed use with their doctor as very high doses of human C1 inhibitors could increase risk for clots.

A review article by Busse and Christiansen (2020) state that the mechanism of swelling in hereditary angioedema with normal C1 inhibitor levels is less well characterized but is thought to involve enhanced bradykinin signaling. The disorder is classified into subtypes according to the associated genetic mutation: a mutation affecting factor XII, angiopoietin-1, plasminogen, or kininogen-1 heavy chain or an unknown genetic mutation. The mechanisms underlying angioedema in hereditary angioedema with plasminogen dysfunction, hereditary angioedema with angiopoietin-1 (ANGPT1) dysfunction, and hereditary angioedema with kininogen-1 heavy-chain dysfunction are unclear. The majority of patients who have hereditary angioedema with normal C1 inhibitor levels remain in the unknown-mutation category, for which many potential pathogenic explanations remain to be investigated. Consensus criteria for the diagnosis of HAE with normal C1 inhibitor levles include: history of recurrent angioedema in the absence of concomitant urticaria or use of a medication known to cause angioedema, normal or near-normal C4 level and C1 inhibitor antigen level and function, documented lack of response to high-dose antihistamines (e.g., secondgeneration antihistamines given 4 times/day), and either a known genetic mutation (factor XII, angiopoietin-1, plasminogen, or kininogen-1) or a family history of angioedema. 

Prophylactic Hereditary Angioedema Agents

Cinryze

U.S. Food and Drug Administration (FDA)-Approved Indications

• Routine prophylaxis against angioedema attacks in adults, adolescents and pediatric patients (6 years of age or older) with hereditary angioedema (HAE)

Cinryze (human C1 inhibitor) is a plasma derived concentrates of C1 Esterase Inhibitor (Human). Administration of Cinryze to patients with C1 esterase inhibitor deficiency replaces the missing or malfunctioning protein in patients. Cinryze has been approved by the U.S. Food and Drug Administration (FDA) for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).

The FDA's approval of Cinryze was based on the results a phase III clinical trial that examined the safety and effectiveness of Cinryze prophylaxis therapy to reduce the incidence, severity, and duration of HAE attacks.  Patients were screened to confirm a diagnosis of HAE and a history of at least 2 HAE attacks per month.  A total of 24 patients (mean age of 38.1 years with a range of 9 to 73) were randomized to one of two treatment groups: 

1. Cinryze prophylaxis for 12 weeks followed by 12 weeks of placebo prophylaxis; or
2. placebo prophylaxis for 12 weeks followed by 12 weeks of Cinryze prophylaxis. 

Two subjects dropped out (1 in each arm); 22 patients crossed-over into period 2 and were included in the effectiveness analysis.  Patients were given blinded injections (Cinryze or placebo) every 3 to 4 days, approximately 2 times per week.  Patients recorded all angioedema symptoms daily.  An attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day.  Subjects in the Cinryze-treated group had a 52 % reduction in the number of HAE attacks compared to the placebo-treated group (6.1 versus 12.7; p < 0.0001).  In addition, subjects in the Cinryze-treated group had a 66 % reduction in days of swelling (10.1 versus 29.6 days; p < 0.0001), a 32 % decrease in the average severity of attacks (1.3 versus 1.9 based on a scoring of 1 to 3; p = 0.0006), and a 38 % reduction in the average duration of attacks (2.1 versus 3.4 days; p = 0.0023).

Currently, there are no submitted data on the safety profile of an intensified dose schedule of Cinryze for routine prophylaxis.  The FDA has requested that post-marketing studies be performed to address the following issues:

1. the optimal dose for prophylaxis in males and females,
2. immunogenicity, and
3. long-term safety.

Caliezi et al (2000) noted that there is accumulating evidence, obtained from studies in animals as well as observations in patients, that administration of C1-INH may have a beneficial effect in clinical conditions such as sepsis, cytokine-induced vascular leak syndrome, myocardial infarction, or other diseases.  In this regard, Wouters et al (2008) considered C1-INH an experimental therapy in diseases such as sepsis and myocardial infarction.  Longhurst (2008) reported that a recombinant human C1-INH is also being investigated for the potential treatment of cerebral ischemic injury.  The clinical value of C1-INH for these indications needs to be validated by well-designed studies.  Zuraw (2008) also noted that more studies are needed to ascertain the value of prophylactic treatment as compared with on-demand treatment for acute HAE attacks as well as to evaluate the risks and benefits of allowing patients to use these new drugs at home to treat attacks at an early point in their course.

Craig and colleagues (2009) determined when newer agents, such as C1-INH, should be considered as prophylaxis to decrease HAE attacks as an alternative to androgens, which have significant adverse events (AEs).  A literature review (PubMed, Google, and Ovid), guideline review, expert panel meeting, and group discussion were performed to decide when prophylaxis is indicated.  The retrieved studies demonstrate that C1-INH is effective and that the half-life makes it attractive for prophylactic use.  The short half-lives of ecallantide, icatibant, and recombinant human C1-INH limit their use as prophylactic agents.  Patients with severe anxiety, more than 1 attack per month, rapid progression of attacks, limited access to health care, more than 10 days lost from work or school per year, previous laryngeal swelling, more than 3 emergency department visits per year, more than 1 hospitalization per year, previous intubation, previous intensive care unit care, significant compromise in quality of life, or narcotic dependency should be considered for androgen or C1-INH prophylaxis therapy.  The authors concluded that patients with HAE with frequent attacks, severe attacks, past laryngeal attacks, excessive loss of work or school, significant anxiety, and poor quality of life should be considered for C1-INH prophylaxis, especially those who fail, are intolerant of, have adverse reactions to, or are not candidates for androgen therapy.

