VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Pegaspargase

Chemical Name:

• (Monomethoxypolyethylene glycol succinimidyl)₇₄-l-asparaginase

Pegaspargase, an Escherichia coli -derived asparaginase enzyme that is conjugated with monomethoxy polyethylene glycol (mPEG), is an antineoplastic agent.1,2,3,5,6

Acute Lymphocytic Leukemia

First-line Therapy for Acute Lymphocytic Leukemia

Pegaspargase is used as a component of combination chemotherapy for the first-line treatment of childhood and adult acute lymphocytic (lymphoblastic) leukemia (ALL).1,7,23,26 Pegaspargase is used as a component of induction therapy; the drug also is used as a component of intensification (consolidation) treatment regimens administered following achievement of remission and prior to initiation of maintenance therapy.1,7,22,23,25,26

Various drugs have been used for combination chemotherapy of childhood and adult ALL,7,8,9,30,31,32 and comparative efficacy of these regimens is continually being evaluated.7,9,30,31,32 Treatment of ALL typically includes remission induction therapy, followed by intensification (consolidation) therapy, and then 2-3 years of maintenance therapy (e.g., methotrexate and mercaptopurine with or without pulses of vincristine and prednisone7,8,31,33 ).7,9,31,32,33 The intensity of both induction and postinduction therapies is based on assessment of the patient's risk of relapse.7,33 Additional therapy (e.g., intrathecal chemotherapy, CNS-directed systemic therapy, and/or cranial radiation therapy) is needed for prophylaxis of CNS involvement (meningeal leukemia) in patients with ALL.7,8,9,30,31,32,46 Other regimens are preferred in certain subsets of patients with ALL (e.g., B-cell ALL, T-cell ALL, Philadelphia chromosome-positive ALL).7,30,32 Certain patients with a poor prognosis or with a poor response to initial treatment may be candidates for hematopoietic stem cell transplantation.7,8,9,30,31,32,33,46 Specialized references and experts should be consulted for additional information.

An asparaginase preparation is used in combination with a corticosteroid (dexamethasone or prednisone) and vincristine, with or without an anthracycline (daunorubicin or doxorubicin), as induction therapy for childhood ALL.7,46 While some clinicians reserve 4-drug induction regimens for patients with high-risk childhood ALL (using 3-drug induction regimens in children with lower-risk disease in an effort to decrease toxicity in these patients),7,8,33,46 other clinicians use a 4-drug induction regimen for all patients with childhood ALL regardless of presenting features.7,46 Multiple-drug induction regimens produce a complete remission in 95% or more of children with ALL.7,33,46

Several different formulations of asparaginase have been used in first-line combination chemotherapeutic regimens for childhood ALL.1,7,35,36,39 Because pegaspargase has similar efficacy and toxicity as asparaginase (Escherichia coli)7,22,25 but requires less frequent administration, many clinicians prefer pegaspargase for use during both induction and postinduction phases of treatment in pediatric patients with newly diagnosed ALL.7,44 Asparaginase (Escherichia coli) no longer is commercially available in the US, and pegaspargase has become a core component in most first-line combination chemotherapeutic regimens for childhood ALL.7,44 More recently, calaspargase pegol, an E. coli -derived asparaginase preparation that is administered less frequently than pegaspargase, also has become commercially available in the US for use in combination chemotherapeutic regimens for childhood and young adult ALL.7,43,47 (See Calaspargase Pegol-mknl 10:00.) Asparaginase (Erwinia chrysanthemi) may be used in patients who are hypersensitive to E. coli -derived asparaginase preparations.7,34,35,36,37,38 (See Asparaginase [Erwinia chrysanthemi] 10:00.)

