Dosing & Uses
Dosage Forms & Strengths
injection, solution
- 10mg/0.5mL
Acute Lymphoblastic Leukemia
Indicated as part of a chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in patients who have developed hypersensitivity or silent inactivation to Escherichia coli–derived asparaginase
25 mg/m2 IM q48hr; duration-dependent regimen, OR
Administer on a Monday/Wednesday/Friday schedule
- 25 mg/m2 IM on every Monday and Wednesday mornings, AND
- 50 mg/m2 IM on Friday afternoon
- Administer Friday afternoon dose 53-58 hr after Wednesday morning dose (eg, 8:00 am on Monday and Wednesday, and 1:00-6:00 pm on Friday)
Lymphoblastic Lymphoma
Indicated as part of a chemotherapeutic regimen for lymphoblastic lymphoma (LBL) in patients who have developed hypersensitivity or silent inactivation to E coli–derived asparaginase
25 mg/m2 IM q48hr; duration-dependent regimen, OR
Administer on a Monday/Wednesday/Friday schedule
- 25 mg/m2 IM on every Monday and Wednesday mornings, AND
- 50 mg/m2 IM on Friday afternoon
- Administer Friday afternoon dose 53-58 hr after Wednesday morning dose (eg, 8:00 am on Monday and Wednesday, and 1:00-6:00 pm on Friday)
Dosage Modifications
Renal or hepatic impairment
- Not studied
Hypersensitivity
- Grade 2: Treat symptoms
- Grade 3-4: Discontinue permanently
Pancreatitis, grade ≥2
- Hold if lipase or amylase >2x ULN, or for symptomatic pancreatitis
- Resume treatment when lipase and amylase <1.5x ULN and symptoms resolve
- Discontinue permanently if clinical necrotizing or hemorrhagic pancreatitis confirmed
Thrombosis
- Uncomplicated: Hold and treat with antithrombotic therapy; consider resuming upon symptom resolution while continuing antithrombotic therapy
- Severe or life-threatening: Discontinue permanently; treat with antithrombotic therapy
Hemorrhage, grade ≥3
- Hold asparaginase
- Evaluate for coagulopathy and consider clotting factor replacement as needed
- Resume with next scheduled dose if bleeding controlled
Hepatotoxicity
- Total bilirubin (TB) >3 x to ≤10x ULN: Hold until TB ≤1.5x ULN
- TB >10x ULN: Discontinue and do not make up missed doses
Dosing Considerations
Test females of reproductive potential for pregnancy before initiating
Recommended duration of asparaginase Erwinia chrysanthemi recombinant to replace calaspargase pegol products
- Q48hr administration: Replace 1 dose of calaspargase pegol products with 11 doses of asparaginase Erwinia chrysanthemi recombinant
- MWF administration: Replace 1 dose of calaspargase pegol products with 9 doses of asparaginase Erwinia chrysanthemi recombinant
Recommended duration of asparaginase Erwinia chrysanthemi recombinant to replace pegaspargase products
- Q48hr administration: Replace 1 dose of pegaspargase products with 7 doses of asparaginase Erwinia chrysanthemi recombinant
- MWF administration: Replace 1 dose of pegaspargase products with 6 doses of asparaginase Erwinia chrysanthemi recombinant
Treatment duration
- When replacing a long-acting asparaginase product, refer to prescribing information of product being replaced to determine treatment duration with asparaginase Erwinia chrysanthemi recombinant
Monitoring
- Monitor bilirubin, transaminases, glucose, and clinical examinations before treatment and q2-3 weeks and as indicated clinically
- If results are abnormal, monitor until recovery from the cycle of therapy
- If an adverse reaction occurs, modify treatment
Dosage Forms & Strengths
injection, solution
- 10mg/0.5mL
Acute Lymphoblastic Leukemia
Indicated as part of a chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in children aged ≥1 month who have developed hypersensitivity or silent inactivation to Escherichia coli–derived asparaginase
<1 month: Safety and efficacy not established
25 mg/m2 IM q48hr; duration-dependent regimen, OR
Administer on a Monday/Wednesday/Friday schedule
- 25 mg/m2 IM on every Monday and Wednesday mornings, AND
- 50 mg/m2 IM on Friday afternoon
- Administer Friday afternoon dose 53-58 hr after Wednesday morning dose (eg, 8:00 am on Monday and Wednesday, and 1:00-6:00 pm on Friday)
Lymphoblastic Lymphoma
Indicated as part of a chemotherapeutic regimen for lymphoblastic lymphoma (LBL) in children aged ≥1 month who have developed hypersensitivity or silent inactivation to E coli–derived asparaginase
<1 month: Safety and efficacy not established
25 mg/m2 IM q48hr; duration-dependent regimen, OR
