Medical Drug Criteria (MDC)

Policy Num: P1.002.010
Policy Name: Ruconest (C1 Esterase Inhibitor [recombinant})
Policy ID: [P1.002.010] [Ac / L / M+ / P+]

Last Review: September 22, 2025
Next Review: September 20, 2026

Related MDC: None

Ruconest (C1 Esterase Inhibitor [recombinant])

Popultation Reference No.	Populations
1	Individuals: Treatment of acute abdominal, peripheral, or facial attacks of Hereditary Angioedema (HAE)

Summary

Ruconest is a recombinant C1 esterase inhibitor indicated for the treatment of acute attacks of hereditary angioedema (HAE). Mechanism: C1 esterase inhibitor is a complement protein regulating the kallikrein–bradykinin pathway. Deficiency or dysfunction leads to recurrent angioedema in HAE. Clinical relevance: HAE is a rare, life-threatening disorder characterized by swelling in extremities, GI tract, face, and airway, with risk of asphyxiation. FDA Indication: Treatment of acute attacks of HAE in patients ≥13 years.

Objective

Ensure medically appropriate and safe access to Ruconest for acute HAE attacks. Standardize coverage across HAE subtypes and reduce risk of inappropriate use. Align payer criteria with FDA label and international consensus guidelines.

Policy Statements

Coverage for Ruconest is provided for patients meeting universal and subtype-specific criteria.

Policy Guidelines

Universal Criteria

Age ≥13 years.

Prescribed by, or in consultation with, a specialist in allergy, immunology, hematology, pulmonology, or medical genetics.

No history of allergy to rabbits/rabbit-derived products.

Avoidance of known HAE triggers:

Estrogen-containing contraceptives or hormone replacement therapy.

ACE inhibitors.

DPP-IV inhibitors (e.g., sitagliptin).

Neprilysin inhibitors (e.g., sacubitril).

Indication-Specific Criteria

1. HAE Type I:

Low C1-INH antigenic level.

Low C1-INH functional level.

Low C4 level.

Onset before age 30, normal C1q, no secondary causes.

2. HAE Type II:

Normal or elevated C1-INH antigenic level.

Low C1-INH functional level.

Low C4 level.

3. HAE with normal C1-INH (HAE-nlC1INH):

Normal C1-INH antigen, C1-INH function, and C4.

Documented genetic mutation (F12, ANGPT1, PLG, KNG1, MYOF, HS3ST6) OR family history with failure of high-dose antihistamines ± corticosteroids.

Coverage is provided in the following conditions:

• Patient is at least 13 years of age; AND

Universal Criteria

• Must be prescribed by, or in consultation with, a specialist in: allergy, immunology, hematology, pulmonology, or medical genetics; AND

• Patient does not have a history of allergy to rabbits or rabbit-derived products; AND

• Confirmation the patient is avoiding the following possible triggers for HAE attacks:

o Estrogen-containing oral contraceptive agents AND hormone replacement therapy;
AND
o Antihypertensive agents containing ACE inhibitors; AND
o Dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin); AND
o Neprilysin inhibitors (e.g., sacubitril); AND

Treatment of acute abdominal, peripheral, or facial attacks of Hereditary Angioedema (HAE)

Patient has a history of moderate to severe cutaneous attacks (without concomitant hives)OR abdominal attacks OR mild to severe airway swelling attacks of HAE (i.e. debilitating cutaneous/gastrointestinal symptoms OR laryngeal/pharyngeal/tongue swelling); AND
Patient has one of the following clinical presentations consistent with a HAE subtype§,which must be confirmed by repeat blood testing (treatment for acute attack should not bedelayed for confirmatory testing):

HAE I (C1-Inhibitor deficiency)

 Low C1 inhibitor (C1-INH) antigenic level (C1-INH antigenic level below the lower limit of
normal as defined by the laboratory performing the test); AND

 Low C4 level (C4 below the lower limit of normal as defined by the laboratory performing
the test); AND

 Low C1-INH functional level (C1-INH functional level below the lower limit of normal as
defined by the laboratory performing the test); AND

o Patient has a family history of HAE; OR

o Acquired angioedema has been ruled out (i.e., patient onset of symptoms occur prior
to 30 years old, normal C1q levels, patient does not have underlying disease such as
lymphoma or benign monoclonal gammopathy [MGUS], etc.)

