Medical Policies - Prescription Drugs


Management of Hereditary Angioedema (HAE) with Cinryze or Kalbitor

Number:RX504.013

Effective Date:10-01-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Cinryze® (C1 esterase inhibitor, human)

Cinryze may be considered medically necessary for routine prophylaxis against angioedema attacks in adults, adolescents and pediatric patients (6 years of age and older) diagnosed with hereditary angioedema (HAE) when the diagnosis has been confirmed by C4 and C1 Inhibitor laboratory testing for HAE type I or II OR for HAE III when testing is normal for C4 and C1 and patient has a known HAE-causing C1-INH mutation (i.e. mutation of coagulation factor XII gene), or a family history of HAE.

Cinryze is considered experimental, investigational and/or unproven for all other treatments including but not limited to treatment of an acute HAE attack.

NOTE #1: Safety and efficacy of Cinryze have not been established in neonates, infants, or children under the age of six years old and Cinryze is contraindicated for patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis to the product.

NOTE: Serum C4 level is a screening test for C1 INH deficiency, as serum C4 is invariably low in untreated HAE (C4 < 30% of mean normal level). If C4 is normal it is not usually necessary to proceed to C1 INH analysis. If the C4 level is low then C1 INH level and function may be assessed.

Kalbitor® (ecallantide)

Kalbitor may be considered medically necessary in patients 12 years of age or older for the treatment of acute attacks of hereditary angioedema (HAE) when administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.

Kalbitor is considered experimental, investigational and/or unproven for all other treatments including but not limited to:

Patients with HAE who are under age 12;

Treatment for prophylactic therapy for HAE;

As dual therapy with another agent for treating acute attacks of HAE; or

Patients without a diagnosis of HAE.

Haegarda® (C1 Esterase Inhibitor Subcutaneous [Human])

This drug is self-administered. Please refer to applicable pharmacy benefit plan.

Description:

Cinryze® (C1 esterase inhibitor, human)

Cinryze is a C1-esterase inhibitor used for the treatment routine prophylaxis against angioedema attacks with hereditary angioedema (HAE). HAE is caused by having insufficient amounts of a plasma protein called C1-esterase inhibitor. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection. Swelling of the airway is potentially fatal without immediate treatment. C is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby preventing the acute attack of swelling (1-2).

HAE affects about 6,000 to 10,000 individuals in the United States. Cinryze is licensed for the prevention of HAE attacks, which can occur spontaneously or during stress, surgery, or infection in patients diagnosed with the disease. Attacks can produce rapid swelling of the hands, feet, limbs, face, intestinal tract or airway. Swelling of the larynx can lead to asphyxiation.

HAE is the result of a defect in the gene controlling the synthesis of C1 inhibitor. C1 inhibitor maintains the natural regulation of the contact, complement, and fibrinolytic systems, that when left unrestricted, can initiate or perpetuate an attack by consuming the already low levels of endogenous C1 inhibitor in HAE patients. C1 inhibitors have been used in Europe for over ten years for the prophylaxis and acute treatment of HAE.

Cinryze is administered intravenously and can be given every three or four days for routine prevention of HAE attacks. It is manufactured by Lev Pharmaceuticals Inc., New York, N.Y., through a contract manufacturing agreement with Sanquin Blood Supply Foundation in The Netherlands.

Dosing Information:

The recommended dosage of Cinryze for routine prophylaxis of angioedema attacks in adults and adolescents, 12 years and older with hereditary angioedema (HAE) is 1000 units intravenously at an initial infusion rate of 1 milliliter/minute over 10 minutes every 3 to 4 days. Doses up to 2,500 U (not exceeding 100 U/kg) every 3 or 4 days may be considered based on individual patient response.

The recommended dosage of Cinryze for routine prophylaxis of angioedema attacks in children (6 to 11 years old) with hereditary angioedema (HAE) is 500 units intravenously at an infusion rate of 1 milliliter/minute over 5 minutes. Doses up to 1,000 U every 3 to 4 days may be considered based on individual patient response.

Kalbitor® (ecallantide)

Kalbitor is a human plasma kallikrein inhibitor for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE). Hereditary angioedema is caused by having insufficient amounts of a plasma protein called C1-esterase inhibitor. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection. Swelling of the airway is potentially fatal without immediate treatment. Kalbitor is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling.

Dosing Information:

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. Kalbitor should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis

Regulatory Status

On October 10, 2008 the U.S. Food and Drug Administration (FDA) licensed Cinryze for marketing as the first product in the U. S. intended to protect people with HAE, a rare and potentially life-threatening genetic disease. The FDA-approved indication: Cinryze is a C1 esterase inhibitor indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE). In June 2018, the FDA modified the label for Cinryze to allow for pediatric patients (6 years of age and older) with Hereditary Angioedema (HAE).

