Description:
Hereditary angioedema (HAE) is characterized by self-limited tissue swelling that most often affects the skin and upper respiratory and gastrointestinal tracts. The prevalence of HAE is estimated between 1 in 10,000 to 1 in 150,000 worldwide, and the estimated population of people with HAE in the United States ranges from 6,000 to 10,000 people. There is a significant age-related difference in frequency of HAE attacks (there is an increase at the time of puberty), but quality of life is affected significantly at all ages. The underlying cause of HAE is attributed to autosomal-dominant inheritance of mutations in the C1-inhibitor (C1-INH) gene, which was mapped to chromosome 11. More than 200 mutations of this gene have been linked to the clinical HAE manifestations. The majority of HAE cases show a familial pattern of inheritance, whereas 25% are related to spontaneous mutations. There are three types of HAE; two types of HAE account for the majority of cases. An estimated 85% of all cases are type 1 HAE, which is characterized by a low levels of normal C1-INH. The majority of individuals with non-type 1 HAE have type 2 HAE, characterized by normal or elevated levels of C1-INH but it doesn’t function properly. Type III HAE is extremely rare, is an estrogen dependent form of angioedema, and occurs predominantly in females.

The initial laboratory test includes two specific blood tests to confirm the diagnosis of HAE: 1) the level of C1-INH and whether it is functioning properly and 2) C2 and C4, which will usually reveal low levels even when an attack is not ongoing. Table 1 describes the expected results for the blood tests. Indications for testing include any of the following: recurrent angioedema, laryngeal edema, abdominal pain in the absence of urticaria, or a family history of HAE.

Treatment options for HAE types I and II vary in terms of treatment for acute attacks, chronic therapy for individuals with frequent attacks, and short-term prophylactic treatment before or during a known exposure to triggers such as infection, surgery, dental work, and trauma. According to the current 2010 international consensus algorithm for the diagnosis, therapy, and management of HAE, supportive therapy combined with specific therapies is the preferred therapy for HAE attacks. General measures for treating attacks involve hydration, pain relief, and treating as soon as possible with plasma-derived C1-INH (i.e., Berinert^®), ecallantide (Kalbitor^®), or icatibant (Firazyr^®). For individuals with frequent episodes of angioedema or severe HAE, preventive measures include attenuated androgens (e.g., danazol), antifibrinolytic agents, or C1-INH (i.e., Cinryze^®).

Currently there are two commercially available C1 inhibitors available in the United States. Cinryze is approved by the US Food and Drug Administration (FDA) for prophylaxis in adolescents and adults; however, it has not been approved for the treatment of acute attacks. In contrast, Berinert is approved for use in acute attacks. The other treatment options, ecallantide and icatibant, work as kinin-pathway modulators. Ecallantide is a recombinant protein that acts as a potent reversible inhibitor of plasma kallikrein that ultimately stops production of bradykinin and the edema progression in acute HAE attacks. The main adverse event is the possibility of anaphylaxis, which can occur in up to 3% of individuals treated with subcutaneous ecallantide. To ensure that the benefits of this product outweigh the risks, the FDA requires a risk evaluation and mitigation strategy (REMS) for this agent. Self-treatment at home is strongly discouraged. Icatibant is a synthetic decapeptide that is a specific and selective competitive antagonist of the bradykinin B2 receptor (BK2R). It is structurally similar to bradykinin and binds to the BK2R with high affinity. Similar to ecallantide, icatibant is indicated for the treatment of acute angioedema in individuals with HAE.

Type III HAE is a relatively new disorder. At this time, a diagnostic test to confirm type III HAE is unavailable and the pathogenic mechanism(s) by which swelling is produced are uncertain. Appropriate treatment modalities have not been determined. The evidence supporting treatment with C1 inhibitors and other treatment options (e.g., ecallantide, icatibant) is limited to observational data (e.g., case reports and case series). 

Policy:

I. C1 Inhibitor (Cinryze and Haegarda) meets the definition of MEDICAL NECESSITY when used for the prophylaxis of hereditary angioedema (HAE) when not used in combination with other approved treatments for prophylaxis AND ALL of the following criteria are met: 

FDA-Approved Indication

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

1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing.
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, or plasminogen gene mutation as confirmed by genetic testing.
   2. Member has a family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month. 
3. Member has experienced attacks of a severity and/or frequency such that they would clinically benefit from prophylactic therapy with Cinryze. 

II. C1 Inhibitor (Berinert) meets the definition of MEDICAL NECESSITY when used to treat an acute angioedema attack (e.g., abdominal, facial, laryngeal) when not used in combination with other approved treatments for acute HAE attacks AND the following criteria are met:

FDA-Approved Indication

Treatment of acute abdominal, facial, or laryngeal attacks of hereditary angioedema (HAE) in adult and pediatric patients.

1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing.
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, or plasminogen gene mutation as confirmed by genetic testing.
   2. Member has a family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month. 

III. Ecallantide (Kalbitor) meets the definition of MEDICAL NECESSITY when used to treat an acute angioedema attack (e.g., abdominal, facial, laryngeal) when not used in combination with other approved treatments for acute HAE attacks AND the following criteria are met:

FDA-Approved Indication

Treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older. 

1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing.
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, or plasminogen gene mutation as confirmed by genetic testing.
   2. Member has a family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month. 

IV. Icatibant (Firazyr) meets the definition of MEDICAL NECESSITY when used to treat an acute angioedema attack (e.g., abdominal, facial, laryngeal) of HAE when not used in combination with other approved treatments for acute HAE attacks AND BOTH of the following criteria are met:

FDA-Approved Indication

Treatment of acute attacks of hereditary angioedema in adults 18 years of age and older. 

1. Member has C1 inhibitor deficiency or dysfunction as confirmed by laboratory testing.
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, or plasminogen gene mutation as confirmed by genetic testing.
   2. Member has a family history of angioedema and the angioedema was refractory to a trial of high-dose antihistamine (e.g., cetirizine) for at least one month.

V. Compendial use of Firazyr: Firazyr may be considered MEDICALLY NECESSARY in the treatment of angiotensin-converting enzyme (ACE) inhibitor-induced angioedema.

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

Dose Adjustment
Dosage adjustments for renal or hepatic impairment are not required. 

PRECAUTIONS:
Boxed Warning-Ecallantide
Anaphylaxis has been reported after administration of ecallantide. Because of the risk of anaphylaxis, ecallantide should only be administered by a health care provider with appropriate medical support to manage anaphylaxis and hereditary angioedema. Health care providers should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema, and patients should be monitored closely. Do not administer ecallantide to patients with known clinical hypersensitivity to ecallantide.

CONTRAINDICATIONS
C1-Inhibitors (Cinryze, Berinert), encallatide: Do not use in members with a history of life-threatening immediate hypersensitivity reactions, including anaphylaxis.

Hypersensitivity Reactions: Epinephrine should be immediately available to treat any acute severe hypersensitivity reactions following discontinuation of administration.

Thrombotic Events: Thrombotic events have been reported in association with C1 inhibitor products (Cinryze and Berinert) when used off-label at high doses. Members with known risk factors for thrombotic events should be monitored closely.

Human Plasma: Because C1 inhibitors (Cinryze and Berinert) are made from human blood, it may carry a risk of transmitting infectious agents (e.g., viruses and, theoretically, the Creutzfeldt-Jakob agent). All infections thought by a health care provider possibly to have been transmitted by C1 inhibitor should be reported by the health care provider to the manufacturer. Discuss the risks and benefits of this product with the patient before prescribing or administering.

Laryngeal Attacks: members should immediately seek medical attention following self-administration for the treatment of laryngeal attacks.

Rationale:
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).

Epstein and Bernstein (2008) stated that currently only Cinryze, a C1-esterase inhibitor product derived from human plasma, has been approved for prophylactic use against HAE attacks in the United States. In clinical trials, Cinryze was effective in preventing or reducing the frequency of attacks in most but not all HAE patients. Moreover, the approval by the Food and Drug Administration (FDA) for other novel agents to treat HAE and for the use of Cinryze in the treatment of acute attacks is pending. 

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: (i) Cinryze prophylaxis for 12 weeks followed by 12 weeks of placebo prophylaxis; or (ii) 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).

On Oct. 9, 2009, the FDA approved Berinert (a human C1 esterase inhibitor) for the treatment of adults and adolescents with acute attacks associated with HAE. The agent has been approved in Europe for about 20 years for prophylaxis as well as for treatment of acute attacks.

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 hours 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 hours 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 hours 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. Adverse events 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.

On Dec. 1, 2009, the FDA approved Kalbitor (ecallantide), a plasma kallikrein inhibitor, for the treatment of acute attacks of HAE in patients 16 years of age and older. The safety and effectiveness of Kalbitor was assessed in 2 randomized, double-blind, placebo-controlled trials, EDEMA 4 and EDEMA 3, 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.

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-hour period. The most serious side effect of Kalbitor is anaphylaxis. Other adverse events include diarrhea, fever, headache, nausea, skin irritations, as well as swelling in the nose and throat.

Icatibant (Firazyr, HOE 140, JE049), a potent and specific peptidomimetic bradykinin 2 receptor antagonist, inhibits the effects of bradykinin, which is thought to cause HAE. 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 hours after intravenous icatibant treatment. Symptom intensity decreased within 4 hours after administration of icatibant; the median time to onset of symptom relief was 1.50, 1.42, and 1.13 hours in the intravenous groups and 0.58 and 0.45 hours in the subcutaneous groups, respectively. The median difference in the 10-cm VAS 4 hours 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 hours (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.

On Aug. 25, 2011, the FDA approved icatibant (Firazyr) injection for the treatment of acute attacks of HAE in people ages 18 years and older. 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 hours compared with almost 20 hours with placebo. Firazyr is the third drug approved in the United States to treat HAE attacks. In October 2009 the FDA approved Berinert to treat facial and abdominal attacks of HAE, and Kalbitor was approved in December 2009 to treat acute attacks of HAE in patients aged 16 years and older. The most common adverse reactions reported by those using Firazyr were injection site reactions, fever, increased liver enzymes, dizziness, and rash. Patients are trained on how to self-administer the Firazyr injection. The majority of patients respond to 1 dose. Sometimes, up to 2 additional doses may be administered within a 24-hour period. If this is necessary, each additional dose must be done at least 6 hours apart.

DEFINITIONS:
C1 esterase inhibitor (C1-INH): A protein found in the plasma part of the blood that controls C1, the first component of the complement system. It also inhibits plasmin, thrombin, and kallikrein. Deficiency of or defect in the protein causes hereditary angioedema. 

Hereditary Angioedema: C1 Inhibitor deficiency, an autosomal dominant disorder of the complement system manifested as recurrent episodes of edema of the skin, upper respiratory tract, and gastrointestinal tract. It may follow minor trauma, sudden changes in environmental temperature, or sudden emotional stress.

References:

1. Berinert (Human C1-Esterase Inhibitor) [package insert]. CSL Behring LLC. Kankakee (IL): July 2012.
2. Bowen T, Brosz J, Brosz K, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010;6(1):24.
3. Cinryze (human C1-Esterase Inhibitor) [package insert]. ViroPharma Biologics, Exton (PA): June 2012.
4. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.;2012. URL www.clinicalpharmacilogy-ip.com Accessed 11/20/2012.
5. C1-Esterase Inhibitor. In McEvoy GK, editor. AHFS drug information 2012 [monograph on the internet]. Bethesda (MD): American Society of Health-System Pharmacists; 2012 [cited 2012 Nov 20]. Available from http://online.statref.com Subscription required to review.
6. Ecallantide. In McEvoy GK, editor. AHFS drug information 2012 [monograph on the internet]. Bethesda (MD): American Society of Health-System Pharmacists; 2012 [cited 2012 Nov 20]. Available from http://online.statref.com Subscription required to review.
7. Firazyr (icatibant) [package insert]. Shire US Manufacturing Inc. Lexington (MA): June 2012.
8. Kalbitor (ecallantide) [package insert]. Dyax Corp., Burlington (MA): February 2012.
9. Kaplan A. Type III hereditary angioedema: defined, but not understood. Ann Allergy Asthma Immunol 2012;109(3):153-4.
10. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 11/20/2012.
11. Sardana N, Craig TJ. Recent advances in management and treatment of hereditary angioedema. Pediatrics 2011;128(6):1173-80.
12. Epstein TG, Bernstein JA. Current and emerging management options for hereditary angioedema in the US. Drugs. 2008;68(18):2561-2573.
13. U.S. Food and Drug Administration (FDA), Center for Biologics Evaluation and Research (CBER). CINRYZE C1 esterase inhibitor (Human). Product Approval Information. Rockville, MD: FDA; October 10, 2008. Available at: http://www.fda.gov/cber/products/cinryze.htm. Accessed January 27, 2009.
14. U.S. Food and Drug Administration (FDA). FDA approves Berinert to treat abdominal attacks, facial swelling associated with hereditary angioedema. FDA News. Rockville, MD: FDA; October 9, 2009. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm186257.htm. Accessed October 30, 2009.
15. U.S. Food and Drug Administration (FDA). FDA approves Kalbitor for treating potentially life-threatening attacks of hereditary angioedema. FDA News. Rockville, MD: FDA; December 2, 2009. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm192687.htm. Accessed March 11, 2010.
16. Bernstein JA. Hereditary angioedema: A current state-of-the-art review, VIII: Current status of emerging therapies. Ann Allergy Asthma Immunol. 2008;100(1 Suppl 2):S41-S46.
17. U.S. Food and Drug Administration (FDA). FDA approves Firazyr to treat acute attacks of hereditary angioedema. FDA News. Rockville, MD: FDA; August 25, 2011. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269616.htm. Accessed August 26, 2011
18. No authors listed. FDA expands label of Berinert for hereditary angioedema. Pharmacy Practice News. December 2011. Available at: http://www.pharmacypracticenews.com/ViewArticle.aspx?d=Clinical&d_id=50&i=December+2011&i_id=801&a_id=19996. Accessed August 31, 2012.

Coding Section

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