Coverage Policy Manual
Policy #: 2020011
Category: Pharmacy
Initiated: June 2020
Last Review: June 2022
  Crizanlizumab (e.g., Adakveo™)

Description:
Crizanlizumab is a humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions between endothelial cells, platelets, red blood cells (RBC), and leukocytes. These multicellular adhesion clusters result in vaso-occlusion and vaso-occlusive crisis (VOC). Vaso-occlusion can lead to VOC, organ damage, and organ failure.  
 
Regulatory Status
 
Crizanlizumab (e.g., AdakveoTM) was approved by the U.S. Food and Drug Administration (FDA) on November 15, 2019 to reduce the frequency of VOC in adults and pediatric patients 16 years of age and older with sickle cell disease.  
 
Coding
 
As of July 1, 202 Crizanlizumab (AdakveoTM) will have a J code assigned.  
J0791– Effective 7/1/20

Policy/
Coverage:
Effective June 1,2020, Prior Approval is required for Crizanlizumab (e.g., Adakveo™)
 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.  
 
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
EFFECTIVE JANUARY 2022
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
The use of Crizanlizumab meets primary coverage criteria for reducing the frequency of vaso-occlusive crisis (VOC) in sickle cell disease when ALL of the following criteria are met:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
  1. Member is 16 years of age or older (FDA, 2019; Ataga, 2017)
  2. Prescribed by, or in consultation, with a hematologist or specialist in the management of sickle cell disease
  3. Member has a confirmed diagnosis of sickle cell disease (homozygous hemoglobin S, sickle hemoglobin C disease, sickle β0-thalassemia, or sickle β+-thalassemia) (FDA, 2019; Ataga, 2017)
  4. Has experienced at least two sickle cell related pain crises in the last 12 months (Ataga, 2017)
  5. Has had inadequate control, intolerance, or contraindication with hydroxyurea (Yawn, 2014)
  6. Will not be receiving chronic RBC transfusion therapy (Ataga, 2017)
  7. Will not be taking with voxelotor (e.g., OxbrytaTM) or l-glutamine (e.g., EndariTM)
  8. Dosage is in accordance with FDA guidelines (FDA, 2019)
 
Continuation of Therapy for 12 months if ALL of the following criteria are met:
  1. Member has experienced a reduction in sickle cell-related VOC and/or decrease in severity of sickle cell-related VOC.
  2. Will not be receiving chronic RBC transfusion therapy
  3. Will not be taking with voxelotor (e.g., OxbrytaTM) or l-glutamine (e.g., EndariTM)
  4. Dosage is in accordance with FDA guidelines
 
Dosage and Administration
The recommended dose of Crizanlizumab is 5mg/kg by intravenous infusion over a period of 30 minutes at Week 0, Week 2, and every 4 weeks thereafter.
 
Crizanlizumab is available as a 100mg/10ml single dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Crizanlizumab does not meet member benefit certificate primary coverage criteria for any other indication.
 
For members with contracts without primary coverage criteria, Crizanlizumab is considered investigational for any other indication.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
EFFECTIVE PRIOR TO JANUARY 2022
 
Policy/Guidelines
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
The use of Crizanlizumab (AdakveoTM) meets primary coverage criteria for reducing the frequency of vaso-occlusive crisis (VOC) in sickle cell disease when ALL of the following criteria are met:
 
Initial approval for 6 months if ALL of the following criteria are met:
 
    1. Member is 16 years of age or older
    2. Prescribed by, or in consultation, with a hematologist or specialist in the management of sickle cell disease
    3. Member has a confirmed diagnosis of sickle cell disease (homozygous hemoglobin S, sickle hemoglobin C disease, sickle β0-thalassemia, or sickle β+-thalassemia)
    4. Has experienced at least two sickle cell related pain crises in the last 12 months
    5. Has had inadequate control, intolerance, or contraindication with hydroxyurea
    6. Will not be receiving chronic RBC transfusion therapy
    7. Will not be taking with voxelotor (OxbrytaTM) or l-glutamine (EndariTM)
    8. Dosage is in accordance with FDA guidelines
 
Continuation of Therapy for 12 months if ALL of the following criteria are met:
 
    1. Member has experienced a reduction in sickle cell-related VOC and/or decrease in severity of sickle cell-related VOC
    2. Will not be receiving chronic RBC transfusion therapy
    3. Will not be taking with voxelotor (OxbrytaTM) or l-glutamine (EndariTM)
    4. Dosage is in accordance with FDA guidelines
 
 
Dosage and Administration
 
The recommended dose of Crizanlizumab (AdakveoTM) is 5mg/kg by intravenous infusion over a period of 30 minutes at Week 0, Week 2, and every 4 weeks thereafter.
 
