Crizanlizumab-tmca (Adakveo)

Number: 0964

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Scope of Policy

This Clinical Policy Bulletin addresses crizanlizumab-tmca (Adakveo) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Required Precertification:

Precertification of crizanlizumab-tmca (Adakveo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of crizanlizumab-tmca (Adakveo), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Site of Care Utilization Management Policy applies. For information on site of service for crizanlizumab (Adakveo), see Utilization Management Policy on Site of Care for Specialty Drug Infusions

  1. Prescriber Specialties

    This medication must be prescribed by or in consultation with a hematologist or specialist in sickle cell disease.

  2. Criteria for Initial Approval

    Aetna considers crizanlizumab-tmca (Adakveo) medically necessary for reducing the frequency of vaso-occlusive crises (VOCs) in members 16 years of age or older with sickle cell disease, when both of the following criteria are met:

      1. The member has experienced at least one vasoocclusive crisis within the previous 12 months; and
      2. The member meets either of the following (1 or 2):

        1. Member has sickle hemoglobin C (HbSC) or sickle β+-thalassemia (HbSβ+) genotype; or
        2. Member has homozygous hemoglobin S (HbSS) or sickle β0-thalassemia (HbSβ0) genotype and meets any of the following:

          1. Has experienced, at any time in the past, an inadequate response or intolerance to a trial of hydroxyurea; or
          2. Has a contraindication to hydroxyurea; or
          3. Will be using Adakveo with concurrent hydroxyurea therapy.

    Aetna considers all other indications as experimental and investigational.

  3. Continuation of Therapy

    Aetna considers continuation of crizanlizumab-tmca (Adakveo) therapy medically necessary when the member has experienced a reduction in the frequency of vaso-occlusive crises, or has maintained such reduction, since initiating therapy with Adakveo.

Dosage and Administration

Adakveo is supplied for injection as 100 mg/10 mL (10 mg/mL) solution in a single-dose vial.

Per the Prescribing Information, administer Adakveo 5 mg/kg by intravenous infusion over a period of 30 minutes at Week 0, Week 2, and every 4 weeks thereafter.

If a dose is missed, administer Adakveo as soon as possible. If Adakveo is administered within 2 weeks after the missed dose, continue dosing according to the individual's original schedule. If Adakveo is administered more than 2 weeks after the missed dose, continue dosing every 4 weeks thereafter. 

Adakveo may be given with or without hydroxyurea.

Source: Novartis, 2022

Experimental and Investigational

Aetna considers crizanlizumab-tmca (Adakveo) experimental and investigational for the treatment and prevention of adverse outcomes in individuals with COVID-19 because the effectiveness of this approach has not been established.


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Other CPT codes related to the CPB:

96365 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour

HCPCS codes covered if selection criteria are met:

J0791 Injection, crizanlizumab-tmca, 5 mg

ICD-10 codes covered if selection criteria are met:

D57.00 - D57.819 Sickle-cell disorders

ICD-10 codes not covered for indications listed in the CPB:

J12.82 Pneumonia due to coronavirus disease 2019
U07.1 COVID-19
U09.9 Post COVID-19 condition, unspecified


U.S. Food and Drug Administration (FDA)-Approved Indications

  • Adakveo is indicated to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric patients aged 16 years and older with sickle cell disease.

Crizanlizumab-tmca is available as Adakveo (Novartis Pharmaceuticals Corporation). Crizanlizumab-tmca is a humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands, including P-selectin glycoprotein ligand 1 (PSGL-1). Crizanlizumab-tmca can also dissociate preformed Pselectin/PSGL-1 complex. Binding P-selectin on the surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes (Novartis, 2022).

The Prescribing Information for Adakveo includes warnings and precautions for infusion-related reactions, in which the label recommends to monitor for and advise patients of signs and symptoms. Adakveo infusion should be discontinued for severe reactions and manage medically. and temporarily interrupt or slow the rate of infusion for mild or moderate infusion-related reactions and initiate symptomatic treatment. It is recommended to exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g., treatment of anaphylaxis). Warnings and precautions also include interference with automated platelet counts (platelet clumping), in which it is recommended to run test as soon as possible or use citrate tubes (Novartis, 2022).  The most common adverse reactions (incidence greater than 10 %) include nausea, arthralgia, back pain, abdominal pain, and pyrexia.