Induction regimens for adult ALL typically include prednisone, vincristine, and an anthracycline; some regimens also add other drugs, such as an asparaginase preparation or cyclophosphamide.26,28,30 Such induction regimens produce a complete remission in about 60-90% of adults with ALL.26,28,30,33 Adolescents and young adults receiving pediatric-based treatment regimens for ALL appear to have better outcomes than those receiving traditional adult treatment regimens.7,45

Clinical Experience

In an open-label, randomized, active-controlled, multicenter study (CCG-1962) involving 118 pediatric patients 1-9 years of age with previously untreated standard-risk ALL, patients received either pegaspargase or native (nonconjugated) asparaginase (Escherichia coli) (no longer commercially available in the US) as a component of combination chemotherapy.1,22 The dosage schedule for pegaspargase was 2500 units/m² IM on day 3 of the 4-week induction phase and on day 3 of each of the two 8-week delayed intensification treatment phases.1,22 The dosage schedule for native asparaginase (Escherichia coli) was 6000 units/m² IM 3 times weekly for a total of 9 doses during the induction phase and for a total of 6 doses during each delayed intensification treatment phase.1,22

At specified time points during all phases of treatment, the proportion of patients with the target level of asparagine depletion (serum asparagine concentration of 1 µM or less) was similar among patients receiving pegaspargase-containing therapy or asparaginase (Escherichia coli)-containing therapy.1 For both groups, serum asparagine concentrations typically decreased within 4 days following the first dose of drug and remained low for approximately 3 weeks.1,22 Similar magnitude and duration of reduction in CSF asparagine concentrations were observed for the 2 groups.1 Similar toxicity was observed between the groups.22 Pharmacokinetic analysis during induction therapy showed that pegaspargase has a longer elimination half-life (5.5 days) than native asparaginase (Escherichia coli) (1.1 days).22

Binding or neutralizing antibodies to pegaspargase were detected in 2% of patients during induction therapy, in 10% of patients during the first phase of delayed intensification therapy, and in 11% of patients during the second phase of delayed intensification therapy.1 The effect of the development of binding antibodies on the pharmacokinetic disposition, antileukemic efficacy, or risk of clinical allergic reactions associated with pegaspargase therapy has not been fully established.1 Reduced activity of pegylated asparaginase has been demonstrated in sera that tested positive for antibodies to the drug in samples collected from pediatric patients receiving pegaspargase for ALL.27

In a study (AALL07P4) in pediatric patients and young adults with previously untreated high-risk B-precursor ALL, activity of pegaspargase was assessed through serial measurements of asparagine in plasma and CSF.1,42 Following a single IV dose of pegaspargase 2500 units/m² during induction therapy, plasma asparagine concentrations were maintained below the assay limit of quantification for at least 11 days.1,42 A sustained reduction in CSF asparagine from a mean pretreatment concentration of 0.6 µg/mL to 0.2 µg/mL on days 4 and 25 following the pegaspargase dose also was observed.1

In one study (Cancer and Leukemia Group B [CALGB] study 9511) in 102 adults with previously untreated ALL or acute undifferentiated leukemia, treatment with a combination chemotherapy regimen that included pegaspargase resulted in complete responses in 77% of patients.26 The pegaspargase dosage schedule for the first 21 patients was 2000 units/m² (maximum dose of 3750 units) given by subcutaneous injection† on day 5 of the 4-week induction phase and on day 15 of the 8-week early intensification treatment phase; subsequent patients received pegaspargase 2000 units/m² (maximum dose of 3750 units) by subcutaneous injection† on days 5 and 22 of the induction phase and on days 15 and 43 of the early intensification treatment phase.26 28 Patients who achieved asparagine depletion (defined as asparaginase concentrations exceeding 0.03 units/mL for 14 consecutive days following at least one pegaspargase dose) had prolonged disease-free and overall survival (median: 25 and 31 months, respectively) compared with those who did not achieve asparagine depletion (median: 12 and 13 months, respectively), although the differences were not statistically significant following adjustment for other patient characteristics.26 Complete response rates and relapse rates did not differ between patients who achieved asparagine depletion and those who did not achieve asparagine depletion.26 Larger studies are needed to more fully evaluate these findings.26

Acute Lymphocytic Leukemia and Hypersensitivity to Native Asparaginase

Pegaspargase is used as a component of combination chemotherapy for the treatment of ALL in patients who are hypersensitive to native (nonconjugated) forms of asparaginase.1,2,3,4,5,6,8 In several open-label studies in patients with multiply-relapsed acute leukemia (principally lymphocytic) and hypersensitivity to asparaginase, remission was reinduced in 50% of patients (36% complete and 14% partial) when pegaspargase was used as a component of combination chemotherapy.1 This response rate is comparable to that reported for reinduction of relapsed acute leukemia when native asparaginase (Escherichia coli) (no longer commercially available in the US) was used as a component of a combination regimen.1,3 Although pegaspargase is less immunogenic than native (nonconjugated) asparaginase,1,2,3,4,5,6,10,11,15,16,17,18,19 hypersensitivity reactions to the PEG-conjugated enzyme (i.e., pegaspargase) can occur.1,3,5,6,12,13,15,16,19

