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FDA News: Issue 22, July 2021

Author: [AUTHOR] Published on 7/16/2021 6:00:00 AM


FDA Approves RYLAZE [Asparaginase Erwinia Chrysanthemi (recombinant)-rywn] for the Treatment of ALL and LBL in Adult and Pediatric Patients with E. Coli-derived Asparaginase Hypersensitivity

On June 30, 2021, the US Food and Drug Administration (FDA) approved RYLAZE [asparaginase erwinia chrysanthemi (recombinant)-rywn] as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli-derived asparaginase.

The recommended dosage of RYLAZE when replacing a long-acting asparaginase product is 25 mg/m2 intramuscularly (IM) every 48 hours (Q48H). Monitor patient’s bilirubin, transaminases, glucose, and clinical examinations prior to treatment every 2-3 weeks and as indicated clinically, and until recovery from the cycle of therapy if results are abnormal.

Additional information regarding dosage and administration as well as warnings and precautions about hypersensitivity reactions, pancreatitis, thrombosis, hemorrhage, and hepatotoxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)
MOA: Asparaginase erwinia chrysanthemi (recombinant)-rywn is an asparagine specific enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia, causing depletion of plasma asparagine.

General PK: The PK parameters of asparaginase erwinia chrysanthemi (recombinant)-rywn are presented based on serum asparaginase activity (SAA) following administration of the approved recommended dosage in pediatric and young adult patients (1 to 24 years), unless otherwise specified. Asparaginase erwinia chrysanthemi (recombinant)-rywn maximum SAA (Cmax) and area under the SAA-time curve (AUC) increase proportionally over a dosage range from 12.5 to 50 mg/m2 (0.5 to 2 times the approved recommended dose). In patients treated with 25 mg/m2 IM Q48H x 7 doses, the accumulation ratio after the seventh dose is 1.24-fold for Cmax, 1.21-fold for C48h, and 1.28-fold for AUC0-48h based on SAA.

Absorption: The median tmax of asparaginase erwinia chrysanthemi (recombinant)-rywn is 10 hours. The mean absolute bioavailability for IM administration is 37% in healthy subjects.

Distribution: The geometric mean (%CV) apparent volume of distribution of asparaginase erwinia chrysanthemi (recombinant)-rywn is 1.48 L/m2 (49%).

Elimination: The geometric mean (%CV) apparent clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn is 0.31 L/hour/m2 (36%) and the apparent half-life is 18.2 hours (16%).

Metabolism: Asparaginase erwinia chrysanthemi (recombinant)-rywn is expected to be metabolized into small peptides by catabolic

Immunogenicity: The incidence of ADA and subsequent effects on PK, pharmacodynamics, safety, or effectiveness have not been established.

Use in Specific Populations
There were no clinically significant differences in the PK of asparaginase erwinia chrysanthemi (recombinant)-rywn based on age (1 to 52 years), weight (9 to 131 kg), or sex after the dose was adjusted by body surface area (BSA). The effect of renal and hepatic impairment on the PK of asparaginase erwinia chrysanthemi (recombinant)-rywn has not been studied.

Body Surface Area: The apparent volume of distribution and apparent clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn increase with increasing BSA (0.44 to 2.53 m2).

Race and Ethnicity: Black (n=10) and Asian (n=5) patients had 29% lower clearance which may increase SAA exposure compared to White (n=61) patients. There were no clinically significant differences in clearance between Hispanic (n=28) and Non-Hispanic (n=53) patients.

Efficacy and Safety
Efficacy of RYLAZE was evaluated in an open-label, multi-cohort, multicenter trial. The determination of efficacy was based on a demonstration of the achievement and maintenance of nadir serum asparaginase activity (NSAA) above the level of 0.1 U/mL. For a dosage of 25 mg/m2 administered intramuscularly Q48H, modeling and simulation predicted that the proportion of patients maintaining NSAA ≥ 0.1 U/mL at 48 hours after a dose of RYLAZE was 93.6% (95% CI: 92.6%, 94.6%). Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

Most common adverse reactions (incidence > 20%) are abnormal liver test, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding, and hyperglycemia.

Full prescribing information is available at https://go.usa.gov/x6HYR.

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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