Policy Applies to

• Commercial plans
• Healthcare Reform plans  

 Drugs Addressed in this Policy

• Berinert [C1 Esterase Inhibitor (Human)]
• Cinryze [C1 Esterase Inhibitor (Human)]
• Firazyr (icatibant)
• Haegarda [C1 Esterase Inhibitor (Human)]
• Ruconest [C1 Esterase Inhibitor (Recombinant)]

FDA Approved Indication

Berinert

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

Cinryze

• Routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).

Firazyr

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

Haegarda

• Indicated for routine prophylaxis to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients.

Ruconest

• Treatment of acute hereditary angioedema (HAE) attacks in adult and adolescent patients 13 years of age and older.

 

Background

Hereditary angioedema (HAE) is a disease that presents with episodes of non-allergic angioedema. Patients experience swelling episodes that resolve within 2 to 5 days without treatment; however laryngeal swelling can be fatal. The swelling occurs without hives or itching. Bradykinin is a vasodilator that results in the swelling that is associated with angioedema. Since the angioedema is non-allergic, histamines are not involved and antihistamines are not effective. HAE can also occur because of a deficiency or malfunction of the C1 inhibitor in the body which regulates the coagulation pathway. There are three types of HAE. HAE type I is caused by a deficiency in C1 inhibitor, HAE  type II is caused by a dysfunction of C1 inhibitor, HAE type III also known as Hereditary with Normal C1 inhibitor is a type not caused by C1 inhibitor deficiency.

Berinert is indicated for the treatment of acute abdominal, facial, or laryngeal attacks of hereditary angioedema in adult and pediatric patients .Berinert was tested in 124 adult patients in a placebo-controlled double blind trial with the primary objective of shortening the time to onset of relief of symptoms. Patients who received Berinert were shown to have a reduction in time to onset of relief with a median of 48 minutes for the Berinert group compared to 4 hours in the placebo group.

Cinryze is a medication indicated for routine prophylaxis against angioedema attacks. The efficacy of Cinryze was evaluated in a placebo controlled trial. 24 patients were randomized to receive Cinryze for 12 weeks followed by placebo for 12 weeks or to receive placebo for 12 weeks followed by Cinryze for 12 weeks. The average number of attacks was 6.1 while patients were receiving Cinryze compared to 12.7 while patients were on placebo.

Firazyr was studied in a randomized, placebo-controlled, double-blind clinical trial with 98 adult patients. The median time to reduction in symptoms was significantly lower in the Firazyr group compared to 19.8 hours in the placebo group.

Haegarda is indicated for routine prophylaxis to prevent angioedema attacks in adolescents and adults. The clinical efficacy was demonstrated in a multicenter, randomized, double-blind, placebo-controlled, crossover study. The primary efficacy endpoint was the difference in the time-normalized number of HAE attacks (the rate of attacks) relative to placebo. Patients were randomized to receive either 60 IU/kg or 40 IU/kg of C1-INH [Human] (Haegarda) for 16 weeks and placebo in the other 16 week treatment period. Patients who were in the Haegarda 60 IU/kg demonstrated a reduction of 3.5 attacks per month.

Ruconest is indicated for the treatment of acute attacks in patients with hereditary angioedema. Ruconest was studied in a placebo-controlled, double-blind, randomized study with the primary outcome of looking at the time to relief of symptoms. The median time to relief of symptoms was significantly lower in the Ruconest group than in the placebo group.

 Limitations of Coverage

• A diagnosis of Type I, Type II, or Type III HAE has been established by, or in consultation with a provider specializing in allergy, immunology, or hematology.

Approval Criteria 

 HAE Type I & II

Approval may be granted when the following criteria are met (1., 2., 3., 4., 5., and 6.):

1. The member meets one of the following criteria (A., B., C., D., or E.,)
   1. Cinryze is being used for prophylaxis management against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).
   2. Haegarda is being used for prophylaxis management against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).
   3. Berinert is being used for the treatment of acute abdominal, facial, or laryngeal attacks of HAE in adults/adolescents.
   4. Firazyr is being used for treatment of acute attacks of hereditary angioedema in adults 18 years of age or older.
   5. Ruconest is being used for treatment of acute HAE attacks in adults/adolescents 13 years of age and older.
2. A low C4 level less than or equal to 14mg/dL or a C4 below the lower limit of the laboratory’s reference range and one of the following criteria (A., or B.,):
   1. C1 inhibitor (C1INH) antigenic level less than or equal to 19 mg/dL (normal range:19 to 37 mg/dL) or below the lower limit of the laboratory’s reference range.
   2. A normal C1INH antigenic level (C1INH greater than or equal to 19 mg/dL) and a low C1INH functional level (functional C1INH less than 50 % or below the laboratory’s reference range).
3. Past medical history of at least one (1) symptom of moderate or severe angioedema attack (e.g. airway swelling, severe abdominal pain, facial swelling, nausea and vomiting, painful facial distortion) in absence of concomitant hives or use of medication to cause angioedema
4. Medications known to cause angioedema (i.e. ACE-inhibitors, estrogens, angiotensin II receptor blockers) have been evaluated and discontinued when appropriate.
5. Members should not be on two claims for acute therapy processed on the same day.
6. Documentation of the member’s weight has been provided.