Administration

Pegaspargase is administered by IM injection or IV infusion.1 Pegaspargase also has been administered by subcutaneous† injection.26

Parenteral pegaspargase solutions should be inspected visually for particulate matter, cloudiness, and discoloration prior to administration.1 The drug should be discarded if the solution is discolored or cloudy or if particulate matter is present.1 No more than one dose should be used from each single-use vial; any unused portion should be discarded since the drug contains no preservative.1

For IM injection, commercially available pegaspargase injection is administered undiluted.1 The manufacturer recommends that not more than 2 mL be administered at any one injection site; IM doses exceeding 2 mL should be divided and administered at separate sites.1

For IV infusion, pegaspargase injection should be diluted in 100 mL of 0.9% sodium chloride injection or 5% dextrose injection and administered over a period of 1-2 hours through a running infusion of either 0.9% sodium chloride injection or 5% dextrose injection.1 IV solutions of pegaspargase should not be infused simultaneously through the same IV line with other drugs.1 After the drug has been diluted for IV infusion, pegaspargase solutions should be used immediately.1 If immediate use is not possible, pegaspargase diluted solutions should be stored at 2-8°C.1 Storage after dilution of the drug should not exceed 48 hours.1 The diluted solution should be protected from direct sunlight.1

Procedures for proper handling and disposal of antineoplastic drugs should be followed when preparing or administering asparaginase preparations.40,41

Dosage

Dosage of pegaspargase is expressed in international units (IU, units) and must be individualized according to body surface area.1

Pegaspargase should be administered in a setting where resuscitation equipment and other agents necessary to treat anaphylaxis are available.1 Following administration of the drug, patients should be monitored for 1 hour for anaphylaxis or serious allergic reactions.1 Bilirubin, aminotransferase, and glucose concentrations should be monitored and clinical examinations should be performed at least weekly until patients have recovered from the cycle of therapy.1 (See Cautions.)

Acute Lymphocytic Leukemia

For use as a component of combination chemotherapy for the treatment of acute lymphocytic leukemia (ALL) in pediatric patients and young adults through 21 years of age, the recommended dosage of pegaspargase is 2500 units/m² administered by IM injection or IV infusion no more frequently than every 14 days.1 In adults older than 21 years of age, the recommended dosage of pegaspargase is 2000 units/m² administered by IM injection or IV infusion no more frequently than every 14 days.1 Clinicians should consult published protocols for the dosage of pegaspargase and other chemotherapeutic agents and the method and sequence of administration.

Therapy Interruption for Toxicity

If adverse reactions occur, treatment should be modified accordingly, as described in Table 1.1

Among patients receiving pegaspargase as a component of combination therapy in first-line treatment for acute lymphocytic (lymphoblastic) leukemia (ALL), the most common serious (grade 3 or 4) adverse effects are hypoalbuminemia, elevated serum aminotransferase concentrations, febrile neutropenia, hypertriglyceridemia, hyperglycemia, hyperbilirubinemia, pancreatitis, clotting study abnormalities, embolic and thrombotic events, and hypersensitivity reactions.1 Like other asparaginase preparations, pegaspargase rarely causes severe bone marrow depression, and usually does not substantially affect GI or oral mucosa or hair follicles.3,19 In general, except for hypersensitivity reactions, adults receiving pegaspargase have a somewhat higher incidence of known asparaginase toxicities (e.g., pancreatic dysfunction, hepatic toxicity, thromboembolism) than children.17,19,44,45 There does not appear to be a substantial difference in adverse effects following IV versus IM administration of the drug.7

