Version May 2024
Note: Do not substitute asparaginase (Erwinia [recombinant]) for asparaginase (Erwinia), or vice versa; the products are different and dosing differs. Asparaginase (Erwinia [recombinant]) should be administered in a setting with resuscitation equipment and agents necessary to manage anaphylaxis.
Premedications: Administer acetaminophen, an H1 antagonist (eg, diphenhydramine), and an H2 antagonist (eg, famotidine) 30 to 60 minutes prior to asparaginase (Erwinia [recombinant]) to decrease the risk and severity of hypersensitivity reactions.
Prophylaxis: Consider thromboprophylaxis with low-molecular-weight heparin (LMWH) during induction and intensification phases of asparaginase therapy, particularly in patients at high risk for venous thromboembolism; withhold LMWH for platelet count <30,000/mm3 (Ref).
Acute lymphoblastic leukemia: As a substitute for a long-acting asparaginase formulation:
Every-48-hour schedule: IM: 25 mg/m2 once every 48 hours; replace 1 dose of calaspargase pegol with 11 doses of asparaginase (Erwinia [recombinant]) and replace 1 dose of pegaspargase with 7 doses of asparaginase (Erwinia [recombinant]); refer to protocol for recommended duration of therapy of the long-acting asparaginase formulation.
Monday, Wednesday, Friday schedule: IM: 25 mg/m2 on Monday morning, 25 mg/m2 on Wednesday morning, and 50 mg/m2 on Friday afternoon (administer the Friday dose 53 to 58 hours after the Wednesday dose); replace 1 dose of calaspargase pegol with 9 doses of asparaginase (Erwinia [recombinant]) and replace 1 dose of pegaspargase with 6 doses of asparaginase (Erwinia [recombinant]); refer to protocol for recommended duration of therapy of the long-acting asparaginase formulation.
Lymphoblastic lymphoma: As a substitute for a long-acting asparaginase formulation:
Every-48-hour schedule: IM: 25 mg/m2 once every 48 hours; replace 1 dose of calaspargase pegol with 11 doses of asparaginase (Erwinia [recombinant]) and replace 1 dose of pegaspargase with 7 doses of asparaginase (Erwinia [recombinant]); refer to protocol for recommended duration of therapy of the long-acting asparaginase formulation.
Monday, Wednesday, Friday schedule: IM: 25 mg/m2 on Monday morning, 25 mg/m2 on Wednesday morning, and 50 mg/m2 on Friday afternoon (administer the Friday dose 53 to 58 hours after the Wednesday dose); replace 1 dose of calaspargase pegol with 9 doses of asparaginase (Erwinia [recombinant]) and replace 1 dose of pegaspargase with 6 doses of asparaginase (Erwinia [recombinant]); refer to protocol for recommended duration of therapy of the long-acting asparaginase formulation.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatic impairment prior to treatment initiation: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment:
Total bilirubin >3 to ≤10 times ULN: Withhold asparaginase (Erwinia [recombinant]) until total bilirubin is ≤1.5 times ULN.
