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Date Printed: February 21, 2017: 06:16 PM

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09-J1000-17

Original Effective Date: 03/15/10

Reviewed: 04/13/16

Revised: 05/15/16

Subject: Eculizumab (Soliris®) Injection

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.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates
           

DESCRIPTION:

Eculizumab (Soliris®) is a humanized monoclonal antibody against C5, a protein in the complement cascade that is essential for the formation of the membrane attack complex responsible for cell lysis. Eculizumab is indicated for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).

PNH is an uncommon, life-threatening hemolytic anemia; the prevalence of PNH ranges from 1 to 5 cases per million people. In the U.S., there are fewer than 500 cases. PNH results from an acquired genetic deficiency in the cytolytic complement cascade that renders red blood cells (RBCs) susceptible to lysis. Chronic destruction of PNH RBCs by complement leads to serious morbidities. Increased hemolysis at night, hypothesized to result from decreased blood pH and activation of the complement system, leads to characteristic bloody morning urination. Excessive or persistent intravascular hemolysis in persons with PNH results in anemia, hemoglobinuria, and complications related to the presence of plasma-free hemoglobin (e.g., thrombosis, abdominal pain, dysphagia, erectile dysfunction, and pulmonary hypertension). In persons with PNH, eculizumab’s inhibition of C5 reduces hemolysis and transfusion requirements.

Evidence for the efficacy and safety of eculizumab in PNH was obtained from the results of the phase 3 study, Transfusion Reduction Efficacy and Safety Clinical Investigation, a Randomized, Multicenter, Double-Blind, Placebo-Controlled, Using Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (TRIUMPH). TRIUMPH included 87 transfusion-dependent PNH subjects who were not thrombocytopenic. Subjects were randomized to receive an intravenous (IV) infusion of eculizumab or placebo. Eculizumab was dosed at 600 mg weekly for 4 weeks, then 900 mg in week 5, and 900 mg every other week to complete 26 weeks of treatment. Outcome measures included the proportion of subjects with hemoglobin levels maintained above an individualized set point, number of blood transfusions, serum levels of lactate dehydrogenase (LDH; an indication of hemolysis), and quality of life (QOL) outcomes.

• Twenty-one of 43 eculizumab-treated subjects (49%) achieved hemoglobin stabilization compared with none of the 44 placebo-treated subjects (p<0.001)

• The median (interquartile range) number of transfusions for 6 months before treatment was 8.5 (7-12.5) units in the placebo group and 9 (6-12) units in the eculizumab group. During six months of treatment, these values were 10 (6-16) and 0 (0-6) in the placebo and eculizumab groups, respectively (p<0.001)

• Mean serum LDH levels [± standard error] after treatment were lower in the eculizumab group compared with the placebo group (327.3 [±67.6] U/L vs. 2,418 [±140.3] U/L, p<0.001).

• QOL measures worsened in the placebo group and improved in the eculizumab group.

Hemolytic uremic syndrome (HUS) describes the clinical condition of persons who present with simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Typical HUS constitutes 90-95% of HUS and is secondary to infection by Shiga toxin-producing Escherichia coli (STEC). Atypical HUS (aHUS) is the result of uncontrolled activation of the complement system. Persons with aHUS present with nonimmune hemolytic anemia, thrombocytopenia, and severe renal impairment. Microvascular lesions (thrombotic microangiopathy) result from uncontrolled complement action on endothelial walls of capillary beds primarily in the kidney. In aHUS, eculizumab binds to C5, preventing the formation of C5a (inflammatory peptide) and the membrane-attack complex C5b-9 (cytotoxic), inhibiting terminal complement-mediated thrombotic microangiopathy.

