Sustained asparaginase activity throughout the entire course of treatment1,a
Through the Real-Time Oncology Review process, FDA approved 25 mg/m2 administered IM every 48 hours based on the initial data readout in order to meet immediate patient needs2
Proportion of patients with NSAA ≥0.1 U/mL1
Activity of ≥0.1 U/mL has been demonstrated to correlate with asparagine depletion and to serum levels that predict clinical efficacy.3,4
aBased on the results of modeling and simulations for a dosage of 25 mg/m2 administered IM every 48 hours.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for ALL and NCCN Guidelines® for Pediatric ALL include asparaginase erwinia chrysanthemi (recombinant)-rywn (RYLAZE) as one option for the asparaginase component of certain multiagent chemotherapeutic regimens in patients who had an allergic reaction to E. coli-derived asparaginase products.5,6,b
bNCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
RYLAZE is indicated as a component of a multi-agent chemotherapeutic regimen given by intramuscular injection 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.
IMPORTANT SAFETY INFORMATION
RYLAZE is contraindicated in patients with a history of:
- Serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis
- Serious pancreatitis during previous asparaginase therapy
- Serious thrombosis during previous asparaginase therapy
- Serious hemorrhagic events during previous asparaginase therapy
Warnings and Precautions
Hypersensitivity reactions after the use of RYLAZE occurred in 25% of patients in clinical trials, and it was severe in 2% of patients. The median time from the first dose of RYLAZE to the onset of the first hypersensitivity event was 27 days (range 1-171 days). The most commonly observed reaction was rash (17%), and no patient experienced a severe rash. The median time from the first dose to the first onset of rash was 33.5 days (range 1-127 days).
Hypersensitivity reactions observed with L-asparaginase class products include angioedema, urticaria, lip swelling, eye swelling, rash or erythema, blood pressure decreased, bronchospasm, dyspnea, and pruritus.
Because of the risk of serious allergic reactions (e.g., life-threatening anaphylaxis), administer RYLAZE in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, intravenous steroids, antihistamines). Discontinue RYLAZE in patients with serious hypersensitivity reactions.
Pancreatitis was reported in 14% of patients in clinical trials of RYLAZE and was severe in 6%. Clinical pancreatitis occurred in 5% of patients, and it was severe in 4% of patients. Elevated amylase or lipase without clinical diagnosis of pancreatitis was observed in 9% of patients, and it was severe in 2% of patients treated with RYLAZE. Hemorrhagic or necrotizing pancreatitis have been reported with L-asparaginase class products.
Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis. Assess serum amylase and lipase levels in patients with any signs or symptoms of pancreatitis. Discontinue RYLAZE in patients with severe or hemorrhagic pancreatitis. In the case of mild pancreatitis, withhold RYLAZE until the signs and symptoms subside and amylase and/or lipase levels return to 1.5 times the ULN. After resolution of mild pancreatitis, treatment with RYLAZE may be resumed.
Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported following treatment with L-asparaginase class products. Discontinue RYLAZE for a thrombotic event, and administer appropriate antithrombotic therapy. Consider resumption of treatment with RYLAZE only if the patient had an uncomplicated thrombosis.
Bleeding was reported in 17% of patients treated with RYLAZE, and it was severe in 1%. Most commonly observed reactions were bruising (8%) (contusion, increased tendency to bruise and injection site bruising) and nose bleeding (6%), which was severe in 1% of patients. Other observed bleeding reactions included hematuria (2%), disseminated intravascular coagulopathy (1%), rectal bleeding (1%) and gingival bleeding (1%).
In patients treated with asparaginase class products, hemorrhage may be associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy.
Elevated bilirubin and/or transaminases occurred in 62% of patients treated with RYLAZE in clinical trials, and 12% had Grade ≥3 elevations.
Inform patients of the signs and symptoms of hepatotoxicity. Evaluate bilirubin and transaminases prior to treatment every 2-3 weeks and as indicated clinically during treatment with RYLAZE. In the event of serious liver toxicity, discontinue treatment with RYLAZE and provide supportive care.
Serious adverse reactions occurred in 55% of patients who received RYLAZE. The most frequent serious adverse reactions (in ≥5% of patients) were febrile neutropenia, dehydration, pyrexia, stomatitis, diarrhea, drug hypersensitivity, infection, nausea, and viral infection.
The most common adverse reactions (incidence >20%) with RYLAZE are abnormal liver test (70%), nausea (46%), musculoskeletal pain (39%), fatigue (36%), infection (30%), headache (30%), pyrexia (27%), drug hypersensitivity (24%), febrile neutropenia (24%), decreased appetite (21%), stomatitis (21%), bleeding (21%), and hyperglycemia (21%).
Use in Specific Populations
Pregnancy and Lactation
RYLAZE can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with RYLAZE and for 3 months after the last dose. Advise women not to breastfeed during treatment with RYLAZE and for 1 week after the last dose.
Please see full Prescribing Information.
ALL=acute lymphoblastic leukemia; CI=confidence interval; E. coli=Escherichia coli; FDA=Food and Drug Administration; IM=intramuscularly; NCCN=National Comprehensive Cancer Network; NSAA=nadir serum asparaginase activity; U=unit.
References: 1. RYLAZE [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc. 2. Jazz Pharmaceuticals announces U.S. FDA approval of Rylaze™ (asparaginase erwinia chrysanthemi (recombinant)-rywn) for the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma. News release. PR Newswire. June 30, 2021. Accessed March 28, 2022. https: //www.prnewswire.com/news-releases/jazz-pharmaceuticals-announces-us-fda-approval-of-rylaze-asparaginase-erwinia-chrysanthemi-recombinant-rywn-for-the-treatment-of-acute-lymphoblastic-leukemia-or-lymphoblastic-lymphoma-301323782. 3. Egler RA, Ahuja SP, Matloub Y. L‑asparaginase in the treatment of patients with acute lymphoblastic leukemia. J Pharmacol Pharmacother. 2016;7(2):62-71. 4. van der Sluis IM, Vrooman LM, Pieters R, et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016;101(3):279-285. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia V.1.2022. ©National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed April 4, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. 6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pediatric Acute Lymphoblastic Leukemia V.1.2022. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed October 1, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org.