On December 1, 2009 the FDA approved Kalbitor (ecallantide) to treat sudden and potentially life-threatening fluid buildup that can occur in people with a rare genetic condition known as hereditary angioedema (HAE).

Rationale:

This policy was originally developed in 2009 and has been updated with searches of scientific literature through July 18, 2018. The following is a summary of the key literature to date

Cinryze®

Adult patients:

In a 24-week, randomized, double-blind, placebo-controlled, cross-over trial (n=22), prophylaxis with nanofiltered C1 inhibitor concentrate (Cinryze) significantly reduced the number of attacks compared with placebo in patients with hereditary angioedema (HAE). Patients aged 6 yr. and older with HAE due to C1 inhibitor deficiency (low C4 level, normal C1q level, and a low antigenic or functional C1 inhibitor level or a mutation in the C1 inhibitor gene which causes HAE who had been randomized to receive C1 inhibitor concentrate for the treatment of acute attacks in a double-blind, placebo-controlled trial and who had a history of 2 or more attacks per month were eligible for enrollment. Eligible patients received either C1 inhibitor concentrate 1000 units in 10 mL of sterile water (n=11) or 10 mL of saline (placebo; n=11) every 3 to 4 days for 12 weeks and then switched to the other therapy for the next 12 weeks. Rescue therapy with open-label C1 inhibitor concentrate for acute attacks was given in 11 patients receiving C1 inhibitor concentrate prophylaxis and 22 patients receiving placebo. The average number of attacks in a 12-week period (primary endpoint) was 6.26 attacks during the C1 inhibitor concentrate prophylaxis period and 12.73 attacks during the placebo period (attack rate difference, 6.47 attacks; 95% CI, 4.21 to 8.73 attacks; p less than 0.001). For attacks which occurred during the C1 inhibitor concentrate prophylaxis period compared with the placebo period, the mean severity score (evaluated using a 3-point scale: mild=1; moderate=2; severe=3) was significantly lower (1.3 +/- 0.85 vs 1.9 +/- 0.36, respectively; p less than 0.001) and the attack duration was significantly shorter (2.1 +/- 1.13 vs 3.4 +/- 2.39 days, respectively; p=0.002). Additionally, fewer rescue C1 inhibitor concentrate injections were required (4.7 +/- 8.66 vs 15.4 +/- 8.41 injections; p less than 0.001) and fewer days of swelling were reported (10.1 +/- 10.73 vs 29.6 +/- 16.9 days; p less than 0.001) during the C1 inhibitor concentrate prophylaxis period compared with the placebo period. Adverse events possibly associated with C1 inhibitor concentrate use included 1 report each of pruritus and rash, lightheadedness, and fever (2).

Replacement therapy with plasma-derived C1-inhibitor concentrate was effective in reducing the median number of angioedema attacks per year in patients with severe HAE who were intolerant to or not responding to danazol. Adult patients (n=22) with severe HAE (defined as having severe gastro abdominal, urogenital, and/or laryngeal attacks at least once weekly) who discontinued long-term (median duration, 11.25 yr; range, 0.5 to 23.5 yr) danazol prophylaxis (doses up to 1000 milligrams/day) due to intolerability or severe side effects received an individualized pasteurized plasma-derived C1-inhibitor concentrate regimen usually ranging between 500 to 1000 units/dose as a self-administered intravenous infusion up to twice weekly administered during the early signs of an acute attack (mean dose, 1115.7 +/- 160.3 units). Data collected in the long-term danazol prophylaxis period were retrospectively reviewed and compared with data obtained prospectively when patients were receiving plasma-derived C1-inhibitor concentrate. The median frequency of attacks/yr were 48 (range, 2 to 104 attacks; 95% confidence limit (CL), 24 to 104 attacks) and zero (range, zero to 104 attacks; 95% CL, zero to 3 attacks) with danazol and plasma-derived C1-inhibitor concentrate therapy, respectively. After switching to plasma-derived C1-inhibitor concentrate therapy, the number of patients experiencing severe attacks decreased from 22 patients (receiving danazol therapy) to 10 patients; additionally, the median number of attacks/year decreased by 43 attacks (95% CL, -52 to -12 attacks; p less than 0.001). No laryngeal edema was reported in patients during the plasma-derived C1-inhibitor concentrate treatment period. Compared to the long-term danazol therapy period, the median overall quality of life total score was significantly improved in the plasma-derived C1-inhibitor concentrate treatment period (12.5 versus 48.5 points, respectively; p less than 0.001). Mild adverse effects experienced during plasma-derived C1-inhibitor concentrate therapy included injection site redness (n=2) and vertigo (n=1). There was no evidence of viral transmission (human immunodeficiency virus 1/2 or hepatitis A, B, or C viruses) with plasma-derived C1-inhibitor concentrate therapy (3).