The efficacy of eculizumab in the treatment of aHUS was evaluated in four prospective single-arm studies, which were published as two abstracts. One abstract describes subjects with plasma therapy-resistant aHUS (n=17 aged 12 years or older) treated with eculizumab for 26 weeks. The comparator was baseline levels at the start of therapy. Outcomes of interest included the reduction in the signs of thrombotic microangiopathy (TMA; e.g., reduction of serum LDH levels, increased platelet count, improvements in creatinine clearance [CrCl]). These subjects experienced a mean platelet count (primary endpoint) increase from 109,000±32,000 at baseline to 210,000±68,000 after 26 weeks of therapy. The second abstract reported subjects with plasma therapy-sensitive aHUS (n=20 aged 12 years or older), also treated with eculizumab for 26 weeks. The comparator in this study was a baseline measure recorded over an 8 week observation period. The outcome of interest was reduction in the signs of TMA, but in subjects already stabilized on plasma therapy and where eculizumab was substituted, outcomes of interest were maintaining the corrected levels of TMA indicators already achieved with plasma therapy (platelet count and serum LDH levels remain stable compared to baseline). The primary endpoint for the cohort with plasma therapy sensitive aHUS was TMA event free status, defined as 12 weeks or more of stable platelet count, no plasma therapy and no new dialysis. The primary endpoint was achieved in 80% (95% CI 0.56-0.94) of the cohort.

Apart from eculizumab, no therapies have been approved for the treatment of hemolytic anemia of PNH or aHUS. Standard treatment options for PNH include corticosteroids, androgens, splenectomy, blood transfusions, and iron and folate supplementation. For persons with an associated bone-marrow failure syndrome or with major complication of PNH (e.g., refractory transfusion-dependent hemolytic anemia or recurrent life-threatening thromboembolic complications), hematopoietic stem-cell transplant is considered. The American Society of Hematology (ASH) recommends eculizumab for the treatment of PNH.

Any person suspected of having aHUS should be transferred to a specialized center able to provide supportive care for acute renal failure and severe hypertension, and where dialysis and plasma exchange are common practice. Plasma exchange or plasma infusion (PE/PI), which have been used for 30 years, reduce mortality related to acute aHUS episodes from 50% to 25%.

POSITION STATEMENT:

Initiation of eculizumab (Soliris) meets the definition of medical necessity when used to treat EITHER of the following indications and the indication-specific criteria are met:

1. Paroxysmal Nocturnal Hemoglobinuria (PNH)

a. Flow cytometry demonstrates at least 10% PNH type III red cells OR greater than 50% of glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient poly-morphonuclear cells (PMNs) – documentation must be provided

b. Member meets TWO OR MORE of the following:

i. Granulocytes greater than or equal to 500/mm3

ii. Platelets greater than or equal to 20,000/mm3

iii. Reticulocytes greater than or equal to 1%

c. Member’s lactate dehydrogenase (LDH) is elevated (i.e., 1.5 times greater than the upper limit of normal [ULN] as determined by the laboratory performing the test)

d. Member has been vaccinated against meningococcal infection at least 2 weeks prior to therapy initiation

e. There is no evidence of an active meningococcal infection

f. EITHER of the following:

i. Member’s disease is transfusion-dependent evidenced by 2 or more transfusions in the 12 months prior to eculizumab initiation

ii. Member has a history of a major adverse vascular event (MAVE) from thromboembolism (e.g., myocardial infarction, cerebrovascular accident, deep vein thrombosis)

g. The dose does not exceed 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later and then 900 mg every 2 weeks

2. Atypical Hemolytic Uremic Syndrome (aHUS)

a. Diagnosis is supported by BOTH of the following (documentation must be provided):

i. the absence of Shiga toxin-producing E. coli infection

ii. ADAMTS-13 level is greater than 5%

b. Member has been vaccinated against meningococcal infection at least 2 weeks prior to therapy initiation

c. There is no evidence of an active meningococcal infection

d. The dose does not exceed 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every 2 weeks

Approval duration: 60 days

Continuation of eculizumab meets the definition of medical necessity when ALL of the following are met

1. Member has a history of beneficial response to eculizumab therapy for the treatment of EITHER of the following indications:

a. Paroxysmal nocturnal hemoglobinuria (PNH) - examples of beneficial response include decreased requirement for transfusions, stabilization of hemoglobin, reduction of LDH

b. Atypical hemolytic uremic syndrome (aHUS) examples of beneficial response include improved platelet count, reduction of LDH, improved renal function

