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Date Printed: October 25, 2014: 06:49 PM

Private Property of Blue Cross and Blue Shield of Florida.
This medical policy (medical coverage guideline) is Copyright 2014, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2014 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. 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.

09-J1000-08

Original Effective Date: 07/15/09

Reviewed: 01/15/14

Revised: 07/15/14

Subject: Hereditary Angioedema Drug Therapy

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

Position Statement

Billing/Coding

Reimbursement

Program Exceptions

Definitions

Related Guidelines

Other

References

Update

Decision Tree

Previous Information

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.

Table 1: Blood tests for different types of angioedema

HAE Type

C1-INH concentration

C1-INH activity

C2 and C4

Type I

Low

Low

Low

Type II

Normal to elevated

Low

Low

Type III

Normal

Normal

Normal

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).

POSITION STATEMENT:

I. C1 Inhibitor (Cinryze) meets the definition of medical necessity when used for the prophylaxis of hereditary angioedema (HAE) and ALL of the following criteria are met:

1. Member is diagnosed with HAE as evidenced by a normal C1 level, low C4 level and EITHER of the following:

a. Low C1-INH activity (as defined by the laboratory performing the test)

b. Known HAE-causing C1-INH mutation

2. Member is 12 years of age or older

3. Member has a history of 2 or more HAE attacks per month

4. Member has no signs of an acute angioedema attack

5. Member has had an inadequate response or contraindication/intolerance to 17-alpha-alkylated androgen (e.g., danazol)

II. C1 Inhibitor (Berinert) meets the definition of medical necessity when used to treat an acute angioedema attack (e.g., abdominal, facial, laryngeal) of HAE when BOTH of the following criteria are met:

1. Member is diagnosed with HAE as evidenced by a normal C1 level, low C4 level and low C1-INH activity (as defined by the laboratory performing the test)

2. Member is 12 years of age or older

3. Berinert is not used concomitantly with either ecallantide (Kalbitor) OR icatibant (Firazyr)

III. Ecallantide (Kalbitor) meets the definition of medical necessity when used to treat an acute angioedema attack (e.g., abdominal, facial, laryngeal) of HAE when BOTH of the following criteria are met:

1. Member is diagnosed with HAE as evidenced by a normal C1 level, low C4 level and low C1-INH activity (as defined by the laboratory performing the test)

2. Member is 12 years of age or older

3. Ecallantide is not used concomitantly with either Berinert OR icatibant (Firazyr)

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 BOTH of the following criteria are met:

1. Member is diagnosed with HAE as evidenced by a normal C1 level, low C4 level and low C1-INH activity (as defined by the laboratory performing the test)

2. Member is 18 years of age or older

3. Icatibant is not used concomitantly with either Berinert OR ecallantide (Kalbitor)

Approval duration: 180 days (all products)

DOSAGE/ADMINISTRATION:

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.

Table 2: FDA-approved Dosing

Drug

Dosage

Comments

Cinryze

1000 units (10 mL) IV over at least 10 minutes every 3-4 days

One unit of Cinryze corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal human plasma

Berinert

20 units/kg via slow IV injection at a rate of approximately 4 mL/min

 

ecallantide (Kalbitor)

30 mg SQ administered as three 10 mg (1 mL) injections

If attack persists, an additional 30 mg dose may be administered within a 24 hour period

icatibant (Firazyr)

30 mg SQ administered in the abdominal area

If attack persists or symptoms recur, additional 30 mg doses may be administered at intervals of at least 6 hours. Max 90 mg (3 doses)/24 hr.

IV, intravenously; SQ, subcutaneously

Dose Adjustment

Dosage adjustments for renal or hepatic impairment are not required.

Table 3: Drug Availability

Drug

How Supplied

Cinryze, Berinert

500 unit powder for injection

ecallantide (Kalbitor)

10 mg/mL solution for injection

icatibant (Firazyr)

30 mg/3 mL solution for injection

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.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding:

J0597

Injection, C-1 Esterase Inhibitor (human), Berinert®, 10 units

J0598

Injection, C1 Esterase Inhibitor (human), Cinryze®, 10 units

J1290

Injection, ecallantide, 1 mg

J1744

Injection, icatibant, 1 mg

NOTE: There is no specific HCPCS code for icatibant.

ICD-9 Diagnoses Codes That Support Medical Necessity:

277.6

Other deficiencies of circulating enzymes (hereditary angioedema)

ICD-10 Diagnoses Codes That Support Medical Necessity: (Effective 10/01/15)

D84.1

Defects in the complement system

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products: No National Coverage Determination (NCD) was found at the time of the last guideline revised date. The following Local Coverage Determination (LCD) was reviewed on the last guideline revised date: Name of Selective Treatment of Hereditary Angioedema with Cinryze, Berinert and Ecallantide. (L31475) located at fcso.com.

Medicare Part D: Florida Blue has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

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.

Table 4: Normal Value Ranges†

Component

Reference Interval

C1-esterase inhibitor (C1-INH) concentration

16 to 33 mg/dL

C1-esterase functional (activity)

67% or greater: normal

41-67%: indeterminate

41% or less: abnormal

Complement component 4 (C4)

Age

Value (mg/dL)

0-30 days

8-30

1 month

9-33

2 months

9-37

3 months

10-35

4 months

10-49

5 months

9-48

6 months

12-55

7-8 months

13-48

9-11 months

16-51

1 year

16-52

2-4 years

12-47

5-11 years

13-44

12-17 years

14-41

18 years and older

10-40

Normal value ranges may vary slightly among different laboratories due to different measurements or testing different specimens. Refer to the normal value ranges of the laboratory performing the test.

RELATED GUIDELINES:

None applicable.

OTHER:

None applicable.

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 12/23/13.
  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 2013 Dec 23]. 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 2013 Dec 23]. 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 12/23/13.
  11. Sardana N, Craig TJ. Recent advances in management and treatment of hereditary angioedema. Pediatrics 2011;128(6):1173-80.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 06/11/14.

GUIDELINE UPDATE INFORMATION:

07/15/09

New Medical Coverage Guideline.

01/01/10

Annual HCPCS coding update: added HCPCS code J0598.

03/15/10

Review and revision to guideline; consisting of adding new C1 Inhibitor, modifying coverage criteria and updating references.

06/15/10

Revision to guideline; consisting of adding new agent and changing the name of the guideline.

01/01/11

Revision to guideline; consisting of updating coding.

06/15/11

Review and revision to guideline; consisting of updating dosage section and references.

02/15/12

Revision to guideline; consisting of updating description, position statement, dosage and references.

01/01/13

Review and revision to guideline; consisting of revising and reformatting position statement; reformatting dosage/administration and precautions sections; adding definition including normal value reference range chart; updating references and coding.

02/15/13

Review and revision to guideline; consisting of reformatting position statement.

11/15/13

Revision to guideline consisting of adding approval durations.

02/15/14

Review and revision to guideline; consisting of updating references and reformatting position statement.

07/15/14

Revision to guideline; consisting of lowering minimum age for use of ecallantide.

Private Property of Blue Cross and Blue Shield of Florida.
This medical policy (medical coverage guideline) is copyright 2013, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2013 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association.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.

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Date Printed: October 25, 2014: 06:49 PM