Total bilirubin >10 times ULN: Discontinue asparaginase (Erwinia [recombinant]) and provide supportive care; do not make up missed doses.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status. If dose reduction for toxicity is recommended in the prescribing information, the dose should be increased back to the initial or previously tolerated dose only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
|
Adverse reaction |
Severity |
Modification |
|---|---|---|
|
a Immediate treatment for hypersensitivity reactions should be available during treatment. Asparaginase (Erwinia [recombinant]) should be administered in a setting with resuscitation equipment and agents necessary to manage anaphylaxis. | ||
|
b For acute management of venous thromboembolism (VTE), consider low-molecular-weight heparin if severe thrombocytopenia (platelets <50,000/mm3) is anticipated; following resolution of severe thrombocytopenia, consider direct oral anticoagulants in the absence of relevant contraindications. For life-threatening VTE (eg, central venous thrombosis, central pulmonary embolism), consider short-term concurrent use of antithrombin concentrate until clinically stable and therapeutic anticoagulation is established. Antithrombin concentrate is suggested for antithrombin levels <50% to 60%, with a suggested repletion target of 80% to 120%. Temporarily withhold asparaginase therapy for high-risk events (eg, central venous/sinus thrombosis, central pulmonary embolism, proximal deep vein thrombosis, arterial thrombosis); resume after thrombotic event is stabilized (ISTH [Zwicker 2020]). | ||
|
Hemorrhage |
Grade 3 or 4 |
Hold asparaginase (Erwinia [recombinant]); evaluate for coagulopathy and consider clotting factor replacement as clinically necessary. If bleeding is controlled, resume asparaginase (Erwinia [recombinant]) with the next scheduled dose. |
|
Hypersensitivitya |
Grade 2 |
Manage symptomatically. |
|
Grade 3 or 4 |
Discontinue asparaginase (Erwinia [recombinant]) permanently. Manage as clinically appropriate. | |
|
Pancreatitis |
Grade 2, 3, or 4 |
Hold asparaginase (Erwinia [recombinant]) for lipase or amylase elevations >2 times ULN or for symptomatic pancreatitis. Resume asparaginase (Erwinia [recombinant]) when lipase and amylase are <1.5 times ULN (and symptoms are resolved). Discontinue asparaginase (Erwinia [recombinant]) permanently if severe, clinical necrotizing, or hemorrhagic pancreatitis is confirmed. |
|
Thrombosisb |
Uncomplicated thrombosis |
Hold asparaginase (Erwinia [recombinant]) and treat with appropriate antithrombotic therapy. When symptoms resolve, consider resuming asparaginase (Erwinia [recombinant]), while continuing antithrombotic therapy. |
|
Severe or life-threatening thrombosis |
Discontinue asparaginase (Erwinia [recombinant]) permanently and treat with appropriate antithrombotic therapy. | |
The following additional adjustments have been recommended for other asparaginase products (Ref) :
Hyperammonemia-related fatigue: Continue therapy for grade 2 toxicity. If grade 3 toxicity occurs, reduce dose by 25%; resume full dose when toxicity ≤ grade 2 (make up for missed doses). If grade 4 toxicity occurs, reduce dose by 50%; resume full dose when toxicity ≤ grade 2 (make up for missed doses).
Hyperglycemia: Continue therapy for uncomplicated hyperglycemia. If hyperglycemia requires insulin therapy, hold the asparaginase product (and any concomitant corticosteroids) until blood glucose is controlled; resume dosing at prior dose level. For life-threatening hyperglycemia or toxicity requiring urgent intervention, hold the asparaginase product (and corticosteroids) until blood glucose is controlled with insulin; resume the asparaginase product and do not make up for missed doses.
Hypertriglyceridemia: If serum triglyceride level <1 g/dL, continue the asparaginase product but monitor closely for pancreatitis. If triglyceride level >1 g/dL, hold the asparaginase product and monitor; resume therapy at prior dose level after triglyceride level returns to baseline.
Refer to adult dosing.
(For additional information see "Recombinant Erwinia asparaginase: Pediatric drug information")
Note: Asparaginase (Erwinia [recombinant]) is a unique formulation (dosing, route of administration) and should not be directly interchanged with other asparaginase formulations; use precaution to ensure the proper formulation, dosing, and route of administration when replacing a long-acting asparaginase product within protocols.
Acute lymphoblastic leukemia: As a substitute for a long-acting asparaginase formulation: Infants, Children, and Adolescents: IM: 25 mg/m2 every 48 hours; refer to protocol to determine the duration of asparaginase (Erwinia [recombinant]) as replacement therapy.
Lymphoblastic lymphoma: As a substitute for a long-acting asparaginase formulation: Infants, Children, and Adolescents:IM: 25 mg/m2 every 48 hours; refer to protocol to determine the duration of asparaginase (Erwinia [recombinant]) as replacement therapy.