2. The member has been previously approved for eculizumab in the treatment of PNH or aHUS by Florida Blue or another health plan in the past 2 years, OR the member has previously met all indication-specific criteria for coverage

3. Member has been revaccinated against meningococcal infection according to current medical guidelines for vaccination while on eculizumab therapy

4. There is no evidence of an active meningococcal infection

5. The dose does not exceed indication specific limitations:

a. PNH: 900 mg every 14 days

b. aHUS: 1200 mg every 14 days

Approval duration: 1 year

NOTE: Quest Diagnostics® can perform the following tests used in the diagnosis of PNH or aHUS

• Flow cytometry assay (PNH with FLAER) used in the diagnosis of PNH

• ADAMTS-13 activity immunoassay used in diagnosis of aHUS

• Shiga Toxin, EIA with reflex to E. coli O157 culture used in the diagnosis of aHUS

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.

FDA-approved: eculizumab is indicated for the treatment of persons with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis and treatment of persons with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Eculizumab is not indicated for the treatment of persons with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). Eculizumab is administered as an intravenous infusion over 35 minutes via gravity feed, a syringe-type pump, or an infusion pump. The recommended dosage regimen is dependent on the disease. Eculizumab should be administered at the recommended dosage regimen time points, or within 2 days of these time points.

1. PNH

a. 600 mg weekly for weeks 1-4

b. 900 mg for the fifth dose on week 5

c. 900 mg every 14 days thereafter

2. aHUS

a. 18 years of age and older

o 900 mg weekly for weeks 1-4

o 1200 mg for the fifth dose on week 5

o 1200 mg every 14 days thereafter

b. Less than 18 years of age: eculizumab dose is based on body weight. The recommended doses based on body weight are outline in table 1.

Table 1

Dosing recommendations in members less than 18 years of age

Member Body Weight

Induction

Maintenance

40 kg and greater

900 mg weekly x 4 doses

1200 mg at week 5; then 1200 mg every 2 weeks

30 kg to less than 40 kg

600 mg weekly x 2 doses

900 mg at week 3; then 900 mg every 2 weeks

20 kg to less than 30 kg

600 mg weekly x 2 doses

600 mg at week 3; then 600 mg every 2 weeks

10 kg to less than 20 kg

600 mg weekly x 1 dose

300 mg at week 2; then 300 mg ever 2 weeks

5 kg to less than 10 kg

300 mg weekly x 1 dose

300 mg at week 2; then 300 mg every 3 weeks

Dose Adjustments

• Supplemental dosing of eculizumab is required in the setting of concomitant support with plasmapheresis/plasma exchange (PE) or fresh frozen plasma infusion (FFPI). Table 2 outlines recommended supplemental dosing following PE or PI.

Table 2

Supplemental dose of eculizumab following PE/FFPI

Intervention

Most recent
eculizumab dose

Supplemental

eculizumab dose with
each PE/PI intervention

Timing of supplemental dose

PE

300 mg

300 mg per each PE

Within 60 minutes after each PE

600 mg or more

600 mg per PE

FFPI

300 mg or more

300 mg per each unit of fresh frozen plasma

60 minutes prior to each 1 unit of FFPI

PE, plasmapheresis or plasma exchange; FFPI, fresh frozen plasma infusion

Drug Availability: eculizumab is available as a 300 mg single-use vial containing 30 mL of 10 mg/mL sterile, preservative-free solution. Due to the risk of meningococcal infections, eculizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the eculizumab REMS, prescribers must enroll in the program. Enrollment in the eculizumab REMS program and additional information are available by telephone: 1-888-765-4747.

PRECAUTIONS:

Boxed Warning

Life-threatening and fatal meningococcal infections have occurred in persons treated with eculizumab and may become rapidly life-threatening or fatal if not recognized and treated early.

1. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in persons with complement deficiencies.