Although pegaspargase is less immunogenic than native (nonconjugated) asparaginase,2,3,4,5,6,10,11,15,16,17,18,19 hypersensitivity reactions,1,5,6,12,13,15,16,19 including life-threatening anaphylaxis, are among the most frequent adverse effects of pegaspargase.1,5,19 Most other adverse effects of pegaspargase are similar to those of native asparaginase3,6,16,18,19 and may be attributed to asparagine and glutamine depletion and, therefore, decreased protein synthesis in tissues with high rates of protein synthesis (e.g., liver [including clotting factors], kidneys, pancreas, CNS) or to increased blood concentrations of ammonia as a product of the breakdown of asparagine.3

Sensitivity Reactions

Among the most frequent adverse effects of pegaspargase are hypersensitivity or allergic reactions,1,5,6,12,13,15,16,19,25 which may include acute anaphylaxis,1,5,12,13,19 bronchospasm,1,5,12,19 hypotension,1 angioedema,1 lip swelling,1 eye swelling,1 urticaria,12,16,19 chills,18,12,16,19 dyspnea,1 erythema,1 pruritus,1 systemic rash,1,12,16,19 and local erythema or swelling.12,19 Pegaspargase is less immunogenic than native forms of asparaginase derived from Escherichia coli or Erwinia chrysanthemi (formerly Erwinia carotovora ; also known as Pectobacterium chrysanthemi );2,3,4,5,6,10,11,15,16,17,18,19 however, in patients with known hypersensitivity to these forms of asparaginase, hypersensitivity reactions to pegaspargase, including life-threatening anaphylaxis, can occur.1,5,6,12,13,15,16,19

Among patients in a randomized trial receiving pegaspargase in combination chemotherapy as first-line therapy for ALL, grade 3 or 4 clinical allergic reactions occurred in 2% of patients.1 In another randomized trial (DFCI 11-001) in children and adolescents receiving pegaspargase in combination chemotherapy as first-line therapy for ALL or lymphoblastic lymphoma, grade 3 or 4 hypersensitivity reactions occurred in 7% of patients.1

In clinical trials for relapsed ALL, the incidence of clinical allergic reactions to pegaspargase was 32% in patients with hypersensitivity to native asparaginase and 10% in asparaginase-nonhypersensitive patients.1,19 Grade 3 or 4 clinical allergic reactions occurred in 8% of patients with hypersensitivity to native asparaginase and 2% of asparaginase-nonhypersensitive patients.1 About 56% of the hypersensitive patients in clinical trials for relapsed ALL were previously hypersensitive to asparaginase (Escherichia coli) and 44% were previously hypersensitive to both asparaginase (Escherichia coli) and asparaginase (Erwinia chrysanthemi).1 Therapy-limiting (i.e., requiring discontinuance of the respective drug) hypersensitivity reactions to pegaspargase occurred in 14% of patients in clinical trials who were previously hypersensitive to asparaginase (Escherichia coli) and in 26% of patients who were previously hypersensitive to both asparaginase (Escherichia coli) and asparaginase (Erwinia chrysanthemi).19 The incidence of therapy-limiting hypersensitivity reactions to pegaspargase in clinical trials was 9% overall (19% in asparaginase-hypersensitive patients and 3% in asparaginase-nonhypersensitive patients).19 Therapy-limiting anaphylactic reactions occurred in 1% of patients.19 The probability of a previously hypersensitive or nonhypersensitive patient completing 8 doses of pegaspargase therapy without developing a therapy-limiting hypersensitivity reaction was 77 and 95%, respectively.19,21

Hematologic Effects

Thrombosis,1,18,19 including superficial and deep-vein thrombosis,12,23,29 sagittal sinus thrombosis,1,12 thrombosis involving a central venous catheter,23,29 and stroke,25,29 is one of the most common adverse effects of pegaspargase and may be severe.1 In a randomized trial (DFCI 11-001) in children and adolescents receiving pegaspargase in combination chemotherapy as first-line therapy for ALL or lymphoblastic lymphoma, grade 3 or 4 embolic or thrombotic events occurred in 8% of patients.1 Thrombosis occurred in 4% of patients receiving the drug for relapsed ALL in clinical trials.1

Coagulopathy,15,16,29 sometimes severe, is a common adverse effect of pegaspargase.1 Among patients in a randomized trial receiving pegaspargase in combination chemotherapy as first-line therapy for ALL, grade 3 or 4 coagulopathy (prolonged prothrombin time [PT],1,16 prolonged partial thromboplastin time [PTT],1,16 or hypofibrinogenemia1,15,16,23,29 ) occurred in 2% of patients.1 In the DFCI 11-001 trial, grade 3 or 4 clotting test abnormalities (prolonged activated partial thromboplastin time, hypofibrinogenemia) occurred in 21% of patients receiving pegaspargase in combination chemotherapy.1 Decreased antithrombin III concentrations12,17,19,23,29 also have been reported in patients receiving pegaspargase.