Bygum and associates (2009) assessed the impact of self-administered home therapy with intravenous C1-INH concentrate on quality of life (QOL) in patients with HAE.  A total of 9 patients experiencing frequent or severe debilitating HAE attacks were offered self-administration of C1-INH concentrate.  Quality of life was evaluated before and after home therapy using the Dermatology Life Quality Index (DLQI) and 36-item Short Form Survey (SF-36) questionnaires.  Seven patients were recruited into the study.  Quality of life was assessed at baseline and after 3 to 48 months of home therapy.  The mean DLQI score fell from 12.6 +/- 4.65 to 2.7 +/- 1.38 (p < 0.001).  Mean SF-36 scores for the individual and combined components also improved significantly.  No serious complications were documented during a follow-up period of 27 to 72 months.  The authors concluded that self-administration of C1-INH improved QOL on both physical and psychological parameters.  Patients were able to resume a normal life without restrictions caused by the condition.

The AE profile of Cinryze is similar to that of placebo.  The most common side effects observed have been headache, rash, sinusitis, and upper respiratory infection.  No drug-related serious AEs, no immunogenicity and no decrease in efficacy have been observed in clinical trials.  Severe hypersensitivity reactions may occur.  Thrombotic events have occurred in patients receiving high dose off-label C1-INH therapy well above the approved treatment dosage regimen.  With any blood or plasma derived product, there may be a risk of transmission of infectious agents (e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease agent).  The risk has been reduced by screening patients for prior exposure to certain virus infections and by manufacturing steps to reduce the risk of viral transmission including pasteurization and nanofiltration.

Cinryze is for intravenous use only. Cinryze (human C1 inhibitor) is available in a single‐use vial that contains 500 units. Cinryze is administered as an injection for adults and adolescents (12 years of age and older) at a rate of 1 mL/min over 10 mins. According to the FDA-approved labeling for Cinryze, the recommended dose for HAE prophylaxis is 1,000 units (two 8-ml vials) every 3 or 4 days. Thus, a maximum of 10,000 units are considered medically necessary per 30 days for HAE prophylaxis. For persons who have not responded adequately to 1,000 U of Cinryze every 3 or 4 days, dose up to 2,500 U (not to exceed 100 U/kg) every 3 or 4 days may be considered based on individual patient response.

As of June 2018, Cinryze received FDA approval for the supplemental indication to include children 6 years of age and older for routine prophylaxis against angioedema attacks. The safety and effectiveness was evaluated in a randomized, single-blind, multi-center, dose-ranging, crossover routine prophylaxis trial of 12 pediatric subjects with HAE (age range 7 to 11 years old). Additionally, 4 of the 24 subjects in the pediatric/adult randomized, placebo-controlled, crossover, routine prophylaxis trial, were under the age of 18 years (9, 14, 16, and 17 years of age). Overall the safety and tolerability of Cinryze were found similar in pediatric, adolescent and adult subjects (Shire ViroPharma Inc, 2018).

Pediatric (ages 6 to 11 years old) dosing is 500 units intravenous (IV) every 3 or 4 days. Infusion rate is 1 mL/min over 5 minutes. The dose may be adjusted according to individual response, up to 1,000 U every 3 to 4 days (Shire ViroPharma Inc, 2018).

Haegarda

U.S. Food and Drug Administration (FDA)-Approved Indications

• Routine prophylaxis to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients

On June 27, 2017, the FDA approved Haegarda (a plasma-derived human C1 esterase inhibitor) for prevention of HAE attacks in adolescent and adult patients. Haegarda, a purified, pasteurized, lyophilized concentrate, is the first C1 esterase inhibitor for subcutaneous administration. The subcutaneous route of administration allows for easier at-home self-injection by the patient or caregiver, once proper training is received.The effectiveness of Haegarda was demonstrated in a multi-center controlled clinical trial, which included 90 symptomatic HAE patients ranging from 12 to 72 years of age.  Participants were randomized to receive twice-weekly subcutaneous doses of either 40 IU/kg or 60 IU/kg, and the treatment effect was compared to a placebo treatment period.  During the 16-week treatment period, patients in both treatment groups experienced a significantly reduced number of HAE attacks compared to their placebo treatment period.  The most common side effects associated with Haegarda administration included injection site reactions, hypersensitivity reactions, nasopharyngitis and dizziness.  Haegarda should not be used in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to a C1-INH preparation or its inactive ingredients.

The dosage of Haegarda is 60 International Units per kg body weight twice-weekly (every 3 or 4 days).  Haegarda  is not indicated for treatment of acute HAE attacks.

