Ruconest C1 esterase inhibitor recombinant...Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit
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Subject: Ruconest (C1 esterase inhibitor [recombinant]) Original Effective Date: 1/13/15
Policy Number: MCP-233 Revision Date(s): 12/13/17
Review Date: 12/15/2016
DISCLAIMER
This Medical Policy is intended to facilitate the Utilization Management process. It expresses Molina's determination as
to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of
determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does
not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a
particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are
covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need
to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to
this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will
govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or
CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage
directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination
(LCD) will supersede the contents of this Molina Clinical Policy (MCP) document and provide the directive for all
Medicare members.
SUMMARY OF EVIDENCE/POSITION
This policy addresses the coverage of Ruconest (C1 esterase inhibitor [recombinant]) for the treatment of acute
attacks in adult and adolescent patients with hereditary angioedema (HAE) when appropriate criteria are met.
This policy is intended to address coverage criteria that are appropriate for the majority of individuals/members with a
particular disease, illness, or condition. Each member's unique clinical circumstances may warrant individual
consideration, based on review of applicable medical records.
androgens is ineffective, poorly tolerated, or inappropriate (e.g., pregnant women, children). Reference: AAAI/ACAAI/AAI (Zuraw, 2013b; Hereditary Angioedema International Working Group (Cicardi, 2012);
Treatment of acute attacks of hereditary angioedema (HAE) in adult and adolescent patients
Limitations of use
Effectiveness not established in HAE patients with laryngeal attacks.
Available as: 2100 U Lyophilized powder for reconstitution for injection in a single-use vial
FDA Approved: July 2014
Black Box Warnings: None at the time of this writing
Warnings/Precautions
• Hypersensitivity reactions, including anaphylaxis may occur. Should symptoms occur, discontinue Ruconest and
administer appropriate treatment.
• Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of plasma
derived C1 esterase inhibitor products in patients with risk factors. Monitor patients with known risk factors for TE
events during and after Ruconest administration. ]
Page 4 of 20
RECOMMENDATIONS/COVERAGE CRITERIA
Ruconest (C1 esterase inhibitor [recombinant]) may be authorized for members who meet ALL of the following
criteria [ALL]
1.� Prescriber specialty [ALL]
¶ Prescribed by, or in consultation with, a board-certified immunologist, allergist, hematologist, or physician
experienced in the treatment of C1-esterase inhibitor deficiency. Submit consultation notes if applicable. ® Due to the complexity and variability of HAE and treatment, it is strongly recommended that every patient with
HAE be followed up by a physician who is (1) knowledgeable about the condition, (2) experienced in managing
patients with HAE, and (3) familiar with all HAE treatment options. US HAE Association Medical Advisory Board 2013
¶ If primary care provider is the prescribing physician, clinical documentation of appropriate specialist visits
must be included in supporting documentation.
NOTE: Consultation notes must be submitted for initial request and for continuation of treatment requests at
least ONCE annually.
2.� Diagnosis/Indication [ALL]
¶ Diagnosis of Type I or Type II HAE confirmed by ONE (1) of the following: [ONE]
û Genetic testing: Presence of a mutation in the C1INH gene altering protein synthesis and/or function
û BOTH of the following (documentation of TWO (2) separate low measurements for each test defined
as below the testing laboratory’s lower limit of the normal range): [BOTH]
¶ All other causes and potentially treatable triggers of HAE attacks (i.e. stress, trauma, infection, etc.) have
been identified and optimally managed
¶ Concurrent therapies that may exacerbate HAE, have been evaluated and has been discontinued as
appropriate, including but not limited to the following: [ALL]
û Estrogen-containing medications [e.g. hormone replacement therapy, contraceptives]
û ACE-inhibitor (ACEI)
û Angiotensin II receptor blockers
MOLINA REVIEWER: Verify pharmacy claims data for the above drugs within the past 30 days, OR for
members new to Molina Healthcare, review member’s current medical records or chart notes to confirm.
¶ Member is NOT concurrently on, or using in combination with, other approved treatments for ACUTE HAE
attacks (e.g. Firazyr®, Ruconest®, and Kalbitor®)
® Insufficient evidence to support use of combination therapy with multiple agents
NOTE: Members will only be authorized for one (1) acute HAE medication* at a time.
*Berinert®, Kalbitor®, Ruconest® and Firazyr® are indicated for treatment of acute HAE attacks.
MOLINA REVIEWER: Verify pharmacy claims data for the above drugs within the past 30 days, OR for
members new to Molina Healthcare, review member’s current medical records or chart notes to confirm.
Page 6 of 20
5. Contraindications*/Exclusions/Discontinuations
Authorization will not be granted if ANY of the following conditions apply: [ANY]
¶ Non-FDA approved indications
¶ Life-threatening immediate hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor
preparations or any component of the formulation; allergy to rabbits or rabbit-derived products ® Ruconest is purified from the milk of transgenic rabbits. It is therefore contraindicated in patients with a known
or suspected allergy to rabbits and rabbit-derived products due to the risk of an anaphylactic reaction.
¶ Less than 13 years of age�Exclusions [ANY]�
¶ Concomitant therapy, or concurrently prescribed with drugs which may exacerbate HAE: [ANY]
û Angiotensin-converting enzyme (ACE) inhibitors
û Angiotensin II receptor blockers
û Estrogen-containing medications [i.e. hormone replacement therapy and contraceptives]
¶ Prescribed for treatment of the following: [ANY]
û ROUTINE PROPHYLAXIS against HAE attacks ® Ruconest is not indicated for the prophylaxis of HAE attacks. The safety and efficacy of Ruconest for
prophylactic therapy has not been established.
û Acquired angioedema (AAE)
6.� Labs/Reports/Documentation required [ALL]
All documentation for determination of medical necessity must be submitted for review. Prescriber to submit
documentation as indicated in the criteria above, including but not limited to chart notes, applicable lab values and/or
tests, adverse outcomes, treatment failures, or any other additional clinical information or clinical notes from the
member’s medical records supporting the diagnosis. Letters of support and/or explanation are often useful, but are
not sufficient documentation unless ALL specific information required by this MCP is included.
NOTE: Additional documentation, rationale, and/or supporting evidence may be requested for review as deemed
necessary or appropriate by Molina Medical/Pharmacy staff.
Page 7 of 20
CONTINUATION OF THERAPY
Ruconest (C1 esterase inhibitor [recombinant]) may be authorized for continuation of therapy if meet ALL of the
following criteria are met: [ALL]
1. Initial Coverage Criteria [ALL]�
ß Member currently meets ALL initial coverage criteria
¶ Subsequent authorizations require re-assessment treatment regimen/plan, an evaluation of the frequency of
HAE attacks and complete clinical review of member’s condition to determine if continuation of treatment
with requested treatment is medically necessary. Submit all relevant clinical notes, chart notes, and
consultation notes (if applicable) for review at least once every 6 months. ® Because disease severity may change over time, the need to start or continue therapy should be periodically
reviewed and discussed with the patient (US HAE, Zuraw, 2013a)
¶ Significant improvement in the following aspects of HAE attacks have been achieved and sustained.
Documentation required. [ALL]
û Frequency: At least a 50% reduction in frequency of HAE attacks has been achieved or sustained
NOTE: More than one severe HAE event per month should prompt a discussion with the
Prescriber regarding the potential need for chronic prophylaxis with antifibrinolytics, attenuated
androgens, or plasma derived C1 inhibitor replacement therapy (to be used in addition to Firazyr
(icatibant) for acute treatment)
û Severity
û Duration
ß Clinical documentation of functional improvement
ß Documentation of ONE (1) of the following: [ONE]
û Adherence to prophylactic therapy for HAE (with antifibrinolytics, attenuated androgens, or plasma
derived C1 inhibitor replacement therapy), IF APPLICABLE
NOTE: Adherence to prescribed prophylactic therapy for HAE must be confirmed by member’s
prescription claims. For member is new to Molina and does not have a prescription claims history,
Prescriber certify that the member has been adherent to the prescribed prophylactic therapy.
OR
û More than one severe HAE event per month should prompt a discussion with the Prescriber regarding
the potential need for chronic prophylaxis (with antifibrinolytics, attenuated androgens, or plasma
derived C1 inhibitor replacement therapy) as part of HAE therapy with Ruconest (C1 esterase
inhibitor [recombinant]) for acute treatment
Page 8 of 20
4.� Discontinuation of Treatment [ANY]
Discontinue treatment if ANY of the following conditions applies: [ANY]
ß Intolerable adverse effects or drug toxicity
ß Poor response to treatment as evidenced by physical findings and/or clinical symptoms
ß Contraindications/Exclusions to Ruconest therapy
û Non-FDA approved indications
û Hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations or any
component of the formulation; allergy to rabbits or rabbit-derived products
û Concurrent use of agents which may exacerbate HAE:
o Angiotensin-converting enzyme (ACE) inhibitors
o Angiotensin II receptor blockers
o Estrogen-containing medications [i.e. hormone replacement therapy and contraceptives]
Exclusions [ANY]
¶ Use of Ruconest in HAE treatment of prophylactic therapy ® Ruconest is not indicated for the prophylaxis of HAE attacks.a The safety and efficacy of Ruconest for
prophylactic therapy has not been established.a
Page 9 of 20
ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD
Consult the manufacturer's labeling for more detailed information on dosage and administration of this drug, cautions,
precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
1.� Recommended Dosage [ALL]
¶ 50 IU per kg with a maximum of 4,200 units (2 vials) to be administered as a slow intravenous injection
over approximately 5 minutes. Body weight < 84 kg: 50 IU/kg Body weight ≥ 84 kg: 4200 IU (2 vials)
¶ If the attack symptoms persist, an additional (second) dose can be administered at the recommended dose
level. Do not exceed 4200 U per dose. No more than two doses should be administered within a 24 hour
period.