Disseminated intravascular coagulation,12,29 clinical hemorrhage (which may be fatal and may include CNS hemorrhage),1,12,13,19,29 and decreases in plasma concentrations of protein C and protein S29 also have been reported.

In the DFCI 11-001 trial, grade 3 or 4 febrile neutropenia occurred in 40% of patients receiving pegaspargase in combination chemotherapy.1

Coagulation tests, including PT, PTT, and fibrinogen concentration, should be evaluated in patients with signs or symptoms of hemorrhage, and the need for appropriate clotting factor replacement therapy should be considered in patients with severe or symptomatic coagulopathy.1

Pancreatic Effects

Impairment of pancreatic function occurs frequently in patients receiving pegaspargase1,12,13,15,17,19 and may be caused by decreased insulin synthesis or necrosis and inflammation of the cells of the pancreas. Among patients in a randomized trial receiving pegaspargase in combination chemotherapy as first-line therapy for ALL, grade 3 or 4 pancreatitis occurred in 2% of patients.1 In a randomized trial (DFCI 11-001) in children and adolescents receiving pegaspargase in combination chemotherapy as first-line therapy for ALL or lymphoblastic lymphoma, grade 3 or 4 pancreatitis occurred in 24% of patients.1 Fatal cases of hemorrhagic or necrotizing pancreatitis have occurred.1

Pancreatitis1,12,13,15,17,19 occurred in 1% of patients receiving pegaspargase for relapsed ALL in clinical trials.1,19 An increased incidence of pancreatitis has been observed in some clinical trials in nonhypersensitive patients who received pegaspargase as part of combination chemotherapy regimens that resulted in prolonged asparagine depletion and included repeated intermediate-dose methotrexate or high-dose cytarabine.19 Increased serum amylase concentrations12,15,29 have occurred in patients receiving pegaspargase. Pancreatic cyst also has been reported in patients receiving pegaspargase.1

Serum amylase and/or lipase concentrations should be measured to confirm early signs of pancreatic inflammation.1 If pancreatitis is suspected, pegaspargase therapy should be withheld; if confirmed, therapy should be discontinued permanently.1

Metabolic Effects

Mild to severe hyperglycemia1,12,13,15,17,23 may occur in patients receiving pegaspargase. Glucose intolerance, sometimes irreversible, is a serious adverse effect of pegaspargase.1 Among patients in a randomized trial receiving pegaspargase in combination chemotherapy as first-line therapy for ALL, grade 3 or 4 hyperglycemia occurred in 5% of patients.1 In a randomized trial (DFCI 11-001) in children and adolescents receiving pegaspargase in combination chemotherapy as first-line therapy for ALL or lymphoblastic lymphoma, grade 3 or 4 hyperglycemia occurred in 24% of patients.1 Hyperglycemia requiring insulin therapy1,12,15,19 occurred in 3% of patients receiving the drug for relapsed ALL in clinical trials.1

Hypoproteinemia,12,13,19 hypoalbuminemia,16,19,29 hyperammonemia,1 and hypercholesterolemia1 also have been reported. In the DFCI 11-001 trial, grade 3 or 4 hypertriglyceridemia and hypoalbuminemia each occurred in 28-30% of patients receiving pegaspargase in combination chemotherapy.1

Hepatic Effects

Hyperbilirubinemia1,23 and elevated serum aminotransferase (ALT,1,12,16,17,19 AST1,12,16,17 ) concentrations are among the most common adverse effects of pegaspargase.1 Among patients in a randomized trial receiving pegaspargase in combination chemotherapy as first-line therapy for ALL, grade 3 or 4 increased serum aminotransferase (AST or ALT) concentrations occurred in 3% and grade 3 or 4 hyperbilirubinemia occurred in 2% of patients.1 In another randomized trial (DFCI 11-001) in children and adolescents receiving pegaspargase in combination chemotherapy as first-line therapy for ALL or lymphoblastic lymphoma, grade 3 or 4 increased serum aminotransferase (AST or ALT) concentrations occurred in 66% and grade 3 or 4 hyperbilirubinemia occurred in 25% of patients.1