HAE II (C1-Inhibitor dysfunction)

Normal to elevated C1-INH antigenic level; AND

• Low C4 level (C4 below the lower limit of normal as defined by the laboratory performing
the test); AND

• Low C1-INH functional level (C1-INH functional level below the lower limit of normal as
defined by the laboratory performing the test)

HAE with normal C1INH (formerly known as HAE III)

 Normal C1-INH antigenic level; AND

 Normal C4 level; AND

 Normal C1-INH functional level; AND

 Repeat blood testing during an attack has confirmed the patient does not have abnormal lab
values indicative of HAE I or HAE II; AND

 Either of the following:

o Patient has a known HAE-causing mutation (e.g., mutation of coagulation factor XII gene [F12 mutation], mutation in the angiopoietin-1 gene, mutation in the plasminogen gene, mutation in the kininogen 1 gene, mutation in the myoferlin gene, mutation in the heparan sulfate 3-O-sulfotransferase 6 gene, etc.); OR

o Patient has a family history of HAE and documented evidence of lack of efficacy of chronic high-dose antihistamine therapy (e.g. cetirizine standard dosing at up to four times daily or an alternative equivalent, given for at least one month or an interval long enough to expect three or more angioedema attacks) AND corticosteroids with or without omalizumab

Renewal Criteria

Patient continues to meet the universal and other indication-specific relevant criteria identified in section III; AND
Significant improvement in severity and duration of attacks have been achieved and sustained; AND
Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: severe hypersensitivity reactions (including anaphylaxis), serious thromboembolic events (arterial or venous), etc.; AND
The cumulative amount of medication(s) the patient has on-hand, indicated for the acute treatment of HAE, will be taken into account when authorizing. The authorization will provide a sufficient quantity in order for the patient to have a cumulative amount of HAEmedication(s) on-hand in order to treat up to 4 acute attacks per 4 weeks for the duration of the authorization (unless otherwise specified).

FDA Approved Indication(s); Ф Orphan Drug

Background

HAE prevalence: ~1:50,000; underdiagnosed.

Subtypes: HAE-I, HAE-II, HAE-nlC1INH.

Burden: Attacks impair quality of life and may be fatal.

Therapies: Acute treatment includes plasma-derived/recombinant C1-INH, bradykinin B2 antagonists, and kallikrein inhibitors.

Regulatory Status

FDA: Approved 2014 for acute HAE attacks (≥13 years).

EMA: Approved for same indication.

Orphan Drug: Yes.

DOSAGE/ADMINISTRATION

Acute Hereditary Angioedema (HAE) attack

Body weight < 84 kg:

Administer 50 international units (IU) per kg body weight by intravenous injection

Body weight ≥ 84 kg:

Administer 4200 IU (2 vials) by intravenous injection If the attack symptoms persist, an additional (second) dose can be administered at the recommended dose level. Do not exceed 4200 IU per dose. No more than two doses should be administered within a 24 hour period.

**Note: Patients may self-administer Ruconest after being instructed by their healthcare provider.

Dosing Limits

A. Quantity Limit (max daily dose) [NDC Unit]:
• Ruconest 2100 IU single-use vial: 16 vials every 28 days

B. Max Units (per dose and over time) [HCPCS Unit]:
• 3360 billable units per 28 days

REQUIRED MEDICAL INFORMATION

Submission of medical records (chart notes) related to the medical necessity criteria is REQUIRED on all requests for authorizations. Records will be reviewed at the time of submission. Please provide documentation related to diagnosis, step therapy, and clinical markers (i.e. genetic and mutational testing) supporting initiation when applicable. Medical records may be submitted via direct upload through the PA web portal or by fax.

EXCLUSION CRITERIA

None, aside from contraindication in rabbit protein allergy.

BENEFIT APPLICATION

Coverage is consistent with contract language and federal/state mandates (e.g., PR Law No. 62, April 2024, requiring HAE coverage).

Rationale

Efficacy: Clinical trials confirm rapid symptom relief in acute HAE attacks.

Safety: Risks include hypersensitivity, thromboembolic events.

Guidelines: WAO/EAACI (2021) and US HAEA (2020) recommend recombinant or plasma-derived C1-INH as standard of care

OTHER CRITERIA

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Determinations (LCDs), and Local Coverage Articles (LCAs) may exist and compliance with these policies is required where applicable. They can be found at: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications may be covered at the discretion of the health plan.

Supplemental Information

Self-administration: Permitted after appropriate training. Attack frequency: Coverage allows medication to treat up to 4 acute attacks per 4 weeks.

Practice Guidelines and Position Statements

WAO/EAACI 2021 Guidelines: Support C1-INH therapy as first-line for acute attacks.

US HAEA 2020 Guidelines: Recombinant C1-INH is a preferred treatment.

References

1. Ruconest [package insert]. Warren, NJ; Pharming Healthcare, Inc; April 2020. AccessedSeptember 2023.
2. Riedl MA, Grivcheva-Panovska V, Moldovan D, et al. Recombinant human C1 esteraseinhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised,double-blind, placebo-controlled crossover trial. Lancet. 2017;390(10102):1595-1602.