Sickle Cell Disease

Sickle cell disease (SCD) is a Mendelian recessive disorder comprised of a group of disorders that affects hemoglobin, the molecule in red blood cells that delivers oxygen to cells throughout the body. People with this disorder have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle, or crescent shape. Clinically, sickle cell disease is manifested most often by acute painful episodes or "crises" but with many other acute and chronic complications including a variety of serious organ system complications, life-long disabilities and even death. When red blood cells sickle, they break down prematurely, leading to hemolytic anemia. Vaso-occlusion (previously called sickle cell crisis) occur when the stiff and inflexible sickled red blood cells get stuck in small blood vessels, resulting in recurrent painful episodes (previously called sickle cell crisis) and a variety of serious organ system complications which can lead to life-long disabilities and even death. According to the Centers for Disease Control and Prevention, sickle cell disease affects approximately 100,000 Americans. The disease occurs most often in African-Americans, where 1 out of every 365 babies born have the disease. The management of acute pain in individuals with SCD is divided into prevention of pain, treatment of acute pain episodes, and management of chronic pain. Prophylactic pain management includes reducing pain triggers such as exposure to cold temperature or respiratory triggers, dehydration, and overexertion. Hydroxyurea and L-glutamine are the two main pharmacotherapy options for reducing pain episodes. Other pain management options include non-opioid (e.g., acetaminophen and NSAIDs) and opioid treatment.

On November 15, 2019, the FDA approved Adakveo (crizanlizumab-tmca) for patients age 16 years and older to reduce the frequency of VOC, a common and painful complication of sickle cell disease that occurs when blood circulation is obstructed by sickled red blood cells. Crizanlizumab-tmca is the first targeted therapy approved for sickle cell disease. Crizanlizumab-tmca is a selectin blocker humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands including P-selectin glycoprotein ligand 1. Binding P-selectin on the surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes.

The crizanlizumab-tmca approval was based on the results of a randomized clinical trial enrolling 198 patients with SCD with a history of VOC (Ataga et al; SUSTAIN Trial; NCT01895361). Ataga et al (2017) stated the up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of VOC and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. In this double-blind, randomized, placebo-controlled, phase 2 trial, patients were assigned to receive low-dose crizanlizumab (2.5 mg/kg of body weight), high-dose crizanlizumab (5.0 mg/kg), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary endpoint was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to 1st and 2nd crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome (ACS), hepatic sequestration, splenic sequestration, or priapism) and the ACS, and patient-reported outcomes were also assessed. A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3 % lower rate with high-dose crizanlizumab, p = 0.01). The median time to the 1st crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 versus 1.38 months, p = 0.001), as was the median time to the 2nd crisis (10.32 versus 5.09 months, p = 0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9 % lower rate with high-dose crizanlizumab, p = 0.02). Adverse events that occurred in 10 % or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. The authors concluded that in patients with SCD, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events.  

Weaver and colleagues (2023) stated that SCD is a hematological disorder that primarily affects individuals of African descent from sub-Saharan Africa and along the Mediterranean. The main complications leading to hospitalizations include VOCs and ACS.  These investigators examined evidence-based management and prevention of VOCs in patients with SCD.  They carried out a literature search of PubMed, Medline Cochrane and Google Scholar database (January 1985 to April 2020) using the following search terms "vaso-occlusive crises", "sickle cell disease", "hydroxyurea", "L-glutamine", "voxelotor", "crizanlizumab", "treatment" and "prevention" as well as a combination of these terms.  All English-language interventional studies evaluating the safety and efficacy of VOC outcomes were examined.  Literature was excluded if published in a language other than English or if it was a review article.  A total of 69 articles were identified and 7 met the search criteria.  The majority of the studies focused on mean and median annual rates of VOCs as primary outcomes while median time to 1st sickle cell crises, median rates of hospitalizations etc. were evaluated as secondary outcomes.  After reviewing the literature, many patients with VOCs will still benefit from hydroxyurea therapy since long-term efficacy data and cost is still a concern for the newer agents including L-glutamine, voxelotor and crizanlizumab.  Other factors such as cost or compliance may also be taken into consideration when making recommendations for therapy.

Other Indications

Treatment and Prevention of Adverse Outcomes in Patients with COVID-19

McCarthy (2022) stated that on September 4, 2020, the National Institutes of Health (NIH) launched a new clinical trial, entitled "A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults with COVID-19".  This open-label, placebo-controlled, multi-center study was designed to examine therapeutic options for patients hospitalized with mild, moderate, or severe COVID-19.  A variety of drugs and drug classes were selected, including heparin, the monoclonal antibody crizanlizumab, sodium-glucose cotransporter-2 inhibitors, and purinergic signaling receptor Y12 inhibitors.  These medications have been widely used in the treatment of other conditions, from sick cell disease to type 2 diabetes mellitus (T2DM) and some forms of cardiovascular disease; however, their inclusion in a study of COVID-19 was somewhat unexpected.  The author examined the rationale behind the use of these disparate agents in the treatment and prevention of adverse outcomes in patients with COVID-19 and investigated how these strategies may be employed in the future to address the severe acute respiratory syndrome coronavirus 2 pandemic. 