Pediatric Patients:

A 24-week, multicenter, single randomized, double-blind, placebo-controlled, crossover, clinical trial demonstrated that prophylaxis with human C1 esterase inhibitor (hC1EI; Cinryze(R)) was superior to placebo in reduction of swelling episodes in adult and adolescent patients with HAE, (n=24). Patients ranging in age from 9 to 73 years and with a history of at least 2 HAE attacks per month were randomized to either hC1EI prophylaxis for 12 weeks, followed by 12 weeks of placebo or to placebo for 12 weeks followed by hC1EI for 12 weeks. Patients received blinded injections every 3 to 4 days, approximately 2 times per week. HAE attacks were defined as patient-reported swelling episodes at anybody location, immediately following a day free from swelling episodes. Efficacy was evaluated by the number of swelling episodes that occurred during the 12-week period with hC1EI treatment. The generalized estimating equations (GEE) analysis revealed that prophylaxis with hC1EI was superior to placebo in reduction of mean number of HAE attacks: 6.1 +/- 5.4 verses (vs) 12.7 +/- 4.8; p less than 0.0001. Secondary outcomes of note revealed that prophylaxis with hC1EI was also superior to placebo in reduction in severity of attacks, reduction of average duration of attacks and reduction in days of swelling. The mean severity of attacks, measured by a score of 1 to 3, was 1.3 vs 1.9; p=0.0006, the mean duration of attacks was 2.1 days vs 3.4 days; p=0.0023 and the mean days of swelling was 10.1 days vs 29.6 days; p less than 0.0001, hC1EI compared with placebo, respectively. The most common adverse effects occurring at 5% or greater were upper respiratory tract infections, sinusitis, rash, and headache. (1)

The safety and efficacy of Cinryze (500 U and 1,000 U) for the prevention of HAE attacks and the reduction of the severity and requirement for acute treatment was demonstrated in a randomized, single-blind, multi-center, dose-ranging cross-over study of 12 pediatric subjects aged 7 to 11 years.

The safety and effectiveness of Cinryze have been evaluated in 12 pediatric subjects with HAE (age range 7 to 11 years old) in a pediatric randomized, dose-ranging, crossover routine prophylaxis trial. During the 12-week study period, a greater reduction in the normalized number of angioedema attacks per month was observed with 1,000 U Cinryze compared to 500 U CINRYZE (p=0.03). When compared to the baseline observational period, a reduction in the normalized number of angioedema attacks was observed for both Cinryze 500 U and Cinryze 1,000 U (mean absolute reduction in number of HAE attacks: 2.6, 3.0 respectively; mean percent reduction in HAE attacks: 71.1% and 84.5%, respectively). In addition, both doses lessened the severity of attacks and reduced the use of acute treatment compared with baseline. Additionally, four of the 24 subjects in the pediatric/adult randomized, placebo-controlled, crossover, routine prophylaxis trial, were under the age of 18 years. Overall the safety and tolerability of Cinryze are similar in pediatric, adolescent and adult subjects. The pharmacokinetics of Cinryze was evaluated in pediatric subjects. (8)

Kalbitor®

The safety and efficacy of Kalbitor to treat acute attacks of hereditary angioedema in adolescents and adults were evaluated in 2 randomized, double-blind, placebo-controlled trials (EDEMA4 and EDEMA3) in 168 patients with HAE. (7) Patients having an attack of hereditary angioedema, at any anatomic location, with at least 1 moderate or severe symptom, was treated with 30 mg subcutaneous Kalbitor or placebo. Because patients could participate in both trials, a total of 143 unique patients participated. Of the 143 patients, 94 were female, 123 were Caucasian, and the mean age was 36 years (range 11-77). There were 64 patients with abdominal attacks, 55 with peripheral attacks, and 24 with laryngeal attacks.

In both trials, the effects of Kalbitor were evaluated using the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). These endpoints evaluated attack severity using the MSCS score and patient response to treatment (TOS) for an acute HAE attack.

MSCS score is a point-in-time measure of symptom severity. At baseline, and post-dosing at 4 hours and 24 hours, patients rated the severity of each affected symptom on a categorical scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe). Patient-reported severity was based on each patient’s assessment of symptom impact on their ability to perform routine activities. Ratings were averaged to obtain the MSCS score. The endpoint was reported as the change in MSCS score from baseline. A decrease in MSCS score reflected an improvement in symptom severity; the maximum possible change toward improvement was -3.

TOS is a measure of symptom response to treatment. At 4 hours and 24 hours post-dosing, patient assessment of response for each anatomic 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 anatomic site was weighted by baseline severity and then the weighted scores across all involved sites were averaged to calculate the TOS. A TOS value >0 reflected an improvement in symptoms from baseline. The maximum possible score was +100.

