Medical Policy

 

Subject: Pharmacotherapy for Hereditary Angioedema
Document #: DRUG.00058 Publish Date:    12/27/2017
Status: Revised Last Review Date:    08/03/2017

Description/Scope

This document addresses drugs that have been specifically developed for the treatment or prevention of hereditary angioedema (HAE) attacks: 

Position Statement

Medically Necessary:

  1. Pharmacotherapy with Berinert (C1 esterase inhibitor [human]), Firazyr (icatibant), Ruconest (C1 esterase inhibitor [recombinant]) or Kalbitor (ecallantide) for the treatment of acute attacks of hereditary angioedema is considered medically necessary when the following criteria are met:
    1. The individual's age is appropriate (5 years and older for Berinert; 13 years and older for Ruconest; 18 years and older for Firazyr; 12 years and older for Kalbitor) for the specific drug requested; and
    2. The diagnosis of hereditary angioedema was confirmed by a C4 level below the lower limit of normal as defined by the laboratory performing the test AND ONE of the following (a or b):
      1. C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test, or
      2. C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test; and
    3. There is a history of moderate or severe attacks (for example, airway swelling, severe abdominal pain, facial swelling, nausea and vomiting, painful facial distortion); and
    4. The drug is being used for treatment of acute attacks (not for prophylaxis); excluding use of Ruconest in individuals with laryngeal attacks.
  2. Pharmacotherapy with Cinryze or Haegarda (C1 esterase inhibitor [human]) for prophylaxis against acute attacks of hereditary angioedema in adults and adolescents is considered medically necessary when the following criteria are met:
    1. The individual's age is 12 years or older; and
    2. The diagnosis of hereditary angioedema was confirmed by a C4 level below the lower limit of normal as defined by the laboratory performing the test AND ANY of the following (a, b, or c):
      1. C1 inhibitor (C1-INH) antigenic level below the lower limit of normal as defined by the laboratory performing the test, or
      2. C1-INH functional level below the lower limit of normal as defined by the laboratory performing the test, or
      3. Presence of a known HAE-causing C1-INH mutation; and
    3. There is a history of moderate or severe attacks (for example, airway swelling, severe abdominal pain, facial swelling, nausea and vomiting, painful facial distortion); and
    4. The drug is being used for prophylaxis for EITHER of the following (a or b) indications:
      1. Short-term prophylaxis prior to surgery, dental procedures or intubation; or
      2. Long-term prophylaxis and the individual has failed, or is intolerant to, or has a contraindication (for example, under the age of 12, or pregnant, or breastfeeding) to 17 alpha-alkylated androgens (for example, danazol) or antifibrinolytic agents (for example, aminocaproic acid).

Investigational and Not Medically Necessary:

The use of Berinert, Haegarda, Cinryze, Firazyr, Kalbitor or Ruconest is considered investigational and not medically necessary when the criteria are not met and for all other indications including acquired angioedema.

Rationale

Description of Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is a chronic autosomal dominant disorder associated with recurrent, unpredictable, and potentially life-threatening acute attacks.  There are three known types of HAE with types I and II being most common.  Type I HAE is considered most common, occurring in approximately 85% of identified cases of HAE.  Type II HAE occurs in approximately 15% of identified cases (Georgy, 2012).  Types I and II are associated with mutations to C1-INH, which is a serine protease inhibitor responsible for regulatory functions in the fibrinolytic systems.  Mutations to C1-INH are located on Chromosome 11q and inherited as an autosomal dominant trait.  C1-INH deficiency results in an overproduction of bradykinin which is a vasodilator thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain.  Mutations that cause type I HAE lead to reduced levels of C1-INH in the blood, while mutations that cause type II HAE result in the production of dysfunctional C1-INH.  Type III HAE, also known as HAE with normal CI-INH, is extremely rare and occurs primarily in women.  Type III HAE may be estrogen dependent and is associated with normal C1-INH and C4 levels, although some will demonstrate activating mutations in the coagulation factor XII (Hageman factor; HAE-FXII) (Wahn, 2012).  Bradykinin is a key mediator of HAE symptoms for all three types of HAE, due to absent or abnormal components in bradykinin metabolizing pathways.  Some cases of type III HAE are noted to have a gain-of-function, (that is, increased activity), in the F12 gene which encodes factor XII; this coagulation factor is considered integral to bradykinin production (Boccon-Gibod, 2012).  Treatments for HAE type III are not established, but tranexamic acid seems to be effective for prophylaxis of symptoms.  Until recently, the main short-term treatment for severe HAE attacks was C1-INH concentrate (Bork, 2009).

According to a review by Bouchard (2012), in addition to the three known types of HAE, acquired forms or forms with no known etiology also exist, (that is, idiopathic HAE).  Increased bradykinin production, leading to increased vessel permeability, is common to all HAE types (Bouchard, 2012).  Acquired angioedema (AAE) is caused by either consumption (type 1) or inactivation (type 2) of CI-INH.  Both HAE and AAE can be life-threatening.  The screening test for both conditions is complement component C4, which is low to absent at times of angioedema or during quiescent periods.  A useful test to differentiate HAE from AAE is C1q protein, which is normal in HAE and low in AAE (Georgy, 2012).

In 2012, a series of international consensus documents were developed by an international workgroup, termed the International Collaboration in Asthma, Allergy, and Immunology, in which the pathogenesis, prevalence, clinical manifestations, diagnosis, and management of angioedema are described.  These consensus papers describe two subtypes of HAE with normal C1-INH, either associated with a mutation in the factor XII gene or of unknown cause.  Some excerpts follow regarding idiopathic HAE and AAE (referred to as ACID in these papers):