3. Bowen T, Cicardi M, Farkas H, et al. Canadian 2003 International Consensus AlgorithmFor the Diagnosis, Therapy, and Management of Hereditary Angioedema. J Allergy ClinImmunol. 2004 Sep;114(3):629-37.
4. Bygum A, Andersen KE, Mikkelsen CS. Self-administration of intravenous C1-inhibitortherapy for hereditary angioedema and associated quality of life benefits. Eur J Dermatol.Mar-Apr 2009;19(2):147-151.
5. Bowen T, Cicardi M, Farkas H, et al. 2010 International consensus algorithm for thediagnosis, therapy and management of hereditary angioedema. Allergy Asthma ClinImmunol. 2010;6(1):24.
6. Craig T, Aygören-Pürsün E, Bork K, et al. WAO Guideline for the Management ofHereditary Angioedema. World Allergy Organ J. 2012 Dec;5(12):182-99.
7. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. ClinExp Immunol. 2005;139(3):379.
8. Betschel S, Badiou J, Binkley K, et al. Canadian hereditary angioedema guideline. AsthmaClin Immunol. 2014 Oct 24;10(1):50. doi: 10.1186/1710-1492-10-50.
9. Zuraw BL, Bernstein JA, Lang DM, et al. A focused parameter update: hereditaryangioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitorassociated angioedema. J Allergy Clin Immunol. 2013 Jun;131(6):1491-3. doi:10.1016/j.jaci.2013.03.034.
10. Zuraw BL, Banerji A, Bernstein JA, et al. US Hereditary Angioedema Association MedicalAdvisory Board 2013 recommendations for the management of hereditary angioedema dueto C1 inhibitor deficiency. J Allergy Clin Immunol Pract. 2013 Sep-Oct;1(5):458-67.
11. Frank MM, Zuraw B, Banerji A, et al. Management of children with HereditaryAngioedema due to C1 Inhibitor deficiency. Pediatrics. 2016 Nov. 135(5)
12. Zuraw BL, Bork K, Binkley KE, et al. Hereditary angioedema with normal C1 inhibitorfunction: Consensus of an international expert panel. Allergy Asthma Proc. 2012;33 Suppl 1:145-156.
13. Maurer M, Mager M, Ansotegui I, et al. The international WAO/EAACI guideline for themanagement of hereditary angioedema-The 2017 revision and update. Allergy. 2018 Jan10. doi: 10.1111/all.13384.
14. Lang DM, Aberer W, Bernstein JA, et al. International consensus on hereditary andacquired angioedema. Ann Alergy Asthma Immunol. 2012;109:395-402.
15. Wintenberger C, Boccon-Gibod I, Launay D, et al. Tranexamic acid as maintenance reatment for non-histaminergic angioedema: analysis of efficacy and safety in 37 patients.Clin Exp Immunol. 2014 Oct; 178(1): 112–117.
16. Saule C, Boccon-Gibod I, Fain O, et al. Benefits of progestin contraception in non-allergicangioedema. Clin Exp Allergy. 2013 Apr;43(4):475-82

17. Frank MM, Sergent JS, Kane MA, et al. Epsilon aminocaproic acid therapy of hereditaryangioneurotic edema; a double-blind study. N Engl J Med. 1972:286:808-812.
18. Riedl MA, Bernstein JA, Li H, et al. Recombinant human C1-esterase inhibitor relievessymptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial.Ann Allergy Asthma Immunol. 2014;112(2):163-169.e1.
19. Betschel S, Badiou J, Binkley K, et al. The International/Canadian Hereditary AngioedemaGuideline. Allergy Asthma Clin Immunol. 2019; 15: 72. Published online 2019 Nov 25. doi:10.1186/s13223-019-0376-8.
20. Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema. J Allergy Clin Immunol Pract. 2021 Jan;9(1):132-150.e3. doi: 10.1016/j.jaip.2020.08.046.
21. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update. Allergy. 2021

Codes

Codes	Number	Description
CPT	96374	IV push, initial drug
	96375	Each additional sequential IV push
HCPCS	J0596	Injection, c1 esterase inhibitor (recombinant), ruconest, 10 units; 1 billable unit = 10 units
ICD-10	D84.1	Defects in the complement system

Policy History

Date	Action	Description
9/22/2025	Annual Review	No changes on statements. Medical Drug Criteria approved at the September 2025 Pharmacy Criteria Meetting.
9/17/2024	Policy Review	PR Law No. 62, April 16, 2024, establishes mandatory coverage for HAE. Medical Drug Criteria approved at the September 2024 Pharmacy Criteria Meetting.
02/19/2024	Review MDC	No change
02/23/2023	New MDC	New medical drug criteria