Administer on a Monday/Wednesday/Friday schedule
- 25 mg/m2 IM on every Monday and Wednesday mornings, AND
- 50 mg/m2 IM on Friday afternoon
- Administer Friday afternoon dose 53-58 hr after Wednesday morning dose (eg, 8:00 am on Monday and Wednesday, and 1:00-6:00 pm on Friday)
Dosage Modifications
Renal or hepatic impairment
- Not studied
Hypersensitivity
- Grade 2: Treat symptoms
- Grade 3-4: Discontinue permanently
Pancreatitis, grade ≥2
- Hold if lipase or amylase >2x ULN, or for symptomatic pancreatitis
- Resume treatment when lipase and amylase <1.5x ULN and symptoms resolve
- Discontinue permanently if clinical necrotizing or hemorrhagic pancreatitis confirmed
Thrombosis
- Uncomplicated: Hold and treat with antithrombotic therapy; consider resuming upon symptom resolution while continuing antithrombotic therapy
- Severe or life-threatening: Discontinue permanently; treat with antithrombotic therapy
Hemorrhage, grade ≥3
- Hold asparaginase
- Evaluate for coagulopathy and consider clotting factor replacement as needed
- Resume with next scheduled dose if bleeding controlled
Hepatotoxicity
- Total bilirubin (TB) >3 x to ≤10x ULN: Hold until TB ≤1.5x ULN
- TB >10x ULN: Discontinue and do not make up missed doses
Dosing Considerations
Test females of reproductive potential for pregnancy before initiating
Recommended duration of asparaginase Erwinia chrysanthemi recombinant to replace calaspargase pegol products
- Q48hr administration: Replace 1 dose of calaspargase pegol products with 11 doses of asparaginase Erwinia chrysanthemi recombinant
- MWF administration: Replace 1 dose of calaspargase pegol products with 9 doses of asparaginase Erwinia chrysanthemi recombinant
Recommended duration of asparaginase Erwinia chrysanthemi recombinant to replace pegaspargase products
- Q48hr administration: Replace 1 dose of pegaspargase products with 7 doses of asparaginase Erwinia chrysanthemi recombinant
- MWF administration: Replace 1 dose of pegaspargase products with 6 doses of asparaginase Erwinia chrysanthemi recombinant
Treatment duration
- When replacing a long-acting asparaginase product, refer to prescribing information of product being replaced to determine treatment duration with asparaginase Erwinia chrysanthemi recombinant
Monitoring
- Monitor bilirubin, transaminases, glucose, and clinical examinations before treatment and q2-3 weeks and as indicated clinically
- If results are abnormal, monitor until recovery from the cycle of therapy
- If an adverse reaction occurs, modify treatment
Adverse Effects
>10%
All grades
- Abnormal liver test (70%)
- Nausea (46%)
- Musculoskeletal pain (39%)
- Fatigue (36%)
- Infection (30%)
- Headache (30%)
- Pyrexia (27%)
- Hypersensitivity (24%)
- Febrile neutropenia (24%)
- Decreased appetite (21%)
- Stomatitis (21%)
- Bleeding (21%)
- Hyperglycemia (21%)
- Abdominal pain (18%)
- Tachycardia (18%)
- Diarrhea (18%)
- Constipation (15%)
- Dehydration (15%)
- Neuropathy peripheral (15%)
- Cough (15%)
- Insomnia (15%)
Grades ≥3
- Febrile neutropenia (24%)
- Abnormal liver test (12%)
- Infection (12%)
Other clinically relevant adverse reactions <15%
- Gastrointestinal disorders: Abdominal discomfort, abdominal distension, pancreatitis
- General disorders and administration site conditions: Infusion site reaction, pain
- Infections and infestations: Viral infection, bacterial infection, fungal infection
- Investigations: Blood fibrinogen decreased, activated partial thromboplastin time prolonged
- Metabolism and nutrition disorders: Acidosis
- Musculoskeletal and connective-tissue disorders: Bone pain, muscular weakness, muscle spasms
- Nervous system disorders: Paresthesia
- Psychiatric disorders: Agitation, anxiety, irritability
- Renal and urinary disorders: Acute kidney injury
- Skin and subcutaneous disorders: Pruritus
- Vascular disorders: Hypotension
1-10%
Grades ≥3
- Nausea (9%)
- Stomatitis (9%)
- Dehydration (9%)
- Musculoskeletal pain (6%)
- Pyrexia (6%)
- Hypersensitivity (6%)
- Decreased appetite (6%)
- Diarrhea (6%)
- Fatigue (3%)
- Hyperglycemia (3%)
Warnings
Contraindications
History of serious hypersensitivity reactions to E asparaginase, including anaphylaxis
Serious pancreatitis during previous asparaginase therapy
Serious thrombosis during previous asparaginase therapy
Serious hemorrhagic events during previous asparaginase therapy
Cautions