HAE Type III

Approval may be granted when the following criteria are met (1., 2., 3., 4., 5., 6., 7., and 8.):

1. The member meets one of the following criteria (A., B., C., D., or E.,)
   1. Cinryze is being used for prophylaxis management against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).
   2. Haegarda is being used for prophylaxis management against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).
   3. Berinert is being used for the treatment of acute abdominal, facial, or laryngeal attacks of HAE in adults/adolescents.
   4. Firazyr is being used for treatment of acute attacks of hereditary angioedema in adults 18 years of age or older.
   5. Ruconest is being used for treatment of acute HAE attacks in adults/adolescents age 13 years of age and older.
2. Clinical laboratory performance of  the following (A., B., or C.,):
   1. C4 within normal limits (normal range:14 to 40 mg/dL) OR C4 within normal limits of the laboratory's normal reference range 
   2. C1INH antigen within normal limits (normal range:19 to 37 mg/dL) OR C1INH antigenic level within normal limits of the laboratory's normal reference range
   3. C1INH functional within normal limits of the laboratory's normal reference range
3. Clinical documentation of at least one of the following (A., or B.,):
   1. Family history of HAE
   2. FXII mutation
4. Past medical history of at least one (1) symptom of moderate or severe angioedema attack (e.g. airway swelling, severe abdominal pain, facial swelling, nausea and vomiting, painful facial distortion) in absence of concomitant hives or use of medication to cause angioedema
5. Medications known to cause angioedema (i.e. ACE-inhibitors, estrogens, angiotensin II receptor blockers) have been evaluated and discontinued when appropriate
6. The member has experienced therapeutic failure, contraindication, or intolerance to antihistamines.
7. Members should not be on two claims for acute therapy processed on the same day.
8. Documentation of the member’s weight has been provided.

For Commercial and Healthcare Reform members, coverage of Cinryze, Haegarda, Firazyr, Ruconest, or Berinert for disease states outside of their FDA-approved indications should be denied based on the lack of clinical data to support their effectiveness and safety in other conditions.

 

For Commercial and Healthcare Reform members with a closed formulary, a non-formulary product will only be approved if the member meets the criteria for a formulary exception in addition to the criteria outlined within this policy.

 

For Commercial and Healthcare Reform members enrolled in a West Virginia Plan, an exception to the step therapy within this policy may be made base on Policy J-513 – West Virginia – Step Therapy Override Exception – Commercial and Healthcare Reform.

Duration of Authorization
If approved, authorization will be granted for 1 year.

References 

1. Cinryze [package insert]. Shire ViroPharma, Inc. Lexington, MA. 2008. Revised December 2016.
2. Cinryze. DRUGDEX System (Micromedex 2.0). Greenwood Village, CO: Truven Health Analytics: 2015. Last Modified: February 26, 2015.
3. Cinryze. Clinical Pharmacology. Tampa, FL: Gold Standard Multimedia; 2015. Last Modified: July 1, 2015.
4. Berinert [package insert]. CSL Behring, Kankakee, IL: 2009. Revised September 2016.
5. Berinert. Clinical Pharmacology. Tampa, FL. Gold Standard Multimedia; 2015. Last Modified: July 1, 2015.
6. Berinert. DRUGDEX System (Micromedex 2.0) Greenwood Village, CO: Truven Health Analytics: 2015. Last Modified: February 26, 2015.
7. Ruconest [package insert]. Santaris. Raleigh, NC. 2014. Revised February 2015.
8. Ruconest. Clinical Pharmacology. Tampa, FL. Gold Standard Multimedia; 2015. Last Modified: July 31, 2014.
9. Ruconest. DRUGDEX System (Micromedex 2.0) Greenwood Village, CO: Truven Health Analytics: 2015.  Last Modified: May 06, 2015.
10. Haegarda [prescriber information].Kankakee, IL: CSL Behring, LLC; June 2017.
11. McEvoy GK,ed. AHFS: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists: 2015.
12. Craig T, Pursun A, Bork K, et al. WAO guideline for the management of hereditary angioedema. Available at: Accessed January 25, 2016.
13. Zuraw BL, Banerji A, Bernstein JA, Busse PJ, et al. US Hereditary Angioedema Association Medical Advisory Board 2013 Recommendations for the Management of Hereditary Angioedema Due to C1 Inhibitor Deficiency. J Allergy Clin Immunol.2013;1:458-67.  
14. Gainer JV, Morrow JD, Loveland A, et al. Effect of Bradykinin-Receptor Blockade on the Response To Angiotensin-Converting-Enzyme Inhibitor In Normotensive And Hypertensive Subjects. NEJM. 1998; 339(18): 1285-1291.
15. Zuraw BL, Bork K, Binkley KE, et al. Hereditary angioedema with normal C1 inhibitor function: Consensus of an international expert panel. Allergy Asthma Proc. 2012;33 Suppl 1:S145-S156.
16. Bowen T, Cicardi M, Farkas H, et al. 2010. International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010;6:24.