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  • CLASSES

    Other Antineoplastic Plant Alkaloids and Natural Products

    DEA CLASS

    Rx

    DESCRIPTION

    A modified version of E. coli L-asparaginase by covalently conjugating units of PEG to the enzyme.
    Used in combination chemotherapy for the treatment of ALL.
    Some cross-sensitivity with native L-asparaginase; however, most previously E. coli hypersensitive patients will tolerate pegaspargase.

    COMMON BRAND NAMES

    Oncaspar

    HOW SUPPLIED

    Oncaspar Intramuscular Inj Sol: 1mL, 750IU
    Oncaspar Intravenous Inj Sol: 1mL, 750IU

    DOSAGE & INDICATIONS

    For the treatment of acute lymphocytic leukemia (ALL).
    NOTE: The FDA has designated pegaspargase as an orphan drug for the treatment of ALL.
    For the treatment of newly diagnosed ALL, in combination with multi-agent chemotherapy.
    Intravenous or Intramuscular Dosage
    Adults older than 21 years

    2,000 units/m2 IV or IM in combination with multi-agent chemotherapy; repeat a single dose no more frequently than every 14 days. Monitor patients for signs and symptoms of infusion or hypersensitivity reactions. Therapy interruption or discontinuation may be necessary in patients who develop severe toxicity.[61310]

    Adults 21 years and younger, Adolescents, Children, and Infants

    2,500 units/m2 IV or IM in combination with multi-agent chemotherapy; repeat a single dose no more frequently than every 14 days. Monitor patients for signs and symptoms of infusion or hypersensitivity reactions. Therapy interruption or discontinuation may be necessary in patients who develop severe toxicity. The rate of depleted serum asparagine concentrations to 1 micromol or less and 3-year event-free survival rates were similar in pediatric patients aged 1 to 9 years with previously untreated, standard-risk ALL who received pegaspargase or native E. coli L-asparaginase intramuscularly as part of multi-agent chemotherapy in a multicenter, randomized study (n = 118; Study CCG-1962). Pegaspargase has been evaluated in pediatric patients aged 1 month to 17 years in clinical trials.

    For the treatment of ALL in patients who had hypersensitivity to native forms of L-asparaginase, in combination with multi-agent chemotherapy.
    Intravenous or Intramuscular Dosage
    Adults older than 21 years

    2,000 units/m2 IV or IM in combination with multi-agent chemotherapy; repeat a single dose no more frequently than every 14 days. Monitor patients for signs and symptoms of infusion or hypersensitivity reactions. Therapy interruption or discontinuation may be necessary in patients who develop severe toxicity. The re-induction response rate was 50% in patients with relapsed acute leukemia (n = 42; ALL, n = 39) and a prior hypersensitivity to native E. coli L-asparaginase who received pegaspargase as a single-agent or in combination with multi-agent chemotherapy in 4 studies. The complete response rate was 36%.

    Adults 21 years and younger, Adolescents, Children, and Infants

    2,500 units/m2 IV or IM in combination with multi-agent chemotherapy; repeat a single dose no more frequently than every 14 days. Monitor patients for signs and symptoms of infusion or hypersensitivity reactions. Therapy interruption or discontinuation may be necessary in patients who develop severe toxicity. The re-induction response rate was 50% in patients with relapsed acute leukemia (n = 42; ALL, n = 39) and a prior hypersensitivity to native E. coli L-asparaginase who received pegaspargase as a single-agent or in combination with multi-agent chemotherapy in 4 studies. The complete response rate was 36%. Pegaspargase has been evaluated in pediatric patients aged 1 month to 17 years in clinical trials.[61310]

    MAXIMUM DOSAGE

    Adults

    2500 IU/m2 IV/IM.

    Elderly

    2500 IU/m2 IV/IM.

    Adolescents

    2500 IU/m2 IV/IM.

    Children

    2500 IU/m2 IV/IM.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; however, these patients may be at increased risk for toxicity.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: Other products: L- Asparaginase Escherichia coli and and Asparaginase Erwinia chrysanthemi are discussed in separate monographs. Verify the selection of the correct product for the individual patient prior to administration to avoid medication errors.
     