Hepatotoxicity,1 jaundice,12,16,21 and abnormal liver function test results,21 including increased serum concentrations of bilirubin (direct and indirect),1,12,16 hypofibrinogenemia,1 and hypoalbuminemia1,21,29 (which may be associated with peripheral edema6,12,16,17 ), also have occurred in patients receiving pegaspargase.

Bilirubin and aminotransferase concentrations should be monitored at least weekly during treatment cycles including pegaspargase and for at least 6 weeks after the last dose of the drug.1 If serious hepatotoxicity occurs, pegaspargase should be discontinued and supportive care provided.1

GI Effects

Nausea,12,14,16,17,19,23 vomiting,12,16,17,19,23 abdominal pain,1,17 diarrhea,12,23 and constipation23 have occurred in patients receiving pegaspargase. Patients who experience abdominal pain should be evaluated for evidence of pancreatitis.1 (See Cautions: Pancreatic Effects.)

Nervous System Effects

CNS thrombosis1,22 (e.g., sagittal sinus thrombosis,1,12 stroke25 ) is one of the most common adverse effects of pegaspargase.1 Among patients in a randomized trial receiving pegaspargase in combination chemotherapy as first-line therapy for ALL, grade 3 or 4 CNS thrombosis occurred in 3% of patients.1,25 (See Cautions: Hematologic Effects.)

Peripheral neuritis,16 neuropathy,23 neurologic disorder,15 and dizziness12,14 also have been reported in patients receiving pegaspargase.

Cardiovascular Effects

Hypotension (which may be severe)1,12 occurred in patients receiving pegaspargase in clinical trials.

Immunologic Effects

Antibody formation has been detected in patients receiving pegaspargase.1 In one clinical trial, antibodies to the drug were detected in 2% of patients during induction therapy, in 10% of patients during the first phase of delayed intensification therapy, and in 11% of patients during the second phase of delayed intensification therapy.1 The effect of the development of binding antibodies on the pharmacokinetic disposition or antileukemic efficacy of pegaspargase or on the risk of clinical allergic reactions associated with such therapy has not been fully established.1

Other Effects

Fever,16,19 increased BUN,12,16 fatigue,12,23 pain in the extremities (which may be local or diffuse),12,16 injection site reactions (including pain, swelling, or erythema),12,16,19 and facial edema14 have occurred in patients receiving pegaspargase.

Precautions and Contraindications

Serious clinical allergic reactions to pegaspargase, including life-threatening anaphylaxis, may occur during therapy with the drug, particularly in patients with known hypersensitivity to other forms of asparaginase.1,3,12,19 Patients receiving pegaspargase should be informed of the possibility of serious allergic reactions, including life-threatening anaphylaxis, and should be monitored for 1 hour after administration of the drug.1,19 Appropriate agents for maintenance of an adequate airway and treatment of a hypersensitivity reaction, such as an antihistamine, epinephrine, oxygen, and IV corticosteroid, should be readily available whenever pegaspargase is administered.1,3,12,19 Pegaspargase should be discontinued if anaphylaxis or other serious allergic reaction occurs.1

Because of the risk of coagulopathy associated with pegaspargase therapy, coagulation tests (including fibrinogen concentration, PT, and PTT) should be evaluated in patients with signs or symptoms of hemorrhage, and the need for appropriate clotting factor replacement therapy should be considered in patients with severe or symptomatic coagulopathy.1

Pegaspargase should be discontinued if a serious thrombotic event occurs.1

Serum amylase and/or lipase concentrations should be measured to confirm early signs of pancreatic inflammation.1 If pancreatitis is suspected, pegaspargase therapy should be withheld; if confirmed, therapy should be discontinued permanently.1

Because of the potential for hyperglycemia, glucose concentrations should be monitored in patients receiving pegaspargase.1