Mutations of the factor XII gene have been identified in some families, but the pathophysiology is still undefined. Acquired C1-INH deficiency (ACID) is frequently associated with lymphoproliferative diseases and/or autoantibodies against C1-INH that may be responsible for C1-INH consumption.  Autoimmune disorders (for example, systemic lupus erythematosus) have also been described in association with ACID. Angioedema may also be caused by an angiotensin-converting enzyme inhibitor (ACEI), which interferes with bradykinin degradation…In ACID, the C1q level, which is normal in HAE patients with rare exceptions, is low in most cases. Presence of an underlying malignant tumor or detection of C1-INH autoantibodies strongly supports a diagnosis of ACID. The diagnosis of idiopathic angioedema is based on the exclusion of known causes of angioedema, including C1-INH deficiency…Because the pathogenesis of ACID entails low levels of C1-INH due to increased catabolism, either related to a malignant tumor (for example, lymphoma) or an autoimmune disorder (for example, systemic lupus erythematosus), treatment of such an underlying condition can result in improvement in ACID. Compared with HAE, anecdotal evidence implies these patients may be less responsive to attenuated androgens but exhibit greater response to treatment with antifibrinolytic agents.   Response to plasma-derived CI-NH may be less reliable based on the presence of C1-INH antibodies.  Icatibant and ecallantide have been reported to be efficacious for treatment of attacks…Although recent advances in our understanding of C1-INH deficiency syndromes and the introduction of the 5 novel medications (Berinert, Cinryze, Firazyr, Kalbitor, and Rhucin [recombinant human C1-INH, Pharming, Group, Leiden, Netherlands – not available in the U.S. ]) carry the promise of improved health care outcomes for patients with HAE, these advances have not translated into improved outcomes for many patients with HAE and ACID in resource-limited environments…These agents are efficacious and safe for on-demand treatment and are most effective when administered early in an attack…(Regarding AAE - ACID), response to plasma-derived CI-NH may be less reliable based on the presence of C1-INH antibodies. Icatibant and ecallantide have been reported to be efficacious for treatment (Lang, 2012).

The signs and symptoms associated with acute HAE attacks include intense and painful swelling of the face, larynx, gastrointestinal (GI) tract, limbs, or genitalia.  Approximately 50% of individuals with untreated HAE have monthly exacerbations and another 40% have 6 to 11 attacks annually (Khan, 2011; Zilberberg, 2011).  Episodic attacks of HAE produce edema in three primary areas: periphery, abdomen, and larynx.  Peripheral attacks are associated with painful disfigurement and physical disability; abdominal attacks result in severe abdominal pain, nausea, and vomiting; and laryngeal attacks may result in death by asphyxiation.  HAE attacks are associated with a variety of triggers, such as infection, trauma (including minor trauma such as dental extraction), menstruation, pregnancy, stress, and medication use, (for example, angiotensin-converting enzyme [ACE] inhibitors or oral contraceptives).  An individual with HAE may be sensitive to multiple triggers related to HAE attacks, and it is often difficult or impossible to identify all of the triggers for a particular individual with HAE.

C1-INH titers less than 30% of normal with profoundly depressed C4 levels confirm the diagnosis of HAE.  Antigenic levels of C1-INH are low in type I HAE with C4 concentrations less than 10 mg/dL even during quiescent asymptomatic periods.  In type II HAE, C1-INH levels are normal but functional analysis reveals reduced activity.  Individuals with type III HAE have normal C1-INH levels and function and normal C4 concentrations.  The absolute concentrations of C1-INH and C4 do not change during periods of acute symptoms of HAE, and, therefore, laboratory testing for C1-INH and C4 can occur prior to acute attacks.  The concentration of C4 is the test of choice to confirm or exclude a diagnosis of HAE (Georgy, 2012). 

U.S. Food and Drug Administration (FDA) Information

All six currently available HAE drugs have been granted marketing approval by the U.S. Food and Drug Administration (FDA) under the Orphan Drug Designation.  Berinert (C1 Esterase Inhibitor [Human]) was initially approved by the FDA in 2009, "As a plasma-derived C1 Esterase Inhibitor (Human) indicated for the treatment of acute abdominal, facial, or laryngeal attacks of hereditary angioedema (HAE) in adult and adolescent patients. The safety and efficacy of Berinert for prophylactic therapy has not been established" (FDA, 2011).  On February 11, 2014 the FDA issued an updated approval letter for Berinert which includes revisions to the Warnings and Precautions section of the package insert regarding the risk factors for thromboembolic events.  This information has been provided to the FDA from the manufacturer in revised labeling for package inserts for Berinert as follows:

Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of C1 Esterase Inhibitor (human) products, including Berinert, following administration in patients with HAE.  Risk factors may include the presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives or certain androgens, morbid obesity, and immobility.  Benefits of treatment of HAE attacks should be weighed against the risks of TE in patients with underlying risk factors.  Monitor patients with known risk factors for TE events during and after Berinert administration.  TE events have been reported following administration of a C1 Esterase Inhibitor (human) product when used off-label at higher than labeled doses (FDA, 2014).

On July 18, 2016 the FDA issued an additional update to the Berinert label with an expanded indication for use in the pediatric population (FDA, 2016).  The revised label reads as follows:

Safety and efficacy of Berinert have been evaluated in 12 pediatric patients with HAE (age range 10 to 16 years) in the placebo controlled and open-label extension studies. Berinert was also evaluated in 18 pediatric patients with HAE (age range 5 to 11 years) in a Registry Study conducted in the US and Europe. The safety profile observed in the pediatric population was similar to that observed in adults. The pharmacokinetics of Berinert were evaluated in 5 pediatric subjects (ages 6 through 13) (FDA, 2016).

In September 2016, the FDA issued additional warnings and precautions for Berinert related to:

On June 22, 2017 the FDA issued approval, under the Orphan Drug Designation, for Haegarda, a plasma-derived concentrate of C1 esterase inhibitor (Human), for subcutaneous use twice weekly.  The approved indications are, "For routine prophylaxis to prevent HAE attacks in adolescents and adult patients" (FDA, 2017).  Haegarda carries the same warnings and precautions as Berinert related to severe hypersensitivity, TE events and potential transmission of infectious agents.  Haegarda is contraindicated in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis to C1-INH preparations or its excipients.  The safety and efficacy of Haegarda was demonstrated in a prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, cross-over phase III trial.  The COMPACT trial (Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy) included 90 subjects with type I or II HAE who had had four or more attacks in a consecutive 2-month period within the 3 months before screening.  Eligible subjects were 12 years of age or older and had a clinical and central laboratory diagnosis of type I or II HAE (that is, a functional C1 inhibitor activity of < 50% and C4 antigen level below the normal level).  Trial participants were randomly assigned to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods.  Trial subjects self-administered Haegarda subcutaneously twice weekly with either 40 IU or 60 IU per kilogram of body weight.  The treatment phase was followed by a 16-week period when placebo was given or vice versa for those who had received placebo in the first phase who were then given Haegarda for the second 16-week period.  The primary efficacy endpoint was the number of attacks of HAE, and secondary efficacy endpoints were the proportion of subjects who responded to Haegarda, which was defined as a ≥ 50% reduction in the number of attacks, as compared with placebo, and the number of times that rescue medication was used. 

