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FDA News: Issue 33, November 2019

Author: [AUTHOR] Published on 11/25/2019 6:03:00 AM


FDA Approves ADAKVEO (Crizanlizumab-tmca) to Reduce the Frequency of Vasoocclusive Crises in Adults and Pediatric Patients Aged 16 Years and Older with Sickle Cell Disease

On November 15, 2019, the US Food and Drug Administration (FDA)-approved ADAKVEO (crizanlizumab-tmca) to reduce the frequency of vasoocclusive crises (VOCs) in adults and pediatric patients aged 16 years and older with sickle cell disease. The approved recommended dosage of ADAKVEO is 5 mg/kg administered by intravenous infusion over a period of 30 minutes at Week 0, Week 2, and every 4 weeks thereafter. ADAKVEO may be given with or without hydroxyurea. Additional information regarding dosage and administration as well as important warnings and precautions related to infusion-related reactions and laboratory test interference can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)
  • MOA: 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.
  • General PK: The mean crizanlizumab-tmca Cmax, AUClast, or AUCinf increased disproportionally over the dose range of 0.2 to 8 mg/kg (0.04 to 1.6 times the approved recommended dosage) in healthy volunteers. In healthy volunteers administered the 5 mg/kg dose, the mean [coefficient of variation (CV%)] crizanlizumab-tmca Cmax, AUClast, or AUCinf were 0.16 (15.3%) mg/mL, 33.6 (12.6%) mg*hr/mL and 34.6 (13.1%) mg*hr/mL, respectively.
  • Distribution: The mean (CV%) volume of distribution was 4.26 (25.1%) L after a single crizanlizumab-tmca 5 mg/kg intravenous infusion in healthy volunteers.
  • Elimination: The mean (CV%) terminal elimination half-life (t1/2) of crizanlizumab-tmca was 10.6 (20.5%) days and the mean clearance was 11.7 (16.2%) mL/hr at 5 mg/kg doses in healthy volunteers. The mean (CV%) elimination t1/2 of crizanlizumab-tmca was 7.6 (28.5%) days during dosing interval in patients with sickle cell disease. 
  • Metabolism: Crizanlizumab-tmca is expected to be metabolized into small peptides by catabolic pathways. 
  • PD: ADAKVEO resulted in a dose-dependent P-selectin inhibition (measured ex vivo) in patients with sickle cell disease and healthy volunteers. 
  • Immunogenicity: In a single arm, open label multiple dose study, 0 of the 45 patients with sickle cell disease treated with ADAKVEO 5 mg/kg tested positive for treatment-induced anti-crizanlizumab-tmca antibodies. In a single-dose study of healthy subjects, 1 of the 61 (1.6%) evaluable subjects tested positive for a treatment-induced anti-crizanlizumab-tmca antibodies.
Drug Interactions
  • Platelet Test: ADAKVEO interferes with automated platelet counts (platelet clumping) in particular when blood samples are collected in tubes containing ethylenediaminetetraacetic acid (EDTA), which may lead to unevaluable or falsely decreased platelet counts. Run blood samples within 4 hours of blood collection or collect blood samples in tubes containing citrate. When needed, estimate platelet count via peripheral blood smear.
  • Hydroxyurea: Hydroxyurea had no clinically meaningful effect on crizanlizumab-tmca pharmacokinetics in patients in clinical studies.
Use in Specific Populations
The effect of renal or hepatic impairment on the pharmacokinetics of crizanlizumab-tmca is unknown.

Efficacy and Safety
Efficacy of ADAKVEO was evaluated in patients with sickle cell disease in a randomized, multicenter, placebo-controlled, double-blind study. The primary efficacy outcome measure was the annual rate of VOCs leading to a healthcare visit, defined as an acute episode of pain with no cause other than a vaso-occlusive event that required a medical facility visit and treatment with oral or parenteral opioids, or parenteral non-steroidal anti-inflammatory drugs (NSAIDs). Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

Most common adverse reactions (incidence > 10%) are nausea, arthralgia, back pain, and pyrexia.

Full prescribing information is available at https://go.usa.gov/xp84k.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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