    Due to the differences in formulation, L-asparaginase Escherichia coli and Asparaginase Erwinia chrysanthemi cannot be substituted for pegaspargase on a mg-per-mg basis (see Dosage).
     
    Administer this product in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. If a serious hypersensitivity reaction occurs, discontinue the drug and initiate appropriate therapy.
    CAUTION: Observe and exercise usual cautions for handling and preparing solutions of cytotoxic drugs.

    Injectable Administration

    Pegaspargase is administered by intramuscular injection or intravenous infusion. Intramuscular administration is preferred because of lower incidence of adverse effects such as allergic reactions, hepatotoxicity, coagulopathy, and gastrointestinal and renal disorders.
    Due to risk of hypersensitivity reactions, including life-threatening anaphylaxis, patients should be observed for at least one hour following administration of pegaspargase. Have equipment and medication to treat a reaction available.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    The vials are only for single-use. Discard unused portions, and only enter the vial once. The vials do not contain a preservative.
    Do not freeze. Do not use if cloudy or precipitate is present. Do not use if stored at room temperature for > 48 hours. DO NOT ADMINISTER PEGASPARGASE IF THERE IS ANY INDICATION THAT THE DRUG HAS BEEN FROZEN. Freezing destroys pegaspargase activity.

    Intravenous Administration

    Intravenous infusion:
    Dilute the contents of the commercially available vial in 100 ml of NS or D5W injection.
    Infuse IV over 1—2 hours through a freely running IV solution.

    Intramuscular Administration

    Intramuscular injection:
    No reconstitution or dilution necessary. Each 5 ml vial has 750 IU/ml of pegaspargase.
    Inject into a large muscle. Do not administer more than 2 ml IM at any one injection site. If amount is > 2 ml, administer at multiple injection sites. Aspirate prior to injection to avoid injection into a blood vessel.

    STORAGE

    Oncaspar:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Product should not be stored at room temperature for more than 48 hours
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: The active moiety of pegaspargase is L-asparaginase. L-Asparaginase Escherichia coli and Asparaginase Erwinia chrysanthemi are discussed in separate monographs, respectively.

    Acute bronchospasm, E. coli protein hypersensitivity, hypotension, urticaria

    Pegaspargase is contraindicated in patients who have had previous serious allergic reactions (e.g., urticaria, acute bronchospasm, laryngeal edema, or hypotension) or other unacceptable reactions to pegaspargase. Patients previously hypersensitive to native L-asparaginase (i.e., those with E. coli protein hypersensitivity) may be treated with pegaspargase; however, they are at increased risk for allergic reactions compared to non-hypersensitive patients. Monitor patients for 1 hour following administration of pegaspargase in a setting that has resuscitation equipment and other agents necessary for the treatment of anaphylactic reactions (e.g., epinephrine, oxygen, intravenous corticosteroids, antihistamines) readily available. Discontinue pegaspargase treatment in patients who experience anaphylaxis or other serious allergic reactions. Of 128 patients who received pegaspargase intramuscularly, a hypersensitivity reaction occurred in 30% of patients previously hypersensitive to native L-asparaginase as compared with 11% of non-hypersensitive patients. Data are limited regarding hypersensitivity likelihood after intravenous pegaspargase administration.

    Pancreatitis

    Pegaspargase is contraindicated in patients with pancreatitis, who develop pancreatitis during treatment, or with a history of pancreatitis with prior L-asparaginase therapy. Evaluate patients with abdominal pain during pegaspargase therapy; pancreatitis can occur during pegaspargase therapy. Discontinue pegaspargase in patients who develop pancreatitis.

    Bleeding

    Pegaspargase use is contraindication in patients with a history of serious bleeding events with prior L-asparaginase therapy.

    Thromboembolic disease

    Pegaspargase use is contraindication in patients with a history of serious thromboembolic disease with prior L-asparaginase therapy. Serious thrombotic events including sagittal sinus thrombosis may occur; discontinue pegaspargase therapy in patients who develop serious thrombotic events.