Takhzyro

U.S. Food and Drug Administration (FDA)-Approved Indications

• Prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years of age and older

On August 23, 2018, the FDA approved Takhzyro (lanadelumab-flyo) the first monoclonal antibody approved in the U.S. to treat patients 12 years and older with types I and II hereditary angioedema (HAE). Takhzyro is a plasma kallikrein inhibitor that is used to prevent swelling attacks from occurring. Takhzyro is a fully human IgG1 monoclonal antibody made in recombinant Chinese Hamster Ovary cells. FDA based its approval on data from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 125 patients with HAE. Patients were randomized into 1 of 4 parallel treatment arms, stratified by baseline attack rate, in a 3:2:2:2 ratio (placebo, lanadelumab-flyo 150 mg q4wks, lanadelumab-flyo 300 mg q4wks, or lanadelumab-flyo 300 mg q2wks by subcutaneous injection) for the 26-week treatment period. Patients 18 years of age or older were required to discontinue other prophylactic HAE medications prior to entering the study; however, all patients were allowed to use rescue medications for treatment of breakthrough HAE attacks.

Patients who received Takhzyro had clinically meaningful and statistically significant reductions in the rate of investigator-confirmed HAE attacks compared to placebo. The percentage of attack-free patients for the entire 26-week treatment period was 44%, 31%, and 39% in the Takhzyro 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks groups respectively, compared to 2% of placebo patients. A 50% or greater reduction in HAE attack rate was observed in 100% of patients on 300 mg q2wks or q4wks and 89% on 150 mg q4wks compared to 32% of placebo patients. A 70% or greater reduction in HAE attack rates was observed in 89%, 76%, and 79% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 10% of placebo patients. A 90% or greater reduction in HAE attack rates was observed 67%, 55%, and 64% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 5% of placebo patients.

Patients who completed Trial 1 were eligible to rollover into an open-label extension study. Rollover patients, regardless of randomization group in Trial 1, received a single dose of Takhzyro 300 mg at study entry and were followed until the first HAE attack occurred. All efficacy endpoints were exploratory in this uncontrolled, unblinded study. At week 4 post-dose, approximately 80% of patients who had been in the 300 mg q2wks treatment group (N=25) in Trial 1 remained attack-free. After the first HAE attack, all patients received open-label treatment with Takhzyro 300 mg q2wks.

The most common adverse drug reactions in patients taking Takhzyro in clinical trials are injection site reactions, upper respiratory infections, headache, rash, muscle pain, dizziness and diarrhea. Takhzyro is administered subcutaneously only.

The recommended starting dose of Takhzyro is 300 mg every 2 weeks. A dosing interval of 300 mg every 4 weeks is also effective and may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months.

In randomized, double-blind, parallel-group, placebo-controlled, phase-III clinical trial, Banerji and colleagues (2018) examined the efficacy of lanadelumab in preventing HAE attacks.  This trial was conducted at 41 sites in Canada, Europe, Jordan, and the United States.  Patients were randomized between March 3, 2016 and September 9, 2016; last day of follow-up was April 13, 2017.  Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens.  Patients 12 years or older with HAE type I or II underwent a 4-week run-in period and those with 1 or more HAE attacks during run-in were randomized.  Subjects received 26-week treatment with subcutaneous lanadelumab 150-mg every 4 weeks (n = 28), 300-mg every 4 weeks (n = 29), 300-mg every 2 weeks (n = 27), or placebo (n = 41).  All participants received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments.  The primary efficacy end-point was the number of investigator-confirmed attacks of HAE over the treatment period.  Among 125 patients randomized (mean age of 40.7 years [SD, 14.7 years]; 88 women [70.4 %]; 113 white [90.4 %]), 113 (90.4 %) completed the study.  During the run-in period, the mean number of HAE attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group.  During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group.  Compared with placebo, the mean differences in the attack rate per month were -1.49 (95 % CI: -1.90 to -1.08; p < 0.001); -1.44 (95 % CI: -1.84 to -1.04; p < 0.001); and -1.71 (95 % CI: -2.09 to -1.33; p < 0.001).  The most commonly occurring AEs with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1 % placebo, 52.4 % lanadelumab) and dizziness (0 % placebo, 6.0 % lanadelumab).  The authors concluded that among patients with HAE type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo.  These researchers stated that these findings supported the use of lanadelumab as a prophylactic therapy for HAE; further research is needed to determine long-term safety and efficacy.

