Pegaspargase

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection [preservative free]:

Oncaspar: 750 units/mL (5 mL)

Pharmacology

Mechanism of Action

Pegaspargase is a modified version of L-asparaginase, conjugated with monomethoxypolyethylene glycol (mPEG). In leukemic cells, asparaginase hydrolyzes L-asparagine to ammonia and L-aspartic acid, leading to depletion of asparagine. Leukemia cells require exogenous asparagine; normal cells can synthesize asparagine. Asparagine depletion in leukemic cells leads to inhibition of protein synthesis and apoptosis.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 1.86 L/m² (following a single IM dose of 2,500 units/m²); 2 L (following a single IV dose of 2,500 units/m²); Asparaginase-naive adults: IV: 2.4 L/m² (Douer 2007)

Metabolism

Systemically degraded

Excretion

Clearance: 0.17 L/m²/day (following a single IM dose of 2,500 units/m²); 0.2 L/day (following a single IV dose of 2,500 units/m²)

Onset of Action

Mean maximum asparaginase activity: On day 5 (following a single IM dose of 2,500 units/m²)

Duration of Action

Asparagine depletion: IV (in asparaginase-naive adults): 2 to 4 weeks (Douer 2007); IM: ~21 days

Half-Life Elimination

~5.8 days (following a single IM dose of 2,500 units/m²); ~5.3 days (following a single IV dose of 2,500 units/m²); Asparaginase-naive adults: IV: 7 days (Douer 2007)

Use: Labeled Indications

Acute lymphoblastic leukemia and hypersensitivity to asparaginase: Treatment of acute lymphoblastic leukemia (ALL) in pediatric and adult patients with hypersensitivity to native forms of L-asparaginase (as a component of a multiagent chemotherapy regimen)

Acute lymphoblastic leukemia, first-line treatment: First-line treatment of ALL (as a component of a multiagent chemotherapy regimen) in pediatric and adult patients

Contraindications

History of serious hypersensitivity reactions (including anaphylaxis) to pegaspargase or any component of the formulation; history of serious thrombosis with prior L-asparaginase therapy; history of pancreatitis (including pancreatitis associated with prior L-asparaginase therapy; history of serious hemorrhagic events with prior L-asparaginase therapy; severe hepatic impairment

Dosage and Administration

Dosing: Adult

Acute lymphoblastic leukemia (ALL), as first-line treatment or in patients with hypersensitivity to native asparaginase: IM, IV:

≤21 years: 2,500 units/m² (as part of a multi-agent combination chemotherapy regimen); do not administer more frequently than every 14 days

>21 years: 2,000 units/m² (as part of a multi-agent combination chemotherapy regimen); do not administer more frequently than every 14 days

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Acute lymphoblastic leukemia (ALL): Infants, Children, and Adolescents: IM, IV: 2,500 units/m²/dose (as part of a combination chemotherapy regimen); do not administer more frequently than every 14 days

Dosing adjustment for toxicity: Infants, Children, and Adolescents:

Hemorrhage: Grade 3 or 4: Hold therapy, evaluate for coagulopathy, and consider clotting factor replacement as needed; if resolution (ie, bleeding controlled), resume therapy with the next scheduled dose

Hypersensitivity or infusion reactions:

Grade 1: Reduce infusion rate by 50%

Grade 2: Interrupt infusion and treat symptoms; after resolution of symptoms, resume infusion at 50% of previous rate

Grade 3 or 4: Discontinue permanently

Pancreatitis: Grade 3 or 4: If lipase or amylase >3 times ULN, hold therapy until enzyme levels stabilize or are declining. Discontinue permanently if clinical pancreatitis confirmed.

Thromboembolism:

Uncomplicated deep vein thrombosis (DVT): Hold therapy, evaluate and treat DVT with antithrombotic therapy; upon resolution of symptoms, may resume therapy with concomitant antithrombotic agent(s)

Severe or life-threatening thrombosis: Discontinue permanently; treat thrombosis with necessary medical management

The following additional adjustments have been recommended for other asparaginase products (Stock 2011): 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 the asparaginase product (and any concomitant corticosteroids) until blood glucose 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.