    Hyperglycemia

    Hyperglycemia has been reported with pegaspargase therapy; irreversible cases of glucose intolerance have occurred. Monitor patients for signs (e.g., serum glucose) and symptoms (e.g., excessive thirst or increase in the volume or frequency of urination) of glucose intolerance.

    Hepatotoxicity

    Hepatotoxicity including elevated hepatic enzymes (e.g., increased AST, ALT, and alkaline phosphatase levels), hyperbilirubinemia, hypoalbuminemia, and low plasma fibrinogen may occur with pegaspargase therapy. Hepatic function monitoring is recommended.

    Pregnancy

    Pegaspargase is classified as FDA pregnancy-risk category C. Animal reproductive studies have not been performed with pegaspargase. It is also not known if pegaspargase can cause fetal harm when administered to a pregnant woman or can affect fertility. Pegaspargase should be given to a pregnant woman only if clearly needed.

    Breast-feeding

    It is uncertain if pegaspargase is distributed into breast milk. The potential for serious adverse effects on the infant indicates that breast-feeding should be discontinued during pegaspargase therapy.

    ADVERSE REACTIONS

    Severe

    bronchospasm / Rapid / 3.0-32.0
    anaphylactoid reactions / Rapid / 3.0-32.0
    laryngeal edema / Rapid / 3.0-32.0
    elevated hepatic enzymes / Delayed / 3.0-11.0
    coagulopathy / Delayed / 2.0-7.0
    thrombosis / Delayed / 2.0-4.0
    pancreatitis / Delayed / 1.0-2.0
    hyperbilirubinemia / Delayed / 1.0-2.0
    intracranial bleeding / Delayed / 0-2.0

    Moderate

    hypotension / Rapid / 3.0-32.0
    erythema / Early / 3.0-32.0
    antibody formation / Delayed / 2.0-11.0
    hyperglycemia / Delayed / 3.0-5.0
    prolonged bleeding time / Delayed / 0-2.0
    hyperammonemia / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    hypoalbuminemia / Delayed / Incidence not known

    Mild

    urticaria / Rapid / 3.0-32.0
    rash / Early / 3.0-32.0

    DRUG INTERACTIONS

    Abciximab: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Alteplase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Anagrelide: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Anticoagulants: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Antithrombin III: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Apixaban: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Argatroban: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Aspirin, ASA; Dipyridamole: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Azelastine; Fluticasone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Beclomethasone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Betamethasone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Betrixaban: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Bivalirudin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Budesonide: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Budesonide; Formoterol: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    Celecoxib: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ciclesonide: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Cilostazol: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Clopidogrel: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Corticotropin, ACTH: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Cortisone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Cytarabine, ARA-C: (Major) Acute pancreatitis has been reported in patients being treated with cytarabine who have had prior treatment with L-asparaginase. This may be schedule dependent. L-asparaginase may have schedule-dependent synergy and antagonism with high-dose cytarabine. Similar reactions may occur with pegaspargase.
    Dabigatran: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Dalteparin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Danaparoid: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Deflazacort: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Desirudin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Dexamethasone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Diclofenac: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Dipyridamole: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Edoxaban: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Enoxaparin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Eptifibatide: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Esomeprazole; Naproxen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Etodolac: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Famotidine; Ibuprofen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Fludrocortisone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Flunisolide: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Flurbiprofen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fluticasone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Fluticasone; Salmeterol: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Fluticasone; Vilanterol: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Fondaparinux: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Formoterol; Mometasone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Heparin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Hydrocortisone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Ibuprofen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Indomethacin: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Ketoprofen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lansoprazole; Naproxen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lepirudin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Methotrexate: (Major) L-Asparaginase with methotrexate has shown both therapeutic synergistic and antagonistic effects depending upon the schedule of administration of these agents. When methotrexate is given 3-24 hours prior to L-Asparaginase Escherichia coli, the L-asparaginase blocks the antifolate effects of methotrexate and decreases methotrexate toxicity. If L-asparaginase is given prior to methotