U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 27

Name of the Drug-    RYLAZE

Active Ingredient -   Asaparginase erwina chrysanthem (recombinant)-rywn

Pharmacological Classification- To treat acute lymphoblastic leukemia in patients                                                          who are allergic to E.Coli derived asparginase                                                                 products, as a component of a chemotherapy                                                                 regimen

                                                                                                                                              Date of Approval-          6/30/2021 

HIGHLIGHTS OF PRESCRIBING INFORMATION -

These highlights do not include all the information needed to use                            RYLAZE safely and effectively.

See full prescribing information for RYLAZE. RYLAZETM (asparaginase erwinia chrysanthemi (recombinant)- rywn) injection, for intramuscular use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

 RYLAZE is an asparagine specific enzyme indicated 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.

ADVERSE REACTIONS

 Most common adverse reactions (incidence > 20%) are abnormal liver test, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensi

CONTRAINDICATIONS-

 RYLAZE is contraindicated in patients with a history of: • Serious hypersensitivity reactions to RYLAZE, including anaphylaxis.

 • Serious pancreatitis during previous L-asparaginase therapy.                                         • Serious thrombosis during previous L-asparaginase therapy.                                          • Serious hemorrhagic events during previous L-asparaginase therapy. 

WARNINGS AND PRECAUTIONS-

 • Hypersensitivity: Monitor for signs or symptoms. Discontinue RYLAZE for serious reaction.                                                                                                                               • Pancreatitis: Monitor for symptoms. Discontinue if pancreatitis occurs                             • Thrombosis: Discontinue RYLAZE for severe or life-threatening thrombosis. Provide            anticoagulation therapy as indicated.                                                                         • Hemorrhage: Discontinue RYLAZE for severe or life-threatening hemorrhage.           • Hepatotoxicity: Discontinue RYLAZE for grade 4 increases of bilirubin. 

DOSAGE AND ADMINISTRATION

 When replacing a long-acting asparaginase product, the recommended dosage of RYLAZE is 25 mg/m2 administered intramuscularly every 48 hours.

DOSAGE FORMS AND STRENGTHS

 Injection: 10 mg/0.5 mL solution in a single-dose vial.

 PATIENT COUNSELING INFORMATION

• Hypersensitivity-

Inform patients of the risk of allergic reactions, including anaphylaxis. Instruct the patient on the symptoms of allergic reactions and to seek medical advice immediately if they experience such symptoms 

. • Pancreatitis-                                                                                                                 Instruct patients on signs and symptoms of pancreatitis and to seek medical attention if they experience severe abdominal pain

• Thrombosis-                                                                                                                   Instruct patients on the risk of thrombosis and to seek medical advice immediat

• Hemorrhage -                                                                                                               Advise patients to report any unusual bleeding or bruising to their healthcare provider .

• Hepatotoxicity-                                                                                                                 Advise patients to report any jaundice, severe nausea or vomiting, or easy bleeding or bruising to their healthcare provider

• Pregnancy -                                                                                                                   Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with RYLAZE and for 3 months after the last dose

• Lactation -                                                                                                                    Advise women not to breastfeed during treatment with RYLAZE and for 1 week after the last dose 

Manufactured by: Jazz Pharmaceuticals Ireland Limited Leinster, Ireland U.S. License No. 2167 Distributed by: Jazz Pharmaceuticals, Inc. 3170 Porter Drive, Palo Alto, CA 94304

 CLINICAL PHARMACOLOGY

1. Mechanism of Action -                                                                                      Asparaginase erwinia chrysanthemi (recombinant)-rywn is an enzyme that ca

The pharmacological effect of RYLAZE is based on the killing of leukemic cells due to depletion of plasma asparagine. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize asparagine, and therefore depend on an exogenous source of asparagine for survival.

2. Pharmacodynamics Asparaginase erwinia chrysanthemi (recombinant)-rywn exposure-response relationships and the time course of pharmacodynamic response are unknown.

3. Pharmacokinetics The pharmacokinetic 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.

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 (recom

Specific Populations- There were no clinically significant differences in the pharmacokinetics 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 pharmacokinetics 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and impairment of fertility studies have not been conducted with asparaginase erwinia chrysanthemi (recombinant)-rywn.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary Based on findings from animal reproduction studies, RYLAZE can cause fetal harm when administered to a pregnant woman.

There are no available data on RYLAZE use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

2. Lactation Risk Summary-                                                                                         There are no data on the presence of asparaginase erwinia chrysanthemi (recombinant)-rywn in human milk, the effects on the breastfed child, or the effects on milk production.

Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with RYLAZE and for 1 week after the last dose.

3. Females and Males of Reproductive Potential RYLAZE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing- Pregnancy testing is recommended in females of reproductive potential prior to initiating RYLAZE.

Contraception -Advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with RYLAZE and for 3 months after the last dose.

4. Pediatric Use -                                                                                                                  The safety and effectiveness of RYLAZE in the treatment of ALL and LBL have been established in pediatric patients 1 month to < 17 years who have developed hypersensitivity to a long-acting E. coliderived asparaginase.

Use of RYLAZE in these age groups is supported by evidence from an adequate and well-controlled study in adults and pediatric patients. The trial included 84 pediatric patients, including 2 infants (1 month to < 2 years), 62 children (2 years to < 12 years old), and 20 adolescents (12 years to < 17 years old). There were no clinically meaningful differences in safety or nadir serum asparaginase activity across age groups. The safety and effectiveness of RYLAZE have not been established in pediatric patients younger than 1 month of age.

5. Geriatric Use-                                                                                                       Clinical studies of RYLAZE did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.