2.� Authorization Limit [ALL]
ß Quantity limit: May authorize up to a sufficient quantity for member to have a cumulative amount on-hand to
treat up to 2 acute attacks per month [8 vials per 30 days]
¶ Dispensing limit: 1-month supply sufficient for 2 acute attacks for member to have on-hand
MOLINA PHARMACY: Prior to dispensing, verify that the member does not have more than a 1-month
supply (sufficient for 2 acute attacks) currently on-hand
EXCEPTIONS: For dosages or regimens exceeding the allowable quantity/dispensing limit of 2 acute
attacks per month: Prescriber submit supporting clinical documentation for Medical Director review (e.g.
frequency of attacks within the past 3 months has been more than 2 attacks per month)
Rationale for quantity on-hand: All patients with HAE due to C1-INH deficiency should have access to at
least two standard doses of one “on-demand” treatment for acute HAE attacks (Firazyr, Berinert, Kalbitor,
Ruconest). [2013 US HAE Association Consensus Guidelines]
¶ Duration of Authorization: [AS APPLICABLE]
û Initial authorization: THREE (3) months
û Re-authorization for continuation of treatment is required SIX (6) months to determine continued
need based on documented clinical response
ß Authorization for ONE (1) acute HAE medication at a time
[MOLINA REVIEWER TO VERIFY CLAIMS/AUTHORIZATION PROFILE]
Page 10 of 20
3. Route of Administration [ALL]�
ß Ruconest (C1 esterase inhibitor [recombinant]) may be provider-administered or self-administered. Self-
administration may be authorized after training by a healthcare professional. Verification of patient education
on medication administration upon initiation of therapy must be submitted for authorization of Berinert for
self-administration.
ß If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty
pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed
for self-administration and billed through the medical benefit by a provider; they must be dispensed through a
participating pharmacy.
COVERAGE EXCLUSIONS
This policy addresses the coverage of Ruconest (C1 esterase inhibitor [recombinant]) for the treatment of acute attacks of
hereditary angioedema in patients 12 years and older when appropriate criteria are met.
All other uses of Ruconest (C1 esterase inhibitor [recombinant]), including §acquired angioedema, that are not an FDA-
approved indication or not included in the ‘Coverage Criteria’ section of this policy are considered
experimental/investigational or not a covered benefit of this policy. This subject to change based on research and medical
literature, or at the discretion of Molina Healthcare.
§The etiology and management of Acquired C1 inhibitor deficiency (AAE) differ from Type I and II HAE and treatment of
AAE is not an FDA-approved indication for Haegarda, Berinert, Firazyr, Kalbitor, Cinryze, or Ruconest; therefore, AAE
is not addressed in this document.
*Pharmaceutical samples: The use of pharmaceutical samples (from the prescriber or manufacturer assistance program)
will not be considered when evaluating the medical condition, prior prescription history, or as continuation of therapy.
*FDA-approved indication does not, in itself, dictate coverage. Molina Clinical Policy may not recommend coverage for
all FDA-approved indications. Please review this Policy in its entirety for indications covered by Molina Healthcare.
Primary End Point(s)�Median time to onset of sustained relief (from baseline to the first time point at which the patient reported a response�of "a little better," "better," or "much better" to TEQ question 1, response of "yes" to TEQ question 2, and persistence�of improvement at the next assessment time point) at the primary attack location was 90 minutes (95% CI, 61 to 150)�with C1 esterase inhibitor (recombinant) and 152 minutes (95% CI, 93 to not estimable) with placebo (P = 0.031).�Secondary End Point(s)�
• Time to minimal symptoms based on the TEQ (time from dosing to the first time point when the patient
reported a response of "yes" to TEQ question 3 for all attack locations) was 303 minutes with C1 esterase
inhibitor (recombinant) compared with 483 minutes with placebo (P = 0.078). The time to minimal symptoms
at all attack locations, based on the VAS score, was shorter in patients treated with C1 esterase inhibitor
(recombinant) than placebo (240 minutes vs 362 minutes; P = 0.005).
• Time to onset of sustained relief from symptoms based on the VAS score was shorter in patients treated with
C1 esterase inhibitor (recombinant) than placebo (75 vs 303 minutes; P = 0.003).