Agboola and associates (2019) noted that HAE is a rare autosomal dominant genetic disorder characterized by recurrent and unpredictable episodes of tissue swelling (angioedema).  It is caused by mutations in the SERPING1 gene that encodes for the C1-INH.  Low levels of C1-INH (HAE type 1) or dysfunctional C1-INH (HAE type 2) lead to the buildup of bradykinin, resulting in capillary leakage and ultimately tissue swelling.  There are also other less common forms of HAE in which C1-INH levels and function are normal.  Hereditary angioedema affects about 1 in 50,000 individuals, with males and females equally affected.  The mean age of onset is 10 years, although attacks can begin at any age.  Attacks are usually characterized by mild-to-severe tissue swelling at 1 or more sites in the body (typically the face, hands, feet, airways, and intestinal tract).  The frequency and duration of HAE attacks are highly variable.  On average, HAE attacks can occur every 1 to 2 weeks.  If untreated, swelling is self-limited and usually resolves spontaneously in 2 to 5 days; however, laryngeal edema poses the risk of death due to asphyxiation.  When treatments are administered, death is rare.  Hereditary angioedema attacks are often treated with on-demand administration of C1-INH replacement products, kallikrein inhibitors, or bradykinin receptor antagonists.  Some patients with frequent attacks receive routine (long-term) prophylaxis to prevent or reduce the frequency and severity of attacks.  Human plasma-derived C1-INH concentrate products (Cinryze or Haegarda) have been approved by the FDA for long-term prophylaxis, and lanadelumab-flyo (Takhzyro) was approved on August 23, 2018, as another alternative.  The authors stated that for patients with HAE type 1/2, prophylaxis with Cinryze, Haegarda, and Takhzyro showed significant clinical benefits by reducing the number and severity of HAE attacks, without significant AEs when compared with no long-term prophylaxis.  However, the data were not sufficient to distinguish any drug as clinically superior to the other.  In the absence of long-term safety data for lanadelumab-flyo, which targets a different pathway than the C1-INH products, these researchers were less certain regarding its overall net health benefit.  In the base case and at current pricing, all 3 drugs were judged to represent low or intermediate long-term value for money.  However, these findings were highly influenced by the baseline attack rate, with improved cost-effectiveness for a population with a higher mean attack rate per month and by the cost of treating patients with on-demand therapy, with higher on-demand treatment costs leading to improved cost-effectiveness for prophylaxis.  These investigators stated that further studies are needed to help align the price of these treatments with their demonstrated benefit in order to ensure sustainable access to high-value care for all patients.

Acute Hereditary Angioedema Agents

Berinert

On October 9, 2009, the FDA approved Berinert (a plasma-derived concentrate of human C1 esterase inhibitor) for the treatment of adults and adolescents with acute attacks associated with HAE. Berinert (human C1 inhibitor) is indicated for the treatment of acute abdominal, facial, or laryngeal attacks of hereditary angioedema (HAE) in adult and adolescent patients. Administration of Berinert to patients with C1 esterase inhibitor deficiency replaces the missing or malfunctioning protein in patients. The safety and efficacy of Berinert for prophylactic therapy have not been established.

Berinert for the treatment of acute abdominal or facial attacks in patients with HAE was examined in a prospective, multi-national, randomized, double-blind, placebo-controlled, parallel-group, dose-finding, 3-arm, clinical study -- referred to as the randomized clinical trial (RCT).  The RCT evaluated the safety and effectiveness of Berinert in 124 adult and pediatric subjects with C1 esterase inhibitor deficiency who were experiencing an acute moderate-to-severe attack of abdominal or facial HAE.  Patients ranged in age from 6 to 72 years of age; 67.7 % were female and 32.3 % were male; and approximately 90 % were Caucasian.  The aims of the study were to assess if Berinert shortens the time to onset of relief of symptoms of an abdominal or facial attack compared to placebo and to compare the effectiveness of 2 different doses of Berinert.  The time to onset of relief of symptoms was determined by the patient’s response to a standard question posed at appropriate time intervals for as long as 24 hrs after start of treatment taking into account all single HAE symptoms.  In addition, the severity of the single HAE symptoms were assessed over time.  Subjects were randomized to receive a single 10 unit/kg body weight dose of Berinert (n = 39), a single 20 unit/kg dose of Berinert (n = 43), or a single dose of placebo (n = 42) by slow intravenous infusion (recommended to be given at a rate of approximately 4 ml/min) within 5 hrs of an attack.  At least 70 % of the patients in each treatment group were required to be experiencing an abdominal attack.  If a patient experienced no relief or insufficient relief of symptoms by 4 hrs after infusion, investigators had the option to administer a second infusion of Berinert (20 units/kg for the placebo group, 10 units/kg for the 10 units/kg group), or placebo (for the 20 units/kg group).  This masked (blinded) “rescue study medication” was administered to subjects and they were then followed until complete resolution of symptoms was achieved; AEs were collected for up to 7 to 9 days following the initial administration of Berinert or placebo.  In the rare case that a subject developed life-threatening laryngeal edema after inclusion into the study, immediate start of open-label treatment with a 20 unit/kg body weight dose of Berinert was allowed.

All patients who received confounding medication (rescue medication) before symptom relief were regarded as “non-responders”.  Thus, time to onset of symptom relief was set at 24 hrs if a subject received any rescue medication (i.e., rescue study medication, narcotic analgesics, non-narcotic analgesics, anti-emetics, open-label C1esterase inhibitor, or fresh frozen plasma) between 5 hrs before administration of blinded study medication until time to onset of relief.

Patients treated with 20 units/kg body weight of Berinert experienced a significant reduction (p = 0.0016) in time to onset of relief from symptoms of an HAE attack as compared to placebo (median of 50 mins for Berinert 20 units/kg body weight, as compared to greater than 4 hrs for placebo).  The time to onset of relief from symptoms of an HAE attack for subjects in the 10 unit/kg dose of Berinert was not statistically significantly different from that of subjects in the placebo group.

Berinert (human C1 inhibitor) is available in a single‐use vial that contains 500 units. According to the FDA-approved labeling, the recommended dose of Berinert is 20 units per kg body weight by slow intravenous injection at a rate of approximately 4 mL per minute. Doses more than 20 units/kg body weight should not be administered.