Dosage adjustment for toxicity:
Infants, Children, and Adolescents:
|
Adverse reaction |
Severity |
Modification |
|---|---|---|
|
aImmediate treatment for hypersensitivity reactions should be available during treatment. | ||
|
Hemorrhage |
Grade 3 or 4 |
Hold asparaginase (Erwinia [recombinant]); evaluate for coagulopathy and consider clotting factor replacement as clinically necessary. If bleeding is controlled, resume asparaginase (Erwinia [recombinant]) with the next scheduled dose. |
|
Hypersensitivitya |
Grade 2 |
Manage symptomatically. |
|
Grade 3 or 4 |
Discontinue asparaginase (Erwinia [recombinant]) permanently. Manage as clinically appropriate. | |
|
Pancreatitis |
Grade 2, 3, or 4
|
Hold asparaginase (Erwinia [recombinant]) for lipase or amylase elevations >2 times ULN or for symptomatic pancreatitis. Resume asparaginase (Erwinia [recombinant]) when lipase and amylase are <1.5 times ULN (and symptoms are resolved). Discontinue asparaginase (Erwinia [recombinant]) permanently if clinical necrotizing or hemorrhagic pancreatitis is confirmed. |
|
Thrombosis |
Uncomplicated thrombosis |
Hold asparaginase (Erwinia [recombinant]) and treat with appropriate antithrombotic therapy. When symptoms resolve, consider resuming asparaginase (Erwinia [recombinant]), while continuing antithrombotic therapy. |
|
Severe or life-threatening thrombosis |
Discontinue asparaginase (Erwinia [recombinant]) permanently and treat with appropriate antithrombotic therapy. | |
The following additional adjustments have also been recommended for other asparaginase products (Ref):
Older Adolescents:
Hyperammonemia-related fatigue: Continue therapy for grade 2 toxicity. If grade 3 toxicity occurs, reduce dose by 25%; resume full dose when toxicity ≤ grade 2 (make up for missed doses). If grade 4 toxicity occurs, reduce dose by 50%; resume full dose when toxicity ≤ grade 2 (make up for missed doses).
Hyperglycemia: Continue therapy for uncomplicated hyperglycemia. If hyperglycemia requires insulin therapy, hold asparaginase (and any concomitant corticosteroids) until blood glucose controlled; resume dosing at prior dose level. For life-threatening hyperglycemia or toxicity requiring urgent intervention, hold asparaginase (and corticosteroids) until blood glucose is controlled with insulin; resume asparaginase and do not make up for missed doses.
Hypertriglyceridemia: If serum triglyceride level <1,000 mg/dL, continue asparaginase but monitor closely for pancreatitis. If triglyceride level >1,000 mg/dL, hold asparaginase and monitor; resume therapy at prior dose level after triglyceride level returns to baseline.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Baseline hepatic impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment: Infants, Children, and Adolescents:
Total bilirubin >3 to ≤10 times ULN: Withhold asparaginase (Erwinia [recombinant]) until total bilirubin is ≤1.5 times ULN.
Total bilirubin >10 times ULN: Discontinue asparaginase (Erwinia [recombinant]) and provide supportive care; do not make up missed doses.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions include coadministration with other chemotherapeutic agents in children and young adults.