The author noted that data from a robust randomized trial are lacking.  ACTIV-4a, an open-label, placebo-controlled, multi-center trial, is examining crizanlizumab in the treatment of hospitalized patients with mild or moderate COVID-19.  The objective of this trial aims to enroll approximately 1,000 patients.  Patients are randomly assigned to one dose of crizanlizumab plus standard of care (SOC) or SOC alone and results are expected in 2023. 

Solomon et al (2023) noted that COVID-19 has been associated with endothelial injury, resultant microvascular inflammation and thrombosis.  Activated endothelial cells release and express P-selectin and von Willebrand factor (vWF), both of which are elevated in severe COVID-19 and may be implicated in the disease pathophysiology.  In an international, adaptive, randomized controlled trial (RCT), these researchers hypothesized that crizanlizumab would reduce morbidity and death in patients hospitalized for COVID-19.  In an international, adaptive, randomized controlled platform trial, funded by the National Heart, Lung, and Blood Institute, randomly assigned 422 patients hospitalized with COVID-19 with moderate or severe illness to receive either a single infusion of the P-selectin inhibitor crizanlizumab (at a dose of 5 mg/kg) plus standard of care (SOC) or SOC in an open-label 1:1 ratio.  The primary outcome was organ support-free days, evaluated on an ordinal scale consisting of the number of days alive free of organ support through the first 21 days after trial entry.  The study was stopped for futility by the data safety monitoring committee.  Among 421 randomized patients with known 21-day outcomes, 163 patients (77 %) randomized to the crizanlizumab plus SOC arm did not require any respiratory or cardiovascular organ support compared with 169 (80 %) in the SOC-alone arm.  The adjusted OR for the effect of crizanlizumab on organ support-free days was 0.70 (95 % CI: 0.43 to 1.16), where an OR of greater than 1 indicated treatment benefit, yielding a posterior probability of futility (OR of less than 1.2) of 98 % and a posterior probability of inferiority (OR of less than 1.0) of 91 %.  Overall, there were 37 deaths (17.5 %) in the crizanlizumab arm and 27 deaths (12.8 %) in the SOC arm (HR of 1.33 [95 % CI: 0.85 to 2.21]; [probability of HR greater than 1] = 0.879).  The authors concluded that crizanlizumab did not result in improvement in organ support-free days in patients hospitalized with COVID-19.


The above policy is based on the following references:

  1. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429-439.
  2. Dick MH, Abdelgadir A, Kulkarni VV, et al. Comparing the safety and efficacy of L-glutamine, voxelotor, and crizanlizumab for reducing the frequency of vaso-occlusive crisis in sickle cell disease: A systematic review. Cureus. 2022;14(5):e24920.
  3. Han J, Saraf SL, Gordeuk VR. Systematic review of crizanlizumab: A new parenteral option to reduce vaso-occlusive pain crises in patients with sickle cell disease. Pharmacotherapy. 2020;40(6):535-543.
  4. Lowe M, Bambhroliya Z, Patel H, et al. Emerging therapies for the management of pain and vaso-occlusive crises in patients with sickle cell disease: A systematic review of randomized controlled trials. Cureus. 2023;15(4):e38014.
  5. McCarthy MW. Novel strategies for the treatment of COVID-19. Drugs R D. 2022;22(4):257-262.
  6. Migotsky M, Beestrum M, Badawy SM. Recent advances in sickle-cell disease therapies: A review of voxelotor, crizanlizumab, and L-glutamine. Pharmacy (Basel). 2022;10(5):123.
  7. Novartis Pharmaceuticals Corporation. Adakveo (crizanlizumab-tmca) injection, for intravenous use. Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; revised September 2022.
  8. Solomon SD, Lowenstein CJ, Bhatt AS, et al; ACTIV4a Investigators. Effect of the P-selectin inhibitor crizanlizumab on survival free of organ support in patients hospitalized for COVID-19: A randomized controlled trial. Circulation. 2023;148(5):381-390.
  9. Thom H, Jansen J, Shafrin J, et al. Crizanlizumab and comparators for adults with sickle cell disease: A systematic review and network meta-analysis. BMJ Open. 2020;10(9):e034147.
  10. U.S. Food and Drug Administration (FDA). FDA approves first targeted therapy to treat patients with painful complication of sickle cell disease. Silver Spring, MD: FDA; November 15, 2019.
  11. Weaver SB, Rungkitwattanakul D, Singh D. Contemporary management and prevention of vaso-occlusive crises (VOCs) in adults with sickle cell disease. J Pharm Pract. 2023;36(1):139-148.