Because pegaspargase may cause hepatotoxicity or abnormalities in hepatic function, bilirubin and aminotransferase concentrations should be monitored at least weekly during treatment cycles including pegaspargase and for at least 6 weeks after the last dose of the drug.1 If serious hepatotoxicity occurs, pegaspargase should be discontinued and supportive care provided.1

Patients should be advised to report immediately any possible manifestations of serious adverse effects, such as swellings or difficulty breathing (possibly serious allergic reactions); severe headache, arm or leg swelling, sudden shortness of breath, or chest pain (possibly thrombosis); severe abdominal pain (possibly pancreatitis); excessive thirst or increase in the volume or frequency of urination (possibly glucose intolerance); jaundice, severe nausea or vomiting, or easy bruising or bleeding (possible hepatotoxicity); or unusual bleeding or bruising.1

Pegaspargase is contraindicated in patients with a history of serious thrombosis associated with prior asparaginase therapy;1 patients with a history of pancreatitis, including pancreatitis associated with prior asparaginase therapy;1,12,19 patients who have had serious hemorrhagic events associated with prior asparaginase therapy;1,12,19 and patients who have had previous serious allergic reactions (including anaphylaxis) to the drug or any ingredient in the formulation.1

Pediatric Precautions

Safety and efficacy of pegaspargase for the treatment of ALL in pediatric patients are supported by evidence of efficacy as first-line treatment from one adequate and well-controlled clinical trial, evidence of efficacy in patients with hypersensitivity to asparaginase from 4 adequate and well-controlled clinical trials, and safety data from a total of 7 clinical trials.1 In these clinical trials, 26 infants, 165 children, and 39 adolescents received pegaspargase 2500 units/m².1

Geriatric Precautions

Clinical studies of pegaspargase did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.1

Mutagenicity and Carcinogenicity

The manufacturer states that studies to determine the mutagenic or carcinogenic potential of pegaspargase have not been performed to date.1

Pregnancy, Fertility, and Lactation

Pregnancy

There are no available data on use of pegaspargase in pregnant women to evaluate the drug-associated risk of major birth defects and spontaneous abortion.1 However, results of animal studies suggest that the drug may cause fetal harm if administered to pregnant women.1 Studies in pregnant rabbits administered L-asparaginase or deprived of dietary asparagine suggest that asparagine depletion may harm animal offspring.1

Pregnancy should be avoided during pegaspargase therapy.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of pegaspargase therapy.1 Women of childbearing potential should be advised to use effective methods of contraception, including a barrier method, while receiving pegaspargase and for at least 3 months after the last dose.1 Concomitant use of oral contraceptives and pegaspargase should be avoided.1 (See Drug Interactions: Oral Contraceptives.) Patients should be apprised of the potential fetal hazard if pegaspargase is used during pregnancy or if the patient becomes pregnant while receiving the drug.1

Fertility

Studies to determine the effects of pegaspargase on fertility have not been performed to date, and it is not known whether the drug can affect reproductive capacity.1

Lactation

It is not known whether pegaspargase is distributed into human milk.1,12,19 The effects of the drug on nursing infants and on milk production also are unknown.1 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to pegaspargase in nursing infants, women should be advised to discontinue nursing during pegaspargase therapy and for at least 3 months after the last dose.1

No formal studies of interactions between pegaspargase and other drugs have been conducted.1

During the period of its inhibition of protein synthesis and cell replication, pegaspargase may interfere with the action of other antineoplastic agents that require cell replication for their cytotoxic effects (e.g., methotrexate).21

Oral Contraceptives

Asparaginase-induced hepatotoxicity may impair hepatic clearance of oral contraceptives.41 Since there is a potential for an indirect interaction between pegaspargase and oral contraceptives, concomitant use of pegaspargase and oral contraceptives is not recommended.1

Pharmacokinetics

Pharmacokinetic assessments of pegaspargase are based on an enzymatic assay that measures asparaginase activity.1

Absorption

The relative bioavailability of pegaspargase following IM injection is 82% following the initial dose and 98% with repeat dosing.1 In pediatric patients receiving pegaspargase 2500 units/m² IM as first-line therapy for standard-risk ALL, plasma asparaginase concentrations exceeded 0.1 units/mL in more than 90% of samples for approximately 20 days in those receiving single doses of the drug during induction therapy and during both phases of delayed intensification therapy.1 The mean peak asparaginase concentration was approximately 1 unit/mL on day 5 after a single IM injection of pegaspargase 2500 units/m².1 The mean half-life of absorption from the IM injection site was 1.7 days.1