EDEMA4 was a randomized, double-blind, placebo-controlled trial in which 96 patients were randomized 1:1 to receive Kalbitor 30 mg subcutaneous or placebo for acute attacks of HAE. The primary endpoint was the change from baseline in MSCS score at 4 hours, and the TOS at 4 hours was a key secondary endpoint. Patients treated with Kalbitor demonstrated 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 hours, patients treated with Kalbitor also demonstrated a greater decrease from baseline in the MSCS than placebo (-1.5 vs. -1.1; p = 0.04) and a greater TOS (89 vs. 55, p = 0.03). More patients in the placebo group (24/48, 50%) required medical intervention to treat unresolved symptoms within 24 hours compared to the Kalbitor-treated group (16/48, 33%). Some patients reported improvement following a second 30 mg subcutaneous dose of Kalbitor, administered within 24 hours following the initial dose for symptom persistence or relapse, but efficacy was not systematically assessed for the second dose.

EDEMA3 was a randomized, double-blind, placebo-controlled trial in which 72 patients were randomized 1:1 to receive Kalbitor or placebo for acute attacks of HAE. EDEMA3 was similar in design to EDEMA4 with the exception of the order of the prespecified efficacy endpoints. In EDEMA3, the primary endpoint was the TOS at 4 hours, and the key secondary efficacy endpoint was the change from baseline in MSCS at 4 hours. As in EDEMA4, patients treated with Kalbitor demonstrated 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 (Table 2). In addition, more patients in the placebo group (13/36, 36%) required medical intervention to treat unresolved symptoms within 24 hours compared to the Kalbitor-treated group (5/36, 4%).

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J0598, J1290

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov.

References:

1. Product Information: Cinryze IV injection, C1 inhibitor human IV injection. Lev Pharmaceuticals, Inc, New York, NY, 2008.

2. Zuraw BL, Busse PJ, White M, et al.: Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary Angioedema. N Engl J Med 2010; 363 (6):513-522. PMID: 20818886

3. Kreuz W, Martinez-Saguer I, Aygoren-Pursun E, et al.: C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis. Transfusion 2009; 49(9):1987-1995. PMID: 19497056

4. IBM Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. C1 Esterase Inhibitor Available at: http://www.micromedexsolutions.com/ (last accessed – July 19, 2018)

5. IBM Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Kalbitor (ecallantide) Available at: http://www.micromedexsolutions.com/ (last accessed – July 19, 2018)

6. Cinryze (C1 Esterase Inhibitor [Human]) Prescribing Information. Exton, PA: Shire Medical, (last accessed March 2016).

7. FDA - Kalbitor (ecallantide) - Product Label. Food and Drug Administration (March 2014). Available at <http://www.fda.gov> (last accessed July 19, 2018).

8. FDA – Cinryze (C1 Esterase Inhibitor [Human]) – Product label. Food and Drug Administration (July 2018). Available at <http://www.fda.gov> (accessed July 19, 2018).

Policy History:

DateReason
10/1/2018 Document updated with literature review. The following FDA change was made to the age requirement for Cinryze® (C1 esterase inhibitor, human): changed from age 9 and older to 6 and older. Reference 8 added.
12/1/2017 Reviewed. No changes.
7/15/2017 Document partially updated with literature review. The following coverage clarification was added concerning hereditary angioedema (HAE) testing: When diagnosis confirmed by C4 and C1 Inhibitor laboratory testing for HAE type I or II OR for HAE III when testing is normal for C4 and C1 and patient has a known HAE-causing C1-INH mutation (i.e. mutation of coagulation factor XII gene), or a family history of HAE. Added the following statement regarding Haegarda® (C1 Esterase Inhibitor Subcutaneous [Human]): “This drug is self-administered. Please refer to applicable pharmacy benefit plan.”
8/15/2016 Document updated with literature review. The following was added to the coverage section: 1) Kalbitor may be considered medically necessary in patients 12 years of age or older for the treatment of acute attacks of hereditary angioedema (HAE) when administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema, and 2) Kalbitor is considered experimental, investigational and/or unproven for all other treatments including but not limited to: patients with HAE who are under age 12, treatment for prophylactic therapy for HAE, As dual therapy with another agent for treating acute attacks of HAE, or patients without a diagnosis of HAE. Title changed from: Cinryze [C1 Esterase Inhibitor (Human)] for Routine Prophylaxis of Hereditary Angioedema (HAE).
4/1/2015 Document updated with literature review. Coverage unchanged.
6/15/2011 Document updated with literature review. No change in coverage. Title changed to CINRYZE [C1 Esterase Inhibitor (Human)] for Routine Prophylaxis of Hereditary Angioedema (HAE).
9/15/2009 New medical document with coverage criteria based on approved labeled FDA indications.

Archived Document(s):

Back to Top