Dosing: Adjustment for Toxicity

Hemorrhage: Grade 3 or 4: Withhold pegaspargase. Evaluate for coagulopathy and consider clotting factor replacement as needed. Resume pegaspargase with the next scheduled dose if bleeding is controlled.

Hypersensitivity or infusion reaction:

Grade 1: Reduce the infusion rate by 50%.

Grade 2: Interrupt infusion and manage symptoms; when symptoms resolve, resume the infusion with the infusion rate decreased by 50%.

Grade 3 or 4: Permanently discontinue pegaspargase.

Pancreatitis: Grade 3 or 4: Withhold pegaspargase for lipase or amylase elevations >3 times ULN until enzyme levels stabilize or are declining. Discontinue pegaspargase permanently if clinical pancreatitis is confirmed.

Thromboembolism:

Uncomplicated DVT: Withhold pegaspargase and treat with appropriate antithrombotic therapy. Upon resolution of symptoms, consider resuming pegaspargase while continuing antithrombotic therapy.

Severe or life-threatening thrombosis: Discontinue pegaspargase permanently and treat with appropriate antithrombotic therapy.

The following off-label adjustments have also been recommended (Stock 2011):

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 pegaspargase (and any concomitant corticosteroids) until blood glucose controlled; resume dosing at prior dose level. For life-threatening hyperglycemia or toxicity requiring urgent intervention, hold pegaspargase (and corticosteroids) until blood glucose is controlled with insulin; resume pegaspargase and do not make up for missed doses.

Hypersensitivity reactions: May continue dosing for urticaria without bronchospasm, hypotension, edema, or need for parenteral intervention. If wheezing or other symptomatic bronchospasm with or without urticaria, angioedema, hypotension, and/or life-threatening hypersensitivity reactions occur, discontinue pegaspargase. Replace pegaspargase with asparaginase (Erwinia).

Hypertriglyceridemia: If serum triglyceride level <1,000 mg/dL, continue pegaspargase but monitor closely for pancreatitis. If triglyceride level >1,000 mg/dL, hold pegaspargase and monitor; resume therapy at prior dose level after triglyceride level returns to baseline.

Pancreatitis:

Asymptomatic amylase or lipase >3 times ULN (chemical pancreatitis) or radiologic abnormalities only: Continue pegaspargase and monitor levels closely.

Clinical pancreatitis (abdominal pain with amylase or lipase >3 times ULN for >3 days and/or development of pancreatic pseudocyst): Permanently discontinue pegaspargase.

Thrombosis and bleeding, CNS:

Thrombosis: Continue therapy for abnormal laboratory findings without a clinical correlate. If grade 3 toxicity occurs, discontinue therapy; if CNS signs/symptoms are fully resolved and further pegaspargase doses are required, may resume therapy at a lower dose and/or longer intervals between doses. Discontinue therapy for grade 4 toxicity.

Hemorrhage: Discontinue therapy; do not withhold therapy for abnormal laboratory findings without a clinical correlate. If grade 3 toxicity occurs, discontinue therapy; if CNS signs/symptoms are fully resolved and further pegaspargase doses are required, may resume therapy at a lower dose and/or longer intervals between doses. Discontinue therapy for grade 4 toxicity.

Thrombosis and bleeding, non-CNS:

Thrombosis: Continue therapy for abnormal laboratory findings without a clinical correlate. If grade 3 or 4 toxicity occurs, withhold therapy until acute toxicity and clinical signs resolve and anticoagulant therapy is stable or completed. Do not withhold therapy for abnormal laboratory findings without clinical correlate.

Hemorrhage: If grade 2 bleeding in conjunction with hypofibrinogenemia occurs, withhold therapy until bleeding ≤ grade 1. Do not withhold therapy for abnormal laboratory findings without clinical correlate. For grade 3 or 4 bleeding, withhold therapy until bleeding ≤ grade 1 and until acute toxicity and clinical signs resolve and coagulant replacement therapy is stable or completed.

Reconstitution

IV: Dilute in 100 mL NS or D5W.

Administration

Have available appropriate agents for maintenance of an adequate airway and treatment of a hypersensitivity reaction (antihistamine, epinephrine, oxygen, IV corticosteroids). Be prepared to treat anaphylaxis at each administration.