>10%:
Cardiovascular: Hypertension (<15%), hypotension (<15%), tachycardia (16% to 18%), thrombosis (<15%)
Dermatologic: Pruritus (<15%)
Endocrine & metabolic: Acidosis (<15%), dehydration (12% to 15%), hyperammonemia (<15%), hyperglycemia (12% to 21%), hyperphosphatemia (<15%), hypertriglyceridemia (<15%), hypoglycemia (<15%), hypokalemia (9% to 22%), increased serum cholesterol (<15%)
Gastrointestinal: Abdominal distension (<15%), abdominal distress (<15%), abdominal pain (21% to 25%), constipation (<15%), decreased appetite (21% to 27%), diarrhea (18% to 25%; grades 3/4: 4% to 6%), gastritis (<15%), nausea (45% to 47%; grades 3/4: 8% to 9%), pancreatitis (12% to 22%; including increased serum amylase and increase serum lipase), stomatitis (24% to 27%; grades 3/4: 4% to 12%)
Hematologic & oncologic: Decreased antithrombin III plasma level (<15%), decreased serum fibrinogen (<15%), febrile neutropenia (27% to 30%; grades 3/4: 27% to 30%), hemorrhage (24% to 27%; grades 3/4: 6%; including bruise and epistaxis), prolonged partial thromboplastin time (<15%)
Hepatic: Abnormal hepatic function tests (70% to 75%, including increased serum bilirubin, increased serum transaminases)
Hypersensitivity: Hypersensitivity reaction (21% to 24%; severe hypersensitivity reaction [≤6%]; anaphylaxis [≤2%])
Immunologic: Antibody development (47%)
Infection: Infection (27% to 36%) (including bacterial infection [<15%], fungal infection [<15%], viral infection [<15%])
Local: Infusion-site reaction (<15%), injection-site reaction (<15%)
Nervous system: Abnormal gait (<15%), agitation (<15%), anxiety (<15%), dizziness (<15%), fatigue (22% to 36%), headache (22% to 36%), hyperammonemic encephalopathy (<15%), insomnia (4% to 15%), irritability (<15%), myasthenia (<15%), pain (<15%), paresthesia (<15%), peripheral neuropathy (6% to 15%)
Neuromuscular & skeletal: Muscle spasm (<15%), musculoskeletal pain (35% to 45%), ostealgia (<15%)
Renal: Acute kidney injury (<15%)
Respiratory: Acute respiratory distress syndrome (<15%), cough (14% to 15%), pulmonary edema (<15%)
Miscellaneous: Fever (20% to 30%)
History of serious hypersensitivity reactions (including anaphylaxis) to asparaginase (Erwinia) or any component of the formulation; history of serious pancreatitis, serious thrombosis, or serious hemorrhagic events with prior asparaginase treatment.
Concerns related to adverse effects:
• Hepatotoxicity: Increased bilirubin and/or transaminases were commonly reported; ≥ grade 3 elevations have occurred.
• Hypersensitivity reactions: Hypersensitivity reactions occurred in over one-fourth of patients in clinical trials; severe reactions and anaphylaxis have been reported. Rash is the most commonly observed reaction (was severe in one case); hypersensitivity reactions associated with other asparaginase formulations have included angioedema, urticaria, lip/eye swelling, rash or erythema, decreased BP, bronchospasm, dyspnea, and pruritus. The incidence of hypersensitivity reactions was higher in patients who received asparaginase (Erwinia [recombinant]) intravenously (not an approved route). In patients who received asparaginase (Erwinia [recombinant]) IM, the median number of doses received prior to the onset of the first hypersensitivity event was 12 (range: 1 to 64 doses). Premedications are recommended. Immediate treatment for hypersensitivity reactions should be available during treatment.
• Pancreatitis: Pancreatitis has been reported in clinical trials; some cases were severe and/or symptomatic. Elevated amylase or lipase without symptomatic pancreatitis has occurred. Hemorrhagic or necrotizing pancreatitis have been reported with asparaginase formulations.
• Thrombosis and hemorrhage: Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported (rarely). Bleeding has been observed in 25% of patients who received asparaginase (Erwinia [recombinant]); rare severe events have been reported. The most commonly reported bleeding events were bruising and epistaxis; hematuria, disseminated intravascular coagulopathy, rectal bleeding, and gingival bleeding have also been observed. Hemorrhage may be associated with increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Medication error prevention: Do not interchange asparaginase (Erwinia [recombinant]), asparaginase (Erwinia), asparaginase (E. coli), calaspargase pegol, or pegaspargase; ensure the proper formulation, route of administration, and dose prior to administration.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intramuscular [preservative free]:
Rylaze: Asparaginase erwinia chrysanthemi (recombinant)-rywn 10 mg/0.5 mL (0.5 mL) [contains polysorbate 80]
No
Solution (Rylaze Intramuscular)
10 mg/0.5 mL (per 0.5 mL): $5,976.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intramuscular:
Rylaze: Asparaginase erwinia chrysanthemi (recombinant)-rywn 10 mg/0.5 mL (0.5 mL) [contains polysorbate 80]
IM: The volume of each single injection site should be limited to 2 mL; use multiple syringes/injection sites for volumes >2 mL. Rotate injection sites; do not inject into scar tissue or areas that are reddened, inflamed, or swollen.