2. Immunize members with a meningococcal vaccine at least 2 weeks prior to administering the first dose of eculizumab, unless the risks of delaying eculizumab therapy outweigh the risks of developing a meningococcal infection.

3. Monitor members for early signs of meningococcal infections, and evaluate immediately if infection is suspected.

Contraindications

1. Eculizumab is contraindicated in persons with unresolved serious Neisseria meningitidis infection

2. Eculizumab is contraindicated in persons who are not currently vaccinated against Neisseria meningitidis, unless the risk of delaying treatment outweighs the risk of developing a meningococcal infection.

Precautions/Warnings

1. Discontinue therapy in persons who are being treated for serious meningococcal infections

2. Use caution when administered eculizumab to members with any other systemic infection.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding:

J1300

Injection, eculizumab, 10 mg

ICD-10 Diagnoses Codes That Support Medical Necessity: (Effective 10/01/14)

D59.3

Hemolytic-uremic syndrome

D59.5

Paroxysmal nocturnal hemoglobinuria [Marchiafava-Micheli]

REIMBURSEMENT INFORMATION:

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline revised date.

DEFINITIONS:

Atypical hemolytic uremic syndrome (aHUS): a rare condition characterized by hemolytic anemia, thrombocytopenia and kidney failure that has no obvious cause.

Hemolysis: breakdown of red blood cells.

Microangiopathic hemolytic anemia: a disorder in which narrowing or obstruction of small blood vessels results in distortion and fragmentation of red blood cells, hemolysis, and anemia.

Paroxysmal nocturnal hemoglobinuria (PNH): A chronic acquired blood cell dysplasia with proliferation of a clone of stem cells producing erythrocytes, platelets, and granulocytes that are abnormally susceptible to lysis by complement; it is marked by episodes of intravascular hemolysis, causing hemolytic anemia, particularly following infections, and by venous thromboses, especially of the hepatic veins.

Thrombocytopenia: a reduced level of circulating platelets, which are cell fragments that normally assist with blood clotting.

RELATED GUIDELINES:

None applicable.

OTHER:

None applicable.

REFERENCES:

  1. Brodsky RA, Young NS, Antonioli E. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008 Feb 15;111(4):1840-7.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.;2016. URL www.clinicalpharmacilogy-ip.com Accessed 3/16/16.
  3. Eculizumab. In: McEvoy GK, editor. AHFS drug information 2016[monograph on the Internet]. Bethesda (MD): American Society of Health-System Pharmacists; 2016 [cited 2016 Mar 16]. Available from: http://online.statref.com. Subscription required to view.
  4. Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. NEJM 2006;335:1233-43.
  5. Ingenix HCPCS Level II, Expert 2011.
  6. Ingenix ICD-9-CM for Physicians-Volumes 1 & 2, Expert 2011.
  7. Loschi M, Porcher R, Barraco F Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study. Am J Hematol. 2016.;91(4):366-70
  8. Martí-Carvajal AJ, Anand V, Cardona AF, Solà I. Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria. Cochrane Database Syst Rev. 2014 Oct 30;10
  9. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 3/16/16
  10. Soliris (eculizumab) [package insert]. Alexion Pharmaceuticals, Inc. Cheshire (CT): January 2016.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 04/13/16.

GUIDELINE UPDATE INFORMATION:

03/15/10

New Medical Coverage Guideline.

01/15/11

Revision to guideline; consisting of adding ICD-10 codes.

05/15/11

Review and revision to guideline; consisting of updating references.

11/15/11

Revision to guideline; consisting of adding new FDA-approved indication, updated dosing and coding.

05/15/12

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

05/15/13

Review and revision to guideline; consisting of revising position statement to include duration of approval and orphan drug designations; revised and reformatted description, dosage/administration, and precautions sections; updated references; added pertinent definitions.

10/15/13

Revision to guideline; consisting of updating diagnosis criteria in the position statement.

05/15/14

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

05/15/15

Revision to guideline; consisting of updating references.

11/01/15

Revision: ICD-9 Codes deleted.

05/15/16

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

Date Printed: February 21, 2017: 06:16 PM