The study results showed that both doses of Haegarda reduced the rate of HAE attacks (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; p<0.001 for both comparisons).  Response rates were 76% (95% CI, 62 to 87) in the 40 IU group and 90% (95% CI, 77 to 96) in the 60 IU group.  The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40 IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60 IU group.  Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of subjects who received Haegarda and those who received placebo.  Since the trial had a limited observation period of 14 weeks per treatment period (after the exclusion of the 2-week run-in or washout period), it was not possible to assess the safety and preventive effects of long-term continuous prophylaxis with Haegarda.  An open label extension trial is ongoing to address this question and to investigate whether individual dose adjustments can further improve treatment response.  The authors concluded that use of Haegarda significantly lowered the rate of HAE attacks, as compared with placebo with more than 50% of trial participants having no moderate to severe HAE attacks while on Haegarda (Longhurst, 2017).

Firazyr (icatibant) was approved by the FDA in 2011, "As a bradykinin B2 receptor antagonist indicated for treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older" (FDA, 2013).  Kalbitor (ecallantide) was approved by the FDA in 2009, "As a plasma kallikrein inhibitor indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 16 years of age and older" (FDA, 2009).  Cinryze (C1 Esterase Inhibitor, human) was originally approved by the FDA in 2008, "As a C1 esterase inhibitor indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE)" (FDA, 2014).  Notably, the FDA has issued a Black Box Warning for Kalbitor regarding anaphylaxis: 

Because of the risk of anaphylaxis, KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.  Healthcare professionals should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema and patients should be monitored closely.  Do not administer KALBITOR to patients with known clinical hypersensitivity to KALBITOR (FDA, 2009). 

Due to this FDA warning, Kalbitor must always be administered by a healthcare professional.  Berinert and Cinryze are administered by a short intravenous infusion; Haegarda, Firazyr and Kalbitor are given by subcutaneous injections.  Haegarda, Berinert, Firazyr and Cinryze can be self-administered if the individual can recognize the symptoms of an impending HAE attack and after adequate training and guidance has been provided by a healthcare professional.

In March, 2014 the FDA labeling for Kalbitor was expanded to change the age to 12 years and older for the treatment of acute attacks of HAE.  This expansion, to reduce the age limit from 16 years to 12 years and older, was based on the results of the two randomized, double-blind, placebo-controlled trials (EDEMA3 and EDEMA4, described below), which included subjects from 10 to 78 years of age.  According to the updated FDA labeling:

The efficacy of KALBITOR in the 12-15 year age group is extrapolated from efficacy in patients 16 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and adolescents…The safety profile observed in pediatric patients 12-17 years of age was similar to the adverse reactions observed in the overall clinical trial population.  The safety and effectiveness of KALBITOR in patients less than 12 years of age has not been established (FDA, 2014).

Ruconest (C1 esterase inhibitor [recombinant]) was approved by the FDA in July 2014 as an intravenous therapy for acute attacks in adults and adolescents with HAE.  The product information label (2014) notes a limitation of Ruconest is the lack of established effectiveness to treat individuals with laryngeal attacks.  Safety and efficacy of Ruconest in pediatrics were evaluated in adolescents 13-17 years of age.  Warnings from the product information label (2014) include:

Hypersensitivity reactions, including anaphylaxis may occur.  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 with known risk factors for TE events during and after Ruconest administration.

Clinical Trial Evidence for Ecallantide (Kalbitor)

Although, to date, no head-to-head direct comparative studies have been conducted of these six HAE drugs, small phase III, randomized controlled trials (RCT) have been reported with varying trial designs and efficacy endpoints.  In 2010, Cicardi conducted a double-blind, placebo-controlled trial to evaluate ecallantide (Kalbitor) in the treatment of acute HAE attacks, the Evaluation of DX-88's Effects in Mitigating Angioedema (EDEMA3 trial).  Subjects presenting with an acute attack were randomly assigned, in a 1:1 ratio, to receive subcutaneous ecallantide, at a dose of 30 mg, or placebo.  Two measures of self-reported outcomes were used to assess the response: (1) treatment outcome scores, which ranged from +100 (designated in the protocol as significant improvement in symptoms) to -100 (significant worsening of symptoms), and (2) the change from baseline in the mean symptom complex severity score, which ranged from +2 (representing a change from mild symptoms at baseline to severe symptoms after) to -3 (representing a change from severe symptoms at baseline to no symptoms after).  The primary endpoint was the treatment outcome score at 4 hours after drug administration.  A total of 71 of the 72 trial participants completed the trial.  The median treatment outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in the placebo group (interquartile range [IQR], 0.0 to 100.0 in both groups; p=0.004).  The median change in the mean symptom complex severity score at 4 hours was -1.00 (IQR, -1.50 to 0.00) with ecallantide, versus -0.50 (IQR, -1.00 to 0.00) with placebo (p=0.01).  The estimated time to significant improvement was 165 minutes with ecallantide versus more than 240 minutes with placebo (p=0.14).  There were no deaths, treatment-related serious adverse events, or withdrawals owing to adverse events.  The authors concluded that 4 hours after administration of ecallantide or placebo for acute attacks of HAE, subject self-reported treatment outcome scores and mean symptom complex severity scores were significantly better with ecallantide than with placebo (Cicardi, 2010a). 