Asparaginase (Erwinia [recombinant]) should be administered in a setting with resuscitation equipment and agents necessary to manage anaphylaxis. Immediate treatment for hypersensitivity reactions should be available during administration.
Parenteral: IM: The volume of each single injection site should be limited to 2 mL (or volume appropriate for patient size); use multiple injections if dose volume is larger than appropriate for IM injection (eg, >2 mL). Rotate injection sites; do not inject into scar tissue or areas that are reddened, inflamed, or swollen.
Acute lymphoblastic leukemia: Treatment (as a component of a multiagent chemotherapy regimen) of acute lymphoblastic leukemia in adult and pediatric patients ≥1 month of age with hypersensitivity to Escherichia coli-derived asparaginase.
Lymphoblastic lymphoma: Treatment (as a component of a multiagent chemotherapy regimen) of lymphoblastic lymphoma in adult and pediatric patients ≥1 month of age with hypersensitivity to E. coli-derived asparaginase.
Asparaginase (Erwinia [recombinant]) may be confused with asparaginase (Erwinia), asparaginase (Escherichia coli), calaspargase pegol, pegaspargase.
Rylaze may be confused with Asparlas, Elaprase, Elspar, Erwinaze, Oncaspar.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
Do not interchange asparaginase (Erwinia [recombinant]), asparaginase (Erwinia), asparaginase (E. coli), calaspargase pegol, or pegaspargase; ensure the proper formulation, route of administration, and dose prior to administration.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Hormonal Contraceptives: May enhance the thrombogenic effect of Asparaginase Products. Management: Consider discontinuing hormonal contraceptives and using an alternative contraceptive method in patients treated with asparaginase products. Risk D: Consider therapy modification
Evaluate pregnancy status prior to use in patients who could become pregnant. Patients who could become pregnant should use effective nonhormonal contraception during therapy and for 3 months after the last dose of asparaginase (Erwinia [recombinant]).
Based on data from animal reproduction studies with asparaginase Erwinia chrysanthemi, in utero exposure to asparaginase (Erwinia [recombinant] may cause fetal harm.
It is not known if asparaginase (Erwinia [recombinant]) is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 1 week after the last asparaginase (Erwinia [recombinant]) dose.
Bilirubin, transaminases, and glucose (prior to treatment, every 2 to 3 weeks, and as clinically indicated). Assess amylase and lipase in patients with symptoms of pancreatitis. If appropriate, monitor triglycerides and coagulation parameters. Consider monitoring antithrombin levels weekly during the course of asparaginase treatment (ISTH [Zwicker 2020]). Evaluate pregnancy status prior to use in patients who could become pregnant. Monitor for signs/symptoms of hypersensitivity, pancreatitis, thrombosis, or hemorrhage.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Asparaginase (Erwinia [recombinant]) is an enzyme that catalyzes the deamidation of asparagine to aspartic acid and ammonia, reducing circulating levels of asparagine. Leukemia cells lack asparagine synthetase and are unable to synthesize asparagine. Asparaginase reduces the exogenous asparagine source for the leukemic cells, resulting in cytotoxicity specific to leukemic cells. Asparaginase (Erwinia [recombinant]) is produced by fermentation of a genetically engineered Pseudomonas fluorescens bacterium containing the DNA that encodes for asparaginase Erwinia chrysanthemi.
Distribution: Vd: 1.37 L/m2.
Metabolism: Expected to be metabolized into small peptides by catabolic pathways.
Bioavailability: IM: 37%.
Half-life elimination: ~16 hours.
Time to peak: Median: IM: 12 hours.
Excretion: Clearance: 0.17 L/hour/m2.
Race/ethnicity: Black and African American patients had 29% lower clearance (which may increase serum asparaginase activity), compared to White and Asian patients.
Body surface area: The Vd and clearance of asparaginase (Erwinia [recombinant]) increase with increasing BSA (0.44 to 2.53 m2).
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