Berinert is contraindicated in individuals who have had life-threatening hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations.  The most serious adverse reaction reported in clinical studies was an increase in the severity of pain associated with HAE.  The most common adverse reactions include subsequent HAE attack, headache, abdominal pain, nausea, muscle spasms, pain, diarrhea and vomiting.  Berinert is administered by intravenous infusion.

In December 2011, the FDA has expanded the label of Berinert (C1 esterase inhibitor [human]) to permit self-treatment of HAE during acute attacks.  With appropriate training from a physician, patients can now self-administer Berinert by intravenous infusion at the first sign of an HAE attack, potentially averting more severe symptoms.  Already indicated for acute abdominal and facial attacks of this rare but serious genetic disorder, Berinert, as part of the label expansion, has now also been approved for use in laryngeal attacks.

On July 18, 2016, the FDA approved the use of Berinert [C1 esterase inhibitor (human)] for use in pediatric patients (under 12 years of age) for the treatment of hereditary angioedema (HAE) attacks. This expands the use of Berinert into all age groups, making it the first and only approved HAE treatment available to patients under 12 years of age.  The announcement stated that “In addition to the pediatric indication, the FDA approved an update to the ‘Geriatric Use’ section of the package insert.  The safety and efficacy of Berinert have been established in both children and adults, with safety profiles observed in the pediatric and geriatric populations similar to that observed in other populations.  Clinical studies have shown that intervention with Berinert at the onset of an HAE attack brings significantly faster relief to a patient and reduces the severity of the attack”.

An UpToDate review on “Cold agglutinin disease” (Schrier, 2017) does not mention human C1 esterase inhibitor as a therapeutic option.

Firazyr

On August 25, 2011, the FDA approved Firazyr (icatibant) injection for the treatment of acute attacks of HAE in people ages 18 years and older. Firazyr (icatibant) is a potent and selective antagonist of the B2 receptor, and can alleviate the symptoms of an acute release of bradykinin, which is thought to cause HAE. Acute attacks of hereditary angioedema (HAE), resulting vascular leakage and edema are the most recognizable symptom of HAE and are directly attributable to increases in bradykinin formation. Icatibant has an affinity for the B2 receptor that is equal to that of bradykinin and is a competitive antagonist of the human B2 receptor. According to the FDA, Firazyr provides a new option to treat acute attacks of HAE; and because it can be self-administered via an injection in the abdominal area, patients can treat themselves upon recognition of an HAE attack.  The safety and effectiveness of Firazyr was shown in 3 controlled clinical trials, with open-label extension periods, in which 225 patients received 1,076 doses of 30 mg Firazyr.  The median time for patients treated with Firazyr to report onset of symptom relief was 2 hrs compared with almost 20 hrs with placebo.  Firazyr is the third drug approved in the United States to treat HAE attacks.  

It was studied in 2 phase III clinical trials: FAST-1 (For Angioedema Subcutaneous Treatment) did not achieve statistical significance for the primary end point; but did so for secondary end points, whereas FAST-2 achieved statistical significance for primary and secondary end points.  Icatibant was approved by the European Medicines Agency (EMEA) for the treatment of HAE (Bernstein, 2008; Gras, 2009).

In an uncontrolled pilot study, Bork et al (2007) examined if icatibant is effective in acute edema attacks of hereditary angioedema.  A total of 15 patients with 20 attacks were treated with icatibant.  The attacks were analyzed by using a standardized and validated visual analog scale (VAS) measurement and compared with historical data of untreated attacks.  Plasma bradykinin concentration was measured before and 4 hrs after intravenous icatibant treatment.  Symptom intensity decreased within 4 hrs after administration of icatibant; the median time to onset of symptom relief was 1.50, 1.42, and 1.13 hrs in the intravenous groups and 0.58 and 0.45 hrs in the subcutaneous groups, respectively.  The median difference in the 10-cm VAS 4 hrs after start of treatment was 4.11 cm (95 % confidence interval [CI]: 1.72 to 6.07).  Compared with untreated attacks, icatibant treatment reduced the mean (SD) time to onset of symptom relief by 97 % from 42 +/- 14 to 1.16 +/- 0.95 hrs (all groups combined).  Median bradykinin concentration was 7-fold above the norm during acute attacks at 48.5 pmol/L and decreased to 18.0 pmol/L 4 hours after Icatibant infusion or injection.  The authors concluded that icatibant was effective in treating acute attacks of HAE.

In 2 double-blind, randomized, multi-center trials, Cicardi et al (2010) evaluated the effect of icatibant in patients with HAE presenting with cutaneous or abdominal attacks.  In the FAST-1 trial, patients received either icatibant or placebo; in the FAST-2 trial, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days.  Icatibant was administered once, subcutaneously, at a dose of 30 mg.  The primary end point was the median time to clinically significant relief of symptoms.  A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively.  The primary end point was reached in 2.5 hrs with icatibant versus 4.6 hrs with placebo in the FAST-1 trial (p = 0.14) and in 2.0 hrs with icatibant versus 12.0 hrs with tranexamic acid in the FAST-2 trial (p < 0.001).  In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication.  The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials.  No icatibant-related serious AEs were reported.  The authors concluded that in patients with HAE having acute attacks, a significant benefit of icatibant as compared with tranexamic acid in one trial and a non-significant benefit of icatibant as compared with placebo in the other trial with regard to the primary end poin were reported.  The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial.