A second phase III, double-blind study of subcutaneous ecallantide (Kalbitor) treatment for acute attacks of HAE (the EDEMA4 trial) was reported by Levy, in which subjects with a moderate to severe HAE attack were randomized 1:1 to receive 30 mg of subcutaneous ecallantide or placebo.  The primary efficacy endpoint was change from baseline in mean symptom complex severity score 4 hours after dosing.  Additional endpoints included treatment outcome score 4 hours after dosing and maintenance of significant overall improvement through 24 hours.  A total of 96 subjects were enrolled. Mean standard deviation (SD) change from baseline in mean symptom complex severity score 4 hours after dosing was significantly greater with ecallantide use (-0.8 [0.6]) compared with placebo use (-0.4 [0.8]) (p=0.01 comparing distributions).  Ecallantide therapy was also associated with a significantly larger mean SD treatment outcome score 4 hours after dosing vs. placebo use (ecallantide: 53.4 [49.7]; placebo: 8.1 [63.2]; p=0.003 comparing distributions).  The benefit of ecallantide was apparent within 2 hours after dosing and was maintained through 24 hours after dosing.  More subjects on Kalbitor maintained a significant improvement in response over 24 hours than those on placebo (44% vs. 21%; p=0.02).  The safety profile was similar between the two groups (Levy, 2010).

A post-hoc analysis of the study populations from the EDEMA3 and EDEMA4 studies was conducted in 2012 to assess the potential risk for attack rebound or relapse following ecallantide treatment.  Symptoms were assessed by treatment outcome score (TOS), mean symptom complex severity (MSCS) score, and global response.  Trial subjects with improvement at 4 hours post-dosing in all three measures followed by any sign of worsening at 24 hours were considered to show potential rebound, (if worsening was beyond the baseline) or potential relapse (if not beyond the baseline).  The probability of rebound or relapse was determined by the number of measures showing worsening and the magnitude of worsening.  Subjects receiving placebo who met the criteria for rebound/relapse were evaluated for descriptive comparison only.  The results showed significantly more ecallantide-treated subjects (42 of 70), compared to placebo (26 of 71), showed improvement in the three measures at 4 hours and were considered eligible for rebound/relapse (p=0.006).  Of the 9 ecallantide-treated subjects showing signs of worsening at 24 hours, none were likely rebound; 1 was assessed as possible rebound, 1 as likely relapse, and 2 as possible relapse.  No subjects with potential for rebound/relapse experienced new symptoms after dosing.  Medical intervention was required in 1 ecallantide-treated subject.  The authors concluded that ecallantide was efficacious for treating acute HAE attacks.  Relapse was observed in a small proportion of trial subjects, and there was little evidence of rebound (Bernstein, 2012).

MacGinnitie and colleagues studied the safety and efficacy of ecallantide for treatment of HAE attacks in pediatric subjects less than 18 years of age.  Data for subjects aged 9 to 17 years who were treated subcutaneously with 30 mg ecallantide or placebo were pooled from four clinical studies (two double-blind, placebo-controlled and two open-label).  Efficacy endpoints included two HAE-specific individual subject-reported outcome measures: (1) mean symptom complex severity (MSCS) score and (2) treatment outcome score (TOS).  Times to initial improvement, sustained improvement, and complete or near-complete symptom resolution were calculated.  Overall, 29 pediatric subjects were included in the analysis; 25 of them received ecallantide for 62 total HAE attacks, and 10 received placebo for 10 total attacks.  Ecallantide-treated attacks revealed clinically relevant reductions in symptom severity at 4 hours post-dosing based on mean change in MSCS score (-1.4 ± 0.9 ecallantide versus -0.9 ± 0.6 placebo) and TOS (73.9 ± 35.50 ecallantide versus 45.0 ± 43.78 placebo).  Subjects treated with ecallantide showed rapid improvement in symptoms (median time to complete or near-complete symptom resolution: 181 minutes), and no serious adverse events related to treatment were observed.  The authors concluded that treatment with ecallantide appeared effective for HAE attacks in pediatric subjects with rapid symptom improvement and no unexpected safety issues identified (MacGinnitie, 2013).

Clinical Trials Evidence for Icatibant (Firazyr)

Icatibant (Firazyr) was studied in three double-blind RCT of subjects presenting with HAE involving cutaneous or abdominal symptoms; the For Angioedema Subcutaneous Treatment trials (FAST-1, FAST-2, and FAST-3).  In FAST-1, subjects received either icatibant or placebo; in FAST-2, subjects received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days; and in the FAST-3 trial, subjects with moderate to very severe cutaneous or abdominal symptoms received icatibant (n=43) or placebo (n=45).  Five additional subjects with laryngeal (mild-to-moderate) first attacks received icatibant (n=3) or placebo (n=2), and 5 subjects with severe laryngeal first attacks received open-label icatibant.  In the FAST-1 and FAST-2 trials, a total of 56 and 74 subjects underwent randomization.  The primary endpoint was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (p=0.14) and in 2.0 hours with icatibant versus 12.0 hours 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 trial subjects and by investigators, was significantly shorter with icatibant in both trials.  No icatibant-related serious adverse events were reported.  In the FAST-3 trial, icatibant significantly reduced median times (vs. placebo) to 50% or more reduction in symptom severity (2.0 vs. 19.8 hours; p<0.001, primary endpoint), onset of primary symptom relief (1.5 vs. 18.5 hours; p<0.001, key secondary endpoint), or almost complete symptom relief (8.0 vs. 36.0 hours; p=0.012) and provided a shorter time to initial symptom relief (0.8 vs. 3.5 hours; p<0.001).  For laryngeal attacks, median time to 50% or more reduction in symptom severity was 2.5 hours (icatibant) and 3.2 hours (placebo).  No icatibant-treated subjects required rescue medication before symptom relief occurred.  The incidence of adverse events (AEs) was similar in icatibant- and placebo-treated subjects (41% and 52%, respectively).  All icatibant-treated subjects experienced injection site reactions, but none reported clinically relevant changes in safety parameters or serious AEs.  The investigators of the FAST-1 and FAST-2 trials found a significant benefit of icatibant, as compared with tranexamic acid in the FAST-2 and a non-significant benefit of icatibant, as compared with placebo in the FAST-1 with regard to the primary endpoint.  The authors concluded that early use of rescue medication may have obscured the benefit of icatibant in the FAST-1 trial (Cicardi, 2010b).  Results of the FAST-3 trial demonstrated that icatibant was effective and generally well tolerated in subjects with acute HAE attacks resulting from C1-INH deficiency or dysfunction, type I/II (Lumry, 2011).

To date, only one small Phase II trial has published results for the use of icatibant in ACE inhibitor-induced angioedema.  This randomized trial included 27 subjects with an age range from 18 to 95 years who were receiving ACE inhibitors and who presented to the emergency department with ACE inhibitor-induced angioedema affecting the upper aerodigestive tract (which includes the face, lips, cheeks, tongue, soft palate or uvula, pharynx, and larynx).  Eligible subjects were randomly assigned, in a 1:1 ratio, to receive, within 10 hours after symptom onset, subcutaneous icatibant, at a dose of 30 mg injected into the abdominal wall, or standard therapy consisting of intravenous prednisolone (Solu-Decortin H, Merck) at a dose of 500 mg plus clemastine (Tavegil, Novartis) at a dose of 2 mg.  Randomization was performed online with the use of variable block sizes to ensure balanced numbers of study participants in both groups.  Normal saline was administered as an intravenous placebo to those subjects who were receiving icatibant and as a subcutaneous placebo to those who were receiving standard therapy. The trial participants and investigators who were responsible for the assessment of efficacy outcomes were all blinded to the study assignments.  Individual self-assessments were documented for the intensity of six symptoms (pain, shortness of breath, dysphagia, change in voice, sensation of a foreign body, and feeling of pressure) before treatment and at 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after treatment with the use of a visual-analogue scale that ranged from 0 to 10, with higher scores indicating more severe symptoms.  A composite score on the visual analogue scale was calculated as the average of the measurements for the six symptoms.  The trial investigators also assessed the severity of the same six symptoms at the same time points, using a scale from 0 (no symptoms) to 3 (severe symptoms), and a composite symptom score was calculated from the average of the six symptom scores.  In addition, investigators conducted physical assessments of the severity of angioedema at four specific sites (which were the lips and cheeks, tongue, oropharynx, and hypopharynx or larynx), using a scale from 0 (no angioedema) to 4 (very severe angioedema).  Angioedema of the oropharynx and hypopharynx was assessed by an ear, nose, and throat specialist.  If no reduction in symptoms had occurred by 6 hours after treatment, the investigator could administer rescue medication (30 mg of icatibant with 500 mg of prednisolone), regardless of the group the subject had been assigned to.  The primary endpoint was the time to complete resolution of edema after administration of the study treatment, as evaluated on the basis of investigator-assessed and subject-assessed symptom scores, as well as the investigators' assessment of the severity of angioedema on the basis of the physical examination.  Secondary endpoints included the proportion of subjects who did not respond to treatment (that is, those who required rescue therapy), the proportion of subjects with complete resolution of edema at 4 hours after treatment, and the time to onset of symptom relief. 

The results showed a median time to complete resolution at 8.0 hours (IQR range, 3.0 to 16.0) with icatibant, as compared with 27.1 hours (IQR range, 20.3 to 48.0) with standard therapy (p=0.002).  A total of 3 subjects in the standard therapy arm required rescue intervention with icatibant and prednisolone, and 1 required tracheotomy.  The investigators concluded that significantly more trial subjects 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 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 individual self-assessed symptom scores were used (Bas, 2015).  Although the results of this initial trial of icatibant use in ACE inhibitor-induced angioedema reflected encouraging results, further study is needed to establish the safety and efficacy of icatibant use in this population.

Clinical Trials Evidence for C1-esterase inhibitor, human (Berinert and Cinryze)

Berinert was studied in 2009 in a double-blind RCT of 125 subjects with type I or II HAE.  The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of subjects with worsened intensity of angioedema symptoms between 2 and 4 hours after treatment, and number of vomiting episodes within 4 hours.  Pasteurized C1-esterase inhibitor concentrate (Berinert) at intravenous doses of 10 or 20 U/kg body weight were compared with placebo.  The median time to onset of relief was significantly shorter with Berinert at a dose of 20 U/kg than with placebo (0.5 vs. 1.5 hours; p=0.0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs. 1.5 hours; P=0.2731).  Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs. 13.5 hours).  The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus.  The authors concluded that Berinert given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial HAE attacks with a rapid onset of relief (Craig, 2009).

In 2010, Zuraw reported results of two double-blind, RCT of nanofiltered C1 inhibitor concentrate (Cinryze) for the management of HAE; one study investigated its use in the treatment of acute HAE attacks and the other study investigated Cinryze use in HAE prophylaxis.  In the first study (of HAE acute attack treatment), a total of 68 subjects (35 in the C1 inhibitor group and 33 in the placebo group) were given 1 or 2 intravenous injections of Cinryze (1000 units each).  The primary endpoint was the time to the onset of unequivocal relief.  The second study was a crossover trial involving 22 subjects with HAE that compared prophylactic twice-weekly injections of Cinryze (1000 units) with placebo during two 12-week periods.  The primary endpoint was the number of attacks of HAE per period, with each subject acting as his or her own control.  In the first study, the median time to the onset of unequivocal relief from an attack was 2 hours in the subjects treated with Cinryze but longer than 4 hours in those given placebo (p=0.02).  In the second study, the number of attacks per 12-week period was 6.26 with Cinryze given as prophylaxis, as compared with 12.73 with placebo (p<0.001); the subjects who received Cinryze also had significant reductions in both the severity and the duration of attacks, in the need for open-label rescue therapy, and in the total number of days with swelling (Zuraw, 2010).

Clinical Trials Evidence for C1-esterase inhibitor, human (Haegarda)

The critical COMPACT trial of Haegarda has already been described in detail.  Results of a phase II trial have also been published.  This open-label, dose-ranging, crossover study (COMPACT Phase II) was conducted in 18 subjects with type I or II HAE who received two of twice-weekly 1500, 3000, or 6000 IU SC doses of highly concentrated, volume-reduced Haegarda for 4 weeks each.  The mean trough plasma levels of C1-INH functional activity, C1-INH and C4 antigen levels during Week 4, and overall safety and tolerability were evaluated.  The primary outcome was model-derived steady-state trough C1-INH functional activity.  After SC administration of Haegarda, a dose-dependent increase in trough functional C1-INH activity was observed.  C1-INH and C4 levels both increased.  The two highest dose groups (3000 and 6000 IU) achieved constant C1-INH activity levels above 40% values, which was a threshold that was assumed to provide clinical protection against attacks.  Compared with intravenous injection, C1-INH SC injections of Haegarda showed a lower peak-to-trough ratio and more consistent exposures.  All doses were well tolerated.  Mild-to-moderate local site reactions were noted with pain and swelling being the most common adverse event.  The authors concluded that SC volume-reduced Haegarda was well tolerated and led to a dose-dependent increase in physiologically relevant functional C1-INH plasma levels.  However, the authors of this trial noted that a clinical outcome study of SC Haegarda in HAE warrants further investigation (Zuraw, 2015).

Clinical Trials Evidence for Ruconest C1 esterase inhibitor (recombinant)

Riedl (2014) reported results from a phase III, double-blind, randomized, placebo-controlled trial with an open-label extension phase.  A total of 227 individuals were screened and 75 eligible individuals with acute HAE attacks were randomized for therapy.  Participants were at least 13 years old.  The Ruconest treatment arm included 44 individuals and the placebo arm included 31 individuals.  Individuals in the treatment arm weighing less than 84 kg received Ruconest 50 IU/kg and individuals weighing 84 kg or more received 4,200 IU intravenously.  The study's primary efficacy endpoint was onset of sustained relief from symptoms at the primary attack location.  A Treatment Effect Questionnaire (TEQ) was utilized to record responses and the time to onset of sustained symptom relief was significantly shorter for those in the Ruconest treatment cohort compared to the placebo group (90 minutes vs. 152 minutes, p=0.031).  Overall severity documented by the visual analog scale (VAS) also had significantly shorter time to onset of sustained symptom relief for the treatment group compared to placebo (75 vs. 303 minutes, p=0.003).  Due to insufficient statistical power, effectiveness was not established in individuals with laryngeal attacks (study population: n=2 vs. 3 in the intervention and placebo groups, respectively, for individuals with laryngeal attacks).  FDA labelling reflects this limitation for use.

Specialty Medical Society Guidance

In 2010, a multinational committee published a consensus statement through the Canadian Society of Allergy and Clinical Immunology regarding the management of HAE.  The following is excerpted from the Hereditary Angioedema International Working Group (Cicardi, 2012) and the International Consensus Algorithm (Bowen, 2010):

Interventions for acute HAE attacks include both pharmacological therapy and the possibility of intubation in case of a severe laryngeal attack.  First-line agents for the treatment of an acute attack of HAE include plasma-derived C1-esterase inhibitor (Berinert or Cinryze), ecallantide (Kalbitor) and icatibant (Firazyr).  In the U.S., Berinert is labeled for acute treatment and Cinryze is only labeled for prophylaxis of HAE attacks, however, international guidelines indicate the C1-esterase inhibitors are interchangeable. When first-line agents are not available, fresh frozen plasma (FFP) is recommended. Recommendations for short term prophylaxis depend on the availability of C1-esterase inhibitors (Berinert and Cinryze). In minor manipulations (for example, dental work), no prophylaxis is necessary, as long as a C1-esterase inhibitor is immediately available. Major procedures (for example, surgery or intubation) require administration of C1-esterase inhibitor prior to the procedure. When C1-esterase inhibitor is not available, danazol or stanozolol are recommended for both minor and major procedure prophylaxis. C1-esterase inhibitor, androgens, or antifibrinolytic agents are recommended for long-term prophylaxis.

In 2012, the U.S. Hereditary Angioedema Association (US HAE) issued a consensus statement entitled, An Approach to the Diagnosis and Treatment of HAE, in which Berinert, Firazyr, Kalbitor and Cinryze were listed as approved medications (Danazol was also listed as an "Older drug") with the following recommendations:

Regarding treatment of acute HAE attacks:

Regarding prophylactic treatment of HAE:

In 2013, the US HAE Medical Advisory Board issued Recommendations for the Management of Hereditary Angioedema due to C1 inhibitor deficiency, which reiterated the 2012 recommendations (listed above) and added the following information:

Regarding treatment of acute HAE attacks: 

Regarding prophylactic treatment of HAE:

In 2013, the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), and the Joint Council of Allergy, Asthma and Immunology (AAI) issued a focused parameter update for: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor–associated angioedema.  This practice parameter update provided the following:

Note:  Definition of evidence levels: Grade A = Directly based on Category I (RCT) evidence; Grade B = Directly based on category II (≥1 non-RCT or quasi-experimental study) evidence or extrapolated recommendation from Category I evidence.

Background/Overview

Current research into the causes of HAE has identified greater than 100 different mutations that are responsible for HAE.  Type I HAE is caused by deletions or insertions of nucleotides.  Type I HAE is the most common form of HAE and is characterized by decreased production of C1-INH which results in reduced functional activity down to 5-30% of normal.  Type I HAE occurs in approximately 85% of afflicted individuals.  Type II HAE results from mutations in the C1-INH reactive site, arginine 444, as well as from mutations in coding for the hinge region of the protein. Type II HAE occurs in 15% of cases and is characterized by dysfunctional C1-INH which is detectable in normal or elevated quantities.  Type III HAE is extremely rare and occurs primarily in women.  Type III HAE is estrogen dependent and is associated with normal C1-INH levels.  A similar condition, known as acquired angioedema (AAE), is caused by increased metabolism or increased destruction of C1-INH.  There are two types of AAE: type I results from increased consumption of C1-INH, and type II results from the inactivation of C1-INH due to production of autoantibodies (Georgy, 2012).  The etiology and management of type I and II AAE differ from HAE and are not part of the approved FDA labeling for Haegarda, Berinert, Firazyr, Kalbitor, Cinryze, or Ruconest.  For these reasons, treatment of AAE is not addressed in this document.