Crizanlizumab (AdakveoTM) is available as a 100mg/10ml single dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Crizanlizumab (AdakveoTM) does not meet member benefit certificate primary coverage criteria for any other indication.
 
For members with contracts without primary coverage criteria, Crizanlizumab (AdakveoTM) is considered investigational for any other indication.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
SUSTAIN was a double-blind, multicenter, randomized, placebo-controlled, phase 2 trial that studied the safety and efficacy of Crizanlizumab for reducing the frequency of vaso-occlusive crisis in sickle cell patients (Ataga, 2017). Patients with sickle cell disease who were 16 – 65 years of age and who had two – 10 sickle cell-related pain crisis in the 12 months prior to the study were eligible for enrollment. Patients who were receiving hydroxyurea therapy were allowed to participate in the study if they had been receiving the therapy for at least 6 months and had been on a stable dose for at least the most recent 3 months. These patients were not allowed to have any dose adjustments during the study. If patients were not receiving hydroxyurea prior to the study, it could not be initiated. Patients receiving long-term red blood cell transfusion therapy, had a hemoglobin <4g/dL, or were receiving chronic anticoagulation therapy other than aspirin were excluded from the study.
 
198 patients were randomized to receive an intravenous infusion of one of the following at Week 0, Week 2, Week 4, and every four weeks thereafter for 52 weeks: placebo (N=65), high-dose (5mg/kg) Crizanlizumab (N=67), and low-dose (2.5mg/kg) Crizanlizumab (N=66). Randomization was stratified by patients who were on hydroxyurea therapy and by the number of VOCs in the previous 12 months (2-4, 5-10). 129 patients completed the trial: placebo (N=24), high-dose Crizanlizumab (N=24), and low-dose Crizanlizumab (N=21).
 
The primary endpoint was the rate of VOC in each active dose compared to placebo. At 52 weeks the average VOC per year was 2.98 in the placebo group and 1.63 in the high-dose Crizanlizumab group. High-dose Crizanlizumab had a 45.3% lower rate of VOC compared to placebo. Furthermore 36% of patients in the high-dose Crizanlizumab group, 18% of patients in the low-dose Crizanlizumab group, and 17% of patients in the placebo group had a crisis rate of zero during the treatment phase.
The secondary endpoints included time to first and second VOC, number of hospitalized days per year, and rate of uncomplicated crises per year. The average number of hospitalized days per year was 4 in the high-dose Crizanlizumab group and 6.87 in the placebo group. The average time to the first crisis was 4.07 months in the high-dose Crizanlizumab group and 1.38 months in the placebo group. The average time to the second crisis was 10.32 months in the Crizanlizumab group and 5.09 in the placebo group. The rate of uncomplicated crises per year was 62.9% lower in the high-dose Crizanlizumab group than the placebo group.
 
Serious adverse events occurred in 28% of the patients in trial: 17 patients in the high-dose Crizanlizumab group, 21 in the low-dose Crizanlizumab group, and 17 in the placebo group. Most common serious adverse events included pyrexia, influenza, and pneumonia.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
J0791Injection, crizanlizumab tmca, 5 mg
J3490Unclassified drugs
J3590Unclassified biologics

References: Adakveo [package insert]. East Hanover, NJ. Novartis Pharmaceuticals Corporation; November 2019

Ataga KI, Kutlar A, Kanter J, et al.(2020) Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017; Accessed May 11, 2020

Yawn, BP, et. Al.(2014) Management of sickle-cell disease: Summary of the 2014 evidence-based report by expert panel members. JAMA. 2014; Sep 312(10):1033.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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