Pancreatitis, including elevated amylase or lipase, reported; monitor for signs and symptoms; withhold or discontinue depending on severity
Serious thrombotic events reported, including sagittal sinus thrombosis and pulmonary embolism; discontinue if thrombotic event occurs and administer antithrombotic therapy; consider resumption only if event was an uncomplicated thrombosis
Bleeding reported; monitor for bruising, nose bleeds, hematuria, rectal bleeding, and gingival bleeding; monitor PT, PTT, and hypofibrinogenemia
Hepatotoxicity reported; evaluate bilirubin and transaminases before initiating and q2-3 weeks as clinically indicated during treatment
Hypersensitivity
- 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
- Premedicate patients prior to administration of therapy as recommended
- Owing to risk for serious allergic reactions (eg, life-threatening anaphylaxis), administer in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis
Pregnancy & Lactation
Pregnancy
Based on findings from animal reproduction studies, can cause fetal harm when administered to pregnant females
Advise pregnant females of potential fetal risk
Pregnancy testing recommended in females of reproductive potential before initiating
Animal data
- In embryofetal development studies, asparaginase E chrysanthemi was administered IM every other day during organogenesis to pregnant rats (at 3, 6, or 12 mg/m2) and rabbits (at 0.12, 0.30, or 0.48 mg/m2)
- In rats given 12 mg/m2 (~0.48 times the maximum recommended human dose [MRHD]), maternal toxicity of decreased body weight gain was observed, as was a fetal finding of increased incidence of partially undescended thymic tissue
- In rabbits, maternal toxicity consisting of decreased body weight was observed at 0.48 mg/m2 (~0.02 times the MRHD), increased postimplantation loss, decreased number of live fetuses, and gross abnormalities (eg, absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) observed at doses ≥0.12 mg/m2 (~0.005 times the MRHD)
Contraception
- Females of reproductive potential: Use effective nonhormonal contraceptive methods during treatment and for 3 months after last dose
Lactation
Data are unavailable regarding presence in human milk, effects on breastfed children, or effects on milk production
Advise women not to breastfeed during treatment and for 1 week after last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Enzyme that catalyzes conversion of the amino acid L-asparagine into aspartic acid and ammonia
Pharmacological effect based on the killing of leukemic cells owing 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
Absorption
Bioavailability: 37%
Peak plasma time: 10 hr
AUC: 37.9 hr⋅U/mL (dose 1); 48.5 hr⋅U/mL (dose 7)
Peak plasma concentration
- Dose 1: 1.8 U/mL
- Dose 7: 2.24 U/mL
-
48 hr after most recent dose
- Dose 1: 0.33 U/mL
- Dose 7: 0.4 U/mL
Distribution
Vd: 1.48 L/m2
Metabolism
Via catabolic pathways into small peptides
Elimination
Half-life: 18.2 hr
Clearance: 0.31 L/hr/m2
Pharmacogenomics
Black and Asian patients had 29% lower clearance which may increase serum asparaginase activity exposure compared with White patients
Administration
IM Preparation
Visually inspect for particulate matter, cloudiness, or discoloration; if any of these observed, discard vial
Determine dose, total volume of solution required, and the number of vials needed; >1 vial may be needed to obtain full dose
Do not shake vial
Withdraw required volume into syringe; if >2 mL required, divide doses equally into multiple syringes (1 syringe for each injection site)
Discard remaining unused drug in vial
Administer within 4 hr of preparation
IM Administration
M administration only
Rotate injection sites
Do not inject into scar tissues or areas that are reddened, inflamed, or swollen
Premedications
- Premedicate with acetaminophen, an H-1 receptor blocker (eg, diphenhydramine), and an H-2 receptor blocker (eg, famotidine) 30-60 minutes before administering to decrease risk of hypersensitivity reactions
Storage
Does not contain a preservative
Unopened vials
- Refrigerate at 2-8ºC (36-46ºF) in original carton to protect from light
- Do not shake or freeze
Prepared syringes
- If not used immediately, store at room temperature 15-25ºC (59-77ºF) for up to 8 hr OR refrigerate at 2-8ºC (36-46ºF) for up to 24 hr
- Syringe does not need to be protected from light during storage
Images
Formulary
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