Following a single IV dose of pegaspargase 2500 units/m² during induction therapy, the mean peak plasma asparaginase concentration was 1.6 units/mL in pediatric patients and young adults with newly diagnosed high-risk B-precursor ALL.1,42 In 25 adults receiving a single dose of pegaspargase 2000 units/m² IV as part of a standard induction regimen of first-line therapy for ALL, the peak serum concentration of asparaginase enzymatic activity averaged 1 unit/mL.23 Serum trough asparaginase activity of 0.1 units/mL or greater correlates with asparagine depletion in CSF and serum, and has been established as a surrogate pharmacodynamic end point of asparaginase efficacy.44,45,47

Distribution

Following a single IM dose of pegaspargase 2500 units/m² in pediatric patients with newly diagnosed standard-risk ALL, the mean volume of distribution at steady state was estimated to be 1.86 L/m².1 Following a single IV dose of 2500 units/m² in pediatric patients and young adults with newly diagnosed high-risk B-precursor ALL, the mean volume of distribution at steady state was estimated to be 2 L.1,42 In 25 adults receiving a single dose of pegaspargase 2000 units/m² IV as part of a standard induction regimen of first-line therapy for ALL, the volume of distribution was 2.43 L/m² (equivalent to plasma volume).23

Asparaginase does not appear to cross the blood-brain barrier; however, CSF asparagine depletion occurs as a result of plasma asparagine depletion following treatment with the enzyme.48 It is not known whether pegaspargase is distributed into milk.1

Elimination

Following a single IM dose of pegaspargase 2500 units/m² in pediatric patients with newly diagnosed standard-risk ALL, the elimination half-life of pegaspargase was approximately 5.8 days.1 Following a single IV dose of 2500 units/m² in pediatric patients and young adults with newly diagnosed high-risk B-precursor ALL, the mean elimination half-life was approximately 5.3 days.1,42

In 25 adults receiving a single dose of pegaspargase 2000 units/m² IV as part of a standard induction regimen of first-line therapy for ALL, the elimination half-life was 7 days.23

The effect of renal or hepatic impairment on the pharmacokinetics of pegaspargase has not been established.1

Chemistry and Stability

Chemistry

Pegaspargase is an antineoplastic agent.1,2,3,4,5,6 The drug is prepared by conjugating covalently polyethylene glycol monomethyl ether (mPEG) to Escherichia coli -derived L-asparaginase, resulting in the formation of monomethoxy polyethylene glycol succinimidyl asparaginase (pegaspargase).1,2,3,5,6 The asparaginase component is a tetrameric enzyme that is produced endogenously by E. coli and consists of identical 34.5 kilodalton subunits.1 Approximately 69-82 molecules of mPEG are linked to the enzyme; the molecular weight of each mPEG molecule is about 5 kilodaltons.1 By modifying the nonconjugated (native) enzyme with mPEG, resultant pegaspargase has a reduced immunogenic potential and increased plasma half-life compared with native E. coli -derived asparaginase.1,2,3,4,5,6

Pegaspargase is commercially available as a clear, colorless, isotonic sterile solution that is preservative-free.1 Phosphate-buffered saline solution is added to adjust the pH to 7.3.1

The activity of pegaspargase is expressed in International Units (IU; units).1 Each 5-mL vial of the drug contains pegaspargase 3750 units.1

Stability

Pegaspargase injection should be stored at 2-8°C in the original carton to protect the drug from light.1 Pegaspargase injection should not be administered if the drug has been stored at room temperature (15-25°C) for more than 48 hours.1 Because pegaspargase injection contains no preservative, any unused portion should be discarded.1

Pegaspargase diluted solutions should be used immediately after the drug has been diluted for IV infusion.1 If immediate use is not possible, pegaspargase diluted solutions should be stored at 2-8°C.1 Storage after dilution of the drug should not exceed 48 hours.1 The diluted solution should be protected from direct sunlight.1

Pegaspargase injection or diluted solution should not be frozen or shaken.1

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs.

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