IM: Must only be administered as a deep intramuscular injection into a large muscle. Limit the injection volume to 2 mL per single injection site; use multiple injection sites for IM injection volume >2 mL.

IV: Administer over 1 to 2 hours through a running IV infusion line (of either NS or D5W, depending on which fluid was used in preparation of the diluted solution); do not administer IV push.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Intact vials may be stored at 15°C to 25°C (59°F to 77°F) for no more than 48 hours. Store in original carton to protect from light. Do not shake. Discard if previously frozen, stored at room temperature for >48 hours, excessively shaken/agitated, or if cloudy, discolored, or if precipitate is present. Use immediately after preparation; if not used immediately, solutions diluted for infusion in NS or D5W should be protected from light, refrigerated at 2°C to 8°C (36°F to 46°F) and used within 48 hours (including administration time).

Drug Interactions

Pegloticase: May diminish the therapeutic effect of PEGylated Drug Products. Monitor therapy

Pegvaliase: PEGylated Drug Products may enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Monitor therapy

Adverse Reactions

>10%:

Hepatic: Increased serum transaminases (ALT, AST; grades 3/4: 3% to 11%)

Hypersensitivity: Hypersensitivity reaction (grades 3/4: 1%, includes anaphylaxis, bronchospasm, erythema, hives, hypotension, laryngeal edema, skin rash, swelling, urticaria; relapsed acute lymphoblastic leukemia [ALL] with no prior asparaginase hypersensitivity: 10%; relapsed ALL with prior asparaginase hypersensitivity: 32%)

1% to 10%:

Cardiovascular: Thrombosis (4%)

Central nervous system: Cerebral thrombosis (or hemorrhage of the brain: 2%; grades 3/4: 3%)

Endocrine & metabolic: Hyperglycemia (3% [some patients required insulin therapy]; grades 3/4: 5%)

Gastrointestinal: Pancreatitis (1%; grades 3/4: 2% [includes 3 deaths])

Hematologic: Blood coagulation disorder (grades 3/4: 2% to 7%; includes prolonged prothrombin time or partial thromboplastin time or decreased serum fibrogen)

Hepatic: Abnormal hepatic function tests (grades 3/4: 5%), hyperbilirubinemia (grades 3/4: 1% to 2%)

Immunologic: Hypersensitivity to L-asparaginase (grades 3/4: 2%)

<1%, postmarketing, case reports, and/or frequency not defined: Abdominal pain, anemia, anorexia, antithrombin III deficiency, arthralgia, ascites, bacteremia, bronchospasm, bruise, chest pain, chills, coagulation time increased, colitis, confusion, constipation, cough, deep vein thrombosis, disseminated intravascular coagulation, dizziness, dyspnea, edema, emotional lability, endocarditis, epistaxis, facial edema, fatigue, fever, gastrointestinal pain, headache, hematuria, hemolytic anemia, hemorrhagic cystitis, hepatic failure, hepatomegaly, hyperammonemia, hypertension, hyperuricemia, hypoalbuminemia, hypoglycemia, hyponatremia, increased blood urea nitrogen, increased serum amylase, increased serum creatinine, increased serum lipase, increased thirst, injection site pain, jaundice, leukopenia, lip edema, liver steatosis, malaise, metabolic acidosis, myalgia, nausea, night sweats, ostealgia, pancytopenia, paresthesia, petechial rash, prolonged prothrombin time, proteinuria, purpura, renal failure, renal function abnormality, sagittal sinus thrombosis, seizure, sepsis, septic shock, subacute bacterial endocarditis, superficial venous thrombosis, tachycardia, thrombocytopenia, uric acid nephropathy, urticaria, vomiting

Warnings/Precautions

Concerns related to adverse effects:

• Glucose intolerance: Pegaspargase may result in glucose intolerance (was irreversible in some cases). Monitor serum glucose.
• Hemorrhage: Increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia may occur in patients receiving pegaspargase. Severe or symptomatic coagulopathy may require appropriate replacement therapy. Evaluate coagulation parameters (including PT, PTT, and fibrinogen) in patients with signs/symptoms of hemorrhage.
• Hepatotoxicity: Hepatotoxicity and abnormal liver function, including elevations of transaminase and bilirubin (direct and indirect) and reduced serum albumin and fibrinogen may occur with pegaspargase. During treatment cycles that include pegaspargase, monitor bilirubin and transaminases at least weekly; continue monitoring for at least 6 weeks after the last pegaspargase dose. If serious liver toxicity occurs, discontinue pegaspargase and provide supportive care.
• Hypersensitivity: Anaphylaxis and serious hypersensitivity reactions may occur with pegaspargase. The risk of serious hypersensitivity reactions is increased in patients with known hypersensitivity to E. coli derived L-asparaginase products. Hypersensitivity reactions may include angioedema, lip swelling, eye swelling, hypotension, bronchospasm, dyspnea, erythema, pruritus, and rash. Observe patients for 1 hour after administration; equipment and immediate treatment for hypersensitivity reactions (eg, epinephrine, oxygen, intravenous steroids, antihistamines) should be available during administration. Discontinue pegaspargase in patients with serious hypersensitivity reactions.
• Pancreatitis: Pancreatitis may occur in patients receiving pegaspargase; hemorrhagic or necrotizing pancreatitis have been reported (sometimes fatal). Avoid alcohol use (Stock 2011). Inform patients of the signs/symptoms of pancreatitis. Untreated pancreatitis may be fatal. Assess serum amylase and/or lipase levels to confirm early signs of pancreatic inflammation. If pancreatitis is suspected, discontinue pegaspargase; if pancreatitis is confirmed, do not resume pegaspargase. May consider continuing therapy for asymptomatic chemical pancreatitis (amylase or lipase >3 times ULN) or only radiologic abnormalities; monitor closely for rising amylase and/or lipase levels (Stock 2011).
• Thrombotic events: Serious thrombotic events, including sagittal sinus thrombosis may occur with pegaspargase; discontinue with serious thrombotic event. Consider monitoring antithrombin III activity and consider repletion if indicated (Barreto 2017). Anticoagulation prophylaxis during therapy may be considered in some patients (Farge 2013).

Other warnings/precautions:

• Administration route: In a study comparing IV pegaspargase to IM native E. coli asparaginase for post-induction treatment in children with ALL, 5-year disease-free survival did not differ and the overall frequency of asparaginase-related toxicities (including allergy, pancreatitis, and thrombotic or bleeding complications) did not differ between the IV pegaspargase and IM native E. coli asparaginase groups. The median nadir serum asparaginase activity was significantly higher in the IV pegaspargase group. Reported treatment-related anxiety was significantly lower (for both patients and guardians) in the group that received IV pegaspargase (Place 2015).
• Medication error prevention: Do not interchange pegaspargase for asparaginase (E. coli), asparaginase (Erwinia), or calaspargase pegol-mknl; ensure the proper asparaginase formulation, route of administration, and dose prior to administration.

Monitoring Parameters

CBC with differential, platelets (at least weekly during treatment), amylase/lipase, liver function tests (bilirubin, transaminases; baseline and at least weekly during treatment), fibrinogen, PT, PTT (coagulation parameters [baseline and periodically during and after treatment]), renal function tests; urine glucose, blood glucose (at least weekly during treatment); triglycerides; uric acid; pregnancy test (prior to treatment in females of reproductive potential). Consider monitoring antithrombin III activity (Barreto 2017). Monitor vital signs during administration; monitor for onset of abdominal pain; observe for allergic reaction (for 1 hour after administration); monitor for signs/symptoms of thrombosis or bleeding.

Pregnancy

Pregnancy Considerations

Based on animal reproduction studies conducted with L-asparaginase, adverse effects to the fetus may be expected if exposure occurs during pregnancy.

Evaluate pregnancy status prior to use in females of reproductive potential. Effective contraception (which includes a barrier method) should be used during therapy and for at least 3 months after the last pegasparagase dose. Oral contraceptives may not be effective and are not recommended as a form of contraception.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Infection
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• Severe dizziness
• Passing out
• Severe fatigue
• Severe headache
• Bruising
• Bleeding
• Vision changes
• Confusion
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.