Definitions

Antifibrinolytic Agents (also known as plasmin inhibitors): These agents produce inhibition of bradykinin and kallikrein production; an example, є-aminocaproic acid, is occasionally used for HAE prophylaxis when androgens are contraindicated or not well tolerated.

17Alpha-alkylated Androgens: These agents are synthetic anabolic steroids; two examples are Danazol and Stanozolol which have been used to treat the acute symptoms of HAE.

Bradykinin: A potent vasodilator that increases capillary endothelial permeability, causing the localized edema and painful swelling that are the hallmarks of an acute attack of HAE.

C1-esterase inhibitor (C1-INH): This substance is considered a normal constituent of human blood and belongs to the serine protease inhibitor family (serpins). C1-INH acts as a major endogenous inhibitor of plasma kallikrein. The primary function of C1-INH is to regulate the activation of the complement and intrinsic coagulation (contact system) pathway. In addition, C1-INH also regulates the fibrinolytic system.

Danazol (Danocrine® Lannett Company, Inc., Philadelphia, PA): This drug is a synthetic steroid derived from ethisterone. Danocrine is FDA approved for the prevention of attacks of angioedema of all types (cutaneous, abdominal, laryngeal) in males and females. The FDA has issued Black Box Warnings for Danazol related to its teratogenic effects on pregnancy; it is considered contraindicated in pregnancy and is not appropriate for use in children.  

Kallikrein: This substance is considered a subgroup of serine proteases enzymes which is a component of plasma, responsible for the coordination of various physiological functions.

Orphan Drug Designation: This special FDA designation was created in compliance with the Orphan Drug Act (ODA) which provides for granting special status to a product (drug) that treats a rare disease or condition upon request of a sponsor. The combination of the product to treat the rare disease or condition must meet certain criteria. This status is referred to as orphan designation.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

C9015

Injection, C-1 esterase inhibitor (human), Haegarda, 10 units

J0596

Injection, C-1 esterase inhibitor (recombinant), Ruconest, 10 units

J0597

Injection, C-1 esterase inhibitor (human), Berinert, 10 units

J0598

Injection, C-1 esterase inhibitor (human), Cinryze, 10 units

J1290

Injection, ecallantide, 1 mg [Kalbitor]

J1744

Injection, icatibant, 1 mg [Firazyr]

J3490

Unclassified drugs [when specified as C1 esterase inhibitor (human), Haegarda]

 

 

ICD-10 Diagnosis

 

D84.1

Defects in the complement system

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Bartal C, Zeldetz V, Stavi V, Barski L. The role of icatibant-the B2 bradykinin receptor antagonist-in life-threatening laryngeal angioedema in the ED. Am J Emerg Med. 2015; 33(3):479.e1-3.
  2. Bas M, Greve J, Steller K, et al. A randomized trial of icatibant in ACE-inhibitor–induced angioedema. N Engl J Med. 2015; 372(5):418-425.
  3. Bernstein JA, Manning ME, Li H, et al. Escalating doses of C1 esterase inhibitor (CINRYZE) for prophylaxis in patients with hereditary angioedema. J Allergy Clin Immunol Pract. 2014; 2(1):77-84.
  4. Bernstein JA, Shea EP, Koester J, et al. Assessment of rebound and relapse following ecallantide treatment for acute attacks of hereditary angioedema. Allergy. 2012; 67(9):1173-1180.
  5. Bertazzoni G, Bresciani E, Cipollone L, et al. Treatment with icatibant in the management of drug induced angioedema. Eur Rev Med Pharmacol Sci. 2015; 19(1):149-153.
  6. Boccon-Gibod I, Bouillet L. Safety and efficacy of icatibant self-administration for acute hereditary angioedema.  Clin Exper Immun. 2012; 168(3):303-307.
  7. Bork K, Wulff K, Hardt J, et al. Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. J Allergy Clin Immunol. 2009; 124(1):129-134.
  8. Bork K, Wulff K, Witzke G, Hardt J. Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations. Allergy. 2015; 70(8):1004-1012.
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  11. Bowen T, Cicardi M, Farkas H, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Canadian Society of Allergy and Clinical Immunology. Allergy Asthma Clin Immunol. 2010; 6(1):24.
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  17. Craig TJ, Rojavin MA, Machnig T, et al. Effect of time to treatment on response to C1 esterase inhibitor concentrate for hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2013; 111(3):211-215.
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  20. Culley CM, DiBridge JN, Wilson GL Off-label use of agents for management of serious or life-threatening angiotensin converting enzyme inhibitor–induced angioedema. Ann of Pharma. 2016; 50(1):47-59.
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  22. Khan DA. Hereditary angioedema: Historical aspects, classification, pathophysiology, clinical presentation, and laboratory diagnosis. Allergy Asthma Proc. 2011; 32(1):1-10.
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  25. Longhurst H, Cicardi M, Craig T, et al.; COMPACT investigators. Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor. N Engl J Med. 2017; 376(12):1131-1140.
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  29. Mansi M, Zanichelli A, Coerezza A, et al. Presentation, diagnosis and treatment of angioedema without wheals: a retrospective analysis of a cohort of 1058 patients. J Intern Med. 2015; 277(5):585-593.
  30. Maurer M, Aberer W, Bouillet L, et al. Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. Plos One. 2013; 8(2):e53773.
  31. Moldovan D, Reshef A, Fabiani J, et al. Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study. Clin Exp Allergy. 2012; 42(6):929-935.
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  34. Riedl MA, Bygum A, Lumry W, et al. Safety and usage of C1-inhibitor in hereditary angioedema: Berinert Registry Data. J Allergy Clin Immunol Pract. 2016; 4(5):963-971.
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  37. Zilberberg MD, Nathanson BH, Jacobsen T, Tillotson G. Descriptive epidemiology of hereditary angioedema emergency department visits in the United States, 2006-2007. Allergy Asthma Proc. 2011; 32(5):390-394.
  38. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. New Engl J Med. 2010; 363(6):513-522.
  39. Zuraw BL, Cicardi M, Longhurst HJ, et al. Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate. Allergy. 2015; 70:1319-1328.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Berinert [Prescribing Information], Kankakee, IL. CSL Behring LLC. September, 2016. Available at:  http://labeling.cslbehring.com/PI/US/Berinert/EN/Berinert-Prescribing-Information.pdf. Accessed on July 12, 2017.
  2. Caballero T, Farkas H, Bouillet L, et al.; C-1-INH Deficiency Working Group. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012; 129(2):308-320.
  3. Cicardi M, Aberer W, Banerji A, et al.; HAWK under the patronage of EAACI (European Academy of Allergy and Clinical Immunology). Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy. 2014; 69(5):602-616.
  4. Cicardi M, Bork K, Caballero T, et al.; HAWK (Hereditary Angioedema International Working Group). Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012; 67(2):147-157.
  5. Cinryze [Prescribing Information], Exton, PA. ViroPharma Biologics, Inc. February 11, 2014. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM129918.pdf. Accessed on July 12, 2017.
  6. Craig T, Aygören-Pürsün EA, Bork K, et al. World Allergy Organization (WAO) guideline for the management of hereditary angioedema. World Allergy Organ J. 2012; 5(12):182-199.
  7. Craig TJ, Bernstein JA, Farkas H, et al. Diagnosis and treatment of bradykinin-mediated angioedema: outcomes from an angioedema expert consensus meeting. Int Arch Allergy Immunol. 2014; 165(2):119-127.
  8. CSL Behring LLC. A study to evaluate the clinical efficacy and safety of subcutaneously administered C1-esterase inhibitor in the prevention of hereditary angioedema. NLM Identifier: NCT01912456. Last updated June 5, 2017. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01912456?term=csl+830&rank=3 . Accessed on July 12, 2017.
  9. CSL Behring LLC. A study to evaluate the long-term clinical safety and efficacy of subcutaneously administered C1-esterase inhibitor in the prevention of hereditary angioedema. NLM Identifier: NCT02316353. Last updated July 6, 2017. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02316353?term=csl+830&rank=2 . Accessed on July 12, 2017.
  10. Farkas H, Martinez-Saguer I, Bork K, et al. HAWK International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency. Allergy. 2017; 72(2):300-313.
  11. Firazyr [Prescribing Information], Lexington, MA. Shire Orphan Therapies, Inc. August 30, 3013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022150s004lbl.pdf. Accessed on July 12, 2017 2017.
  12. Grompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005; 139(3):379-394.
  13. Haegarda C1 Esterase Inhibitor Subcutaneous (Human) [Prescribing Information], Kankakee, IL. CSL Behring LLC. June 22, 2017. Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM564335.pdf . Accessed on July 13, 2017.
  14. Kalbitor [Prescribing Information], Burlington, MA. Dyax Corporation. March 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125277s070lbl.pdf. Accessed on July 12, 2017.
  15. Lang DM, Aberer W, Bernstein JA, et al. International consensus on hereditary and acquired angioedema. Ann Allergy Asthma Immunol. 2012; 109(6):395-402.
  16. Mansi M, Zanichelli A, Coerezza A, et al. Presentation, diagnosis and treatment of angioedema without wheals: a retrospective analysis of a cohort of 1058 patients. J Intern Med. 2015; 277(5):585-593.
  17. Ruconest [Prescribing Information], Raleigh, NC. Santarus Inc. July 2014. New revision date not provided. Available at: http://www.fda.gov/downloads/biologicsbloodvaccines/bloodbloodproducts/approvedproducts/licensedproductsblas/fractionatedplasmaproducts/ucm405634.pdf. Accessed on July 12, 2017.
  18. U.S. Hereditary Angioedema Association (HAEA) Advisory Board. HAEA Consensus Document: An approach to diagnosis and treatment of HAE. 2012. Available at: http://www.angioedemacenter.com/wp-content/uploads/2012/03/HAEA-MAB-Treament-guidelines-v2.pdf. Accessed on July 12, 2017.
  19. Zuraw BL, Banerji A, Bernstein J, et al. U.S. Hereditary Angioedema Association (US HAE) Medical Advisory Board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency. J Allergy Clin Immunol. 2013a; 1(5):458-467. Available at: http://haei.org/wp-content/uploads/2015/04/Zuraw-B-L-US-HAEA-MAB-2013-Recommendations.pdf. Accessed on July 12, 2017.
  20. Zuraw BL, Bernstein JA, Lang DM, et al. American Academy of Allergy, Asthma & Immunology (AAAAI); American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor–associated angioedema. J Allerg Clin Immunol. 2013b; 131(6):1491-1493.
Websites for Additional Information
  1. National Institutes of Health. Hereditary Angioedema. Reviewed April 2009. Updated July 11, 2017. Available at: https://ghr.nlm.nih.gov/condition/hereditary-angioedema#inheritance . Accessed on July 12, 2017.
Index

Angioedema
Acquired Angioedema, AAE
Berinert
Cinryze
C1 esterase inhibitor
C1-INH
ecallantide
Firazyr
Hereditary Angioedema
HAE
Haegarda
Icatibant
Kalbitor
Ruconest

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
  12/27/2017 The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with 01/01/2018 HCPCS changes, added C9015.
Revised 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Haegarda C1 esterase inhibitor (Human) was added to the MN indications for routine prophylaxis to prevent HAE attacks in adolescents and adults. The age for Cinryze and Haegarda was made 12 years or older. The Rationale was expanded with information about the published trials of Haegarda. Coding and References sections were updated.
Revised 08/04/2016 MPTAC review. Reformatted the Position Statement section. Updated the age limits in the MN criteria for Berinert. Rationale and Reference sections updated.
  01/01/2016 Updated Coding section with 01/01/2016 HCPCS changes, removed C9445 deleted 12/31/2015; also removed ICD-9 codes.
Reviewed 08/06/2015 MPTAC review. The Rationale and References were updated.
  04/01/2015 Updated Coding section with 04/01/2015 HCPCS changes.
Revised 08/14/2014 MPTAC review. The position statement for use of Kalbitor (ecallantide) for the treatment of acute HAE attacks has been revised to consider use in individuals 12 years of age or older as medically necessary when the other criteria are also met. Added criteria for recombinant C1 esterase inhibitor (Ruconest). Updated Description/Scope, Rationale, Coding and References Sections.
New 08/08/2013 MPTAC review. Initial document development.