Policy Applies to

• Commercial plans
• Healthcare Reform plans  

 Drugs Addressed in this Policy

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

 

FDA Approved Indication

Cinryze

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

Berinert

• Treatment of acute abdominal, facial, or laryngeal attacks of hereditary angioedema (HAE) in adult and adolescent patients 13 years of age or older

Ruconest

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

Mechanism of Action

HAE is a form of non-allergic angioedema characterized by a heterozygous C1-esterase–inhibitor deficiency. C1 inhibitor is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). The primary function of C1 esterase inhibitor is to regulate the activation of the complement and intrinsic coagulation (contact-system) pathway. C1 esterase inhibitor also regulates the fibrinolytic system. Regulation of these systems is performed through the formation of complexes between the proteinases and the inhibitor, resulting in inactivation of both and consumption of the C1 inhibitor. Administration of C1 esterase inhibitor to patients with C1 esterase inhibitor deficiency replaces the missing or malfunctioning protein in patients and increases plasma levels of C1 inhibitor activity.

 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.
• Cinryze (C1 Esterase Inhibitor) is used for prophylaxis management of HAE as opposed to the treatment of acute attacks of HAE.
• The safety and efficacy of Berinert and Ruconest for prophylactic therapy have not been established.

 

Approval Criteria 
Approval may be granted when the following criteria are met:HAE Type I & II

1. The member meets one of the following criteria (a, b, or c)
   • (a) Cinryze is being used for prophylaxis management against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE)
   • (b) Berinert is being used for the treatment of acute abdominal, facial, or laryngeal attacks of HAE in adults/adolescents 13 years of age and older 
   • (c) Ruconest is being used for treatment of acute HAE attacks in adults/adolescents age 13 years of age and olde AND
2. Clinical laboratory performance of the following:
   • C4 level less than or equal to 14 mg/dL (normal range:14 to 40 mg/dL) OR C4 below the lower limit of the laboratory's normal reference range AND
   • C1 inhibitor (C1INH) antigenic level less than or equal to 19 mg/dL (normal range:19 to 37 mg/dL) OR C1INH antigenic level below the limits of the laboratory's normal reference range OR 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 C1INH functional level below the limits of the laboratory's normal reference range) AND
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 AND
4. Medications known to cause angioedema (i.e. ACE-inhibitors, estrogens, angiotensin II receptor blockers) have been evaluated and discontinued when appropriate

HAE Type III

1. The member meets one of the following criteria (a, b, or c)
   • (a) Cinryze is being used for prophylaxis management against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE)
   • (b) Berinert is being used for the treatment of acute abdominal, facial, or laryngeal attacks of HAE in adults/adolescents 13 years of age and older 
   • (c) 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:
   • C4 within normal limits (normal range:14 to 40 mg/dL) OR C4 within normal limits of the laboratory's normal reference range AND
   • 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 AND
   • C1INH functional within normal limits of the laboratory's normal reference range AND
3. Clinical documentation of at least one of the following:
   • Family history of HAE OR
   • FXII mutation AND
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 AND
5. Medications known to cause angioedema (i.e. ACE-inhibitors, estrogens, angiotensin II receptor blockers) have been evaluated and discontinued when appropriate

Use of C1 Esterase Inhibitors for disease states outside of FDA-approved indications should be denied based on the lack of clinical data to support effectiveness and safety in other conditions.

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

References 

1. Cinryze [package insert]. Shire ViroPharma, Inc. Lexington, MA. 2008. Revised September 2014.
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 May 2015.
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. McEvoy GK,ed. AHFS: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists: 2015.
11. Craig T, Pursun A, Bork K, et al. WAO guideline for the management of hereditary angioedema. Available at: Accessed January 25, 2016.
12. 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.  
13. 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.
14. 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
15. 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.