FAST-3 was a placebo-controlled study of 98 adult patients with a median age of 36 years.  The primary end point was assessed using a 3-item composite VAS, comprised of averaged assessments of skin swelling, skin pain, and abdominal pain.  The median time to 50 % reduction in symptoms for patients with cutaneous or abdominal attacks treated with icatibant (n = 43) compared to placebo (n = 45) was 2.0 hrs [95 % CI: 1.5 to 3.0] versus 19.8 hrs [95 % CI: 6.1 to 26.3], respectively (p < 0.001).  The median times to almost complete symptom relief were 8.0 versus 36.0 hrs for icatibant and placebo, respectively.  Additional rescue medications were used by 3 patients (7 %) treated with icatibant and 18 patients (40 %) treated with placebo.

The most common adverse reactions reported by those using Firazyr were injection site reactions, fever, increased liver enzymes, dizziness, and rash. 

Icatibant is available as Firazyr in 30mg/3mL, single‐use, prefilled syringes for subcutaneous administration. The recommended dosing for Firazyr is 30 mg injected subcutaneously in the abdominal area. The majority of patients respond to 1 dose. If response is inadequate or symptoms recur, additional injections of 30mg may be administered at intervals of at least 6 hours. Do not administer more than 3 injections in 24 hours. Patients may self‐administer upon recognition of an HAE attack. Patients are trained on how to self-administer the Firazyr injection.

Cruden and Newby (2008) noted that a therapeutic role for icatibant has also been proposed in several other human conditions including acute pancreatitis, airways disease, thermal injury, drug-induced angioedema (e.g., angiotensin-converting enzyme inhibitor-induced angioedema), and refractory ascites in patients with liver cirrhosis, although this work remains largely experimental.

Angioedema induced by treatment with angiotensin-converting-enzyme (ACE) inhibitors accounts for one third of angioedema cases in the emergency room; it is usually manifested in the upper airway and the head and neck region. There is no FDA approved treatment for this potentially life-threatening condition. The current standard therapy for treating ACEI-induced angioedema includes glucocorticoids and antihistamines, even though this type of angioedema is not histamine-mediated. As a result, the therapeutic response is limited. 

A clinical trial by Bas et al (2015) found that, among patients with ACE-inhibitor-induced angioedema, the time to complete resolution of edema was significantly shorter with icatibant than with combination therapy with a glucocorticoid and an antihistamine. In this multicenter, double-blind, double-dummy, randomized phase 2 study, investigators assigned patients who had ACE-inhibitor-induced angioedema of the upper aerodigestive tract to treatment with 30 mg of subcutaneous icatibant or to the current off-label standard therapy consisting of intravenous prednisolone (500 mg) plus clemastine (2 mg). The primary efficacy end point was the median time to complete resolution of edema. All 27 patients in the per-protocol population had complete resolution of edema. The median time to complete resolution was 8.0 hours (interquartile range, 3.0 to 16.0) with icatibant as compared with 27.1 hours (interquartile range, 20.3 to 48.0) with standard therapy (P=0.002). Three patients receiving standard therapy required rescue intervention with icatibant and prednisolone; 1 patient required tracheotomy. Significantly more patients in the icatibant group than in the standard-therapy group had complete resolution of edema within 4 hours after treatment (5 of 13 vs. 0 of 14, P=0.02). The median time to the onset of symptom relief (according to a composite investigator-assessed symptom score) was significantly shorter with icatibant than with standard therapy (2.0 hours vs. 11.7 hours, P=0.03). The results were similar when patient-assessed symptom scores were used. This study was too small to robustly evaluate safety; however, none of the patients discontinued the study because of AEs. The most common AEs were local redness, pain, and swelling at the injection site.

Kalbitor

On December 1, 2009, the FDA approved Kalbitor (ecallantide) to treat acute attacks of HAE in patients aged 16 years and older. Subsequently, in March 2014, the FDA lowered the approved age to patients 12 years and older. Kalbitor (ecallantide) is a potent and specific plasma kallikrein inhibitor. Acute attacks of hereditary angioedema (HAE), are produced by a deregulated kallikrein‐kinin system that results in the excess release of the vasodilator, bradykinin. Ecallantide reversibly inhibits plasma kallikrein, and blocks its binding site, inhibiting the conversion of HMWK to bradykinin, thereby reducing excess endogenous bradykinin and subsequent pathogenomonic signs or acute attacks of HAE.

Schneider et al (2007) stated that ecallantide, a kallikrein inhibitor, is a promising new therapy for HAE attacks.  In a double-blind, placebo-controlled, ascending-dose study, these investigators examined the efficacy and tolerability of ecallantide (5, 10, 20, or 40 mg/m(2) intravenously) in individuals experiencing acute HAE attacks (n = 49).  Twelve patients were assigned to each dose level: 10 to ecallantide and 2 to placebo, per cohort.  Ecallantide treatment improved the symptoms of HAE attacks: 72.5 % (29/40) of patients treated with ecallantide versus 25.0 % (2/8) of placebo patients reported significant improvement in symptoms within 4 hours (p = 0.0169).  Ecallantide was well-tolerated at all doses.  The authors concluded that ecallantide significantly improved HAE symptoms over placebo.  The trial provides strong support for the role of the kallikrein-kinin cascade and its end product, bradykinin, in the pathophysiology of HAE.  Lehmann (2008) noted that ecallantide is a recombinantly produced and engineered small protein based on the first Kunitz domain of human tissue factor pathway inhibitor.  The author stated that the drug is being studied for 2 major indications:

1. treatment of HAE, and
2. reduction of blood loss during on-pump cardiothoracic surgery.

The safety and effectiveness of Kalbitor was assessed in 2 randomized, double-blind, placebo-controlled trials -- EDEMA 4 and EDEMA3 that included 168 patients.  Patients having an attack of HAE, at any anatomic location and at least 1 moderate or severe symptom, were treated with a 30-mg subcutaneous dose of Kalbitor or placebo.  Because patients could participate in both trials, a total of 143 unique patients participated.  There were 24 with laryngeal attacks, 55 with peripheral attacks, and 64 patients with abdominal attacks.

In both clinical trials, the effects of Kalbitor were evaluated using the Mean Symptom Complex Severity (MSCS) score as well as the Treatment Outcome Score (TOS).  These indices measured the severity of attacks at all anatomical locations (MSCS score) and response to therapy (TOS).  The MSCS score is a point-in-time measure of symptom severity.  At baseline, 4 hrs, and 24 hrs, patients rated the severity on a categorical scale (0 = normal to 3 = severe) for symptoms at each affected anatomical site.  Ratings were averaged to obtain the MSCS score.  A decrease in the MSCS score indicated an improvement in symptoms.  The TOS is a measure of symptom response to treatment.  At 4 hrs and 24 hrs, patient assessment of response characterized by their change from baseline in symptom severity and collected by anatomical site of attack involvement, was recorded on a categorical scale (significant improvement = 100, improvement = 50, same = 0, worsening = -50, significant worsening = -100).  The response at each anatomical site was weighted by baseline severity and then the weighted scores across all involved sites were averaged to calculate the TOS.  A TOS value of greater than "0" indicated an improvement in symptoms from baseline.

A total of 96 patients were included in the EDEMA4 trial and they were randomized in a 1:1 manner to receive 30-mg Kalbitor subcutaneous injection or placebo for acute attacks of HAE.  The primary endpoint was the TOS at 4 hrs, and the key secondary efficacy endpoint was the change from baseline in MSCS at 4 hrs.  Patients treated with Kalbitor reported a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients with placebo and the results were statistically significant.  At 24 hrs, patients treated with Kalbitor also demonstrated a greater decrease from baseline in the MSCS than placebo (-1.5 versus -1.1; p = 0.04) and a greater TOS (89 versus 55, p = 0.03).  More patients in the placebo group (24/48, 50 %) needed medical intervention to treat unresolved symptoms within 24 hrs compared to the Kalbitor-treated group (16/48, 33 %).  Some patients reported improvement following a second 30-mg subcutaneous dose of Kalbitor, given within 24 hrs following the initial dose for symptom persistence or relapse, however, effectiveness was not systematically assessed for the second dose.

A total of 72 patients were enrolled in the EDEMA3 trial, and they were randomized 1:1 to receive Kalbitor or placebo for acute attacks of HAE.  The design of EDEMA3 was similar to EDEMA4 with the exception of the order of the pre-specified effectiveness endpoints.  In EDEMA3, the primary endpoint was the TOS at 4 hrs, and the key secondary efficacy endpoint was the change from baseline in MSCS at 4 hrs.  As in EDEMA4, patients treated with Kalbitor reported a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients treated with placebo and the results were statistically significant.  In addition, more patients in the placebo group (13/36, 36 %) needed medical intervention to treat unresolved symptoms within 24 hrs compared to the Kalbitor-treated group (5/36, 14 %).

Ecallantide is available as Kalbitor 10 mg/mL in a one mL single‐use vial. Kalbitor is administered subcutaneously in three 10-mg (1 ml) injections (a total of 30 mgs in 3 mls).  If an attack persists, an additional 30-mg dose may be administered in a 24-hr period. Kalbitor (ecallantide) should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.

The most serious side effect of Kalbitor is anaphylaxis.  Other AEs include diarrhea, fever, headache, nausea, skin irritations, as ell as swelling in the nose and throat.

Kalbitor (ecallantide) should be used with caution under the following conditions:

• Do not administer to a member with known clinical hypersensitivity to Kalbitor.
• Hypersensitivity reactions including anaphylaxis: Anaphylaxis has occurred in 4% of treated patients. Administer Kalbitor in a setting equipped to manage anaphylaxis and hereditary angioedema. Given the similarity in hypersensitivity symptoms and acute HAE symptoms, monitor patients closely for hypersensitivity reactions.

Members should be observed for an appropriate period of time after administration of Kalbitor, taking into account the time to onset of anaphylaxis seen in clinical trials. Given the similarity in hypersensitivity symptoms and acute HAE symptoms, members should be monitored closely in the event of a hypersensitivity reaction.

Ruconest

On Jul 17, 2014, the FDA approved Ruconest (a recombinant C1 esterase inhibitor) for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE). Ruconest is a human recombinant C1-esterase inhibitor purified from the milk of genetically modified (transgenic) rabbits. Ruconest replaces the missing or malfunctioning protein in patient and is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling. 

The safety and efficacy of Ruconest was evaluated in a multicenter controlled clinical trial. Forty-four adult and adolescent patients with acute attacks were treated with Ruconest. The most common adverse reactions reported in patients treated with Ruconest were headache, nausea and diarrhea. Ruconest received orphan-drug designation for acute attacks by the FDA because it is intended for treatment of a rare disease or condition. 

Ruconest is manufactured by Pharming Group NV, Leiden, the Netherlands, and will be distributed in the United States by Santarus Inc., a wholly owned subsidiary of Salix Pharmaceuticals Inc., Raleigh, NC.

Patients who have not previously received Ruconest should first be tested for the presence of IgE antibodies against rabbit epithelium (dander). Only patients shown to have negative results for such a test should be treated with Ruconest. IgE antibody testing should be repeated once a year or after 10 treatments, whichever occurs first.

The recommend dose of Ruconest is one intravenous injection of 50 U/kg for adults with a body weight <84 kg and one intravenous injection of 4200 U (two vials) for adults with a body weight ≥84 kg. It is administered as a slow intravenous infusion over 5 minutes. In the majority of cases, a single dose of Ruconest is sufficient to treat an acute angioedema attack. No more than two doses should be administered within 24 hours.

The effectiveness of Ruconest in the treatment of HAE patients with laryngeal attacks has not been established.

Contraindications:

• Ruconest is contraindicated in patients with a history of allergy to rabbits or rabbit-derived products.
• Ruconest is contraindiated in patients with a history of life-threatening immediate hypersensitivity reactions to C1 esterase inhibitor preparations, including anaphylaxis.

Warnings and Precautions:

• Hypersensitivity reactions, including anaphylaxis, may occur. Should symptoms occur, discontinue Ruconest and administer appropriate treatment.
• Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of plasma derived C1 esterase inhibitor products in patients with risk factors. Monitor patients wtih known risk factors for TE events during and after Ruconest administration.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Cinryze:
Other CPT codes related to the CPB:
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 (specify substance or drug); intravenous push
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
HCPCS codes covered if selection criteria are met:
J0598	Injection, C1 esterase inhibitor (human) cinryze, 10 units
ICD-10 codes covered if selection criteria are met:
D84.1	Defects in the complement system
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A41.9	Sepsis, unspecified
G45.0 - G45.2 G45.4 - G45.9	Transient cerebral ischemic attacks and related syndromes
I21.01 - I22.9	Acute and subsequent ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction
I60.00 - I67.2 I67.4 - I69.998	Cerebrovascular disease
R65.10 - R65.21	Symptoms and signs specifically associated with systemic inflammation and infection
Haegarda:
Other CPT codes related to the CPB:
86160	Complement; antigen, each component [C4 level]
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered for indications listed in the CPB:
J0599	Injection, c-1 esterase inhibitor (human), (haegarda), 10 units
ICD-10 codes covered if selection criteria are met:
D84.1	Defects in the complement system
Takhzyro:
Other CPT codes related to the CPB:
86160	Complement; antigen, each component [C4 level]
96401	Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic
HCPCS codes covered for indications listed in the CPB:
J0593	Injection, lanadelumab-flyo, 1 mg
ICD-10 codes covered if selection criteria are met:
D84.1	Defects in the complement system
Berinert:
Other CPT codes related to the CPB:
86160	Complement; antigen, each component [C4 level]
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96374	intravenous push, single or initial substance/drug
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
HCPCS codes covered if selection criteria are met:
J0597	Injection, C-1 esterase inhibitor (human), berinert, 10 units
ICD-10 codes covered if selection criteria are met:
D84.1	Defects in the complement system
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
D59.1	Other autoimmune hemolytic anemias [cold agglutinin disease]
Kalbitor (ecallantide):
Other CPT codes related to the CPB:
86160	Complement; antigen, each component [C4 level]
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J1290	Injection, ecallantide, 1 mg
ICD-10 codes covered if selection criteria are met:
D84.1	Defects in the complement system
Ruconest (recombinant C1 esterase inhibitor):
Other CPT codes related to the CPB:
86160	Complement; antigen, each component [C4 level]
96374 - 96376	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); intravenous push
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
HCPCS codes covered if selection criteria are met:
J0596	Injection, c1 esterase inhibitor (recombinant), ruconest, 10 units
ICD-10 codes covered if selection criteria are met:
D84.1	Defects in the complement system
E88.09	Other disorders of plasma-protein metabolism, not elsewhere classified
Icatibant (Firazyr):
Other CPT codes related to the CPB:
86160	Complement; antigen, each component [C4 level]
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J1744	Injection, icatibant, 1 mg
Other HCPCS codes related to the CPB:
J1380	Injection, estradiol valerate, up to 10 mg
J1410	Injection, estrogen conjugated, per 25 mg
J1435	Injection, estrone, per 1 mg
ICD-10 codes covered if selection criteria are met:
D84.1	Defects in the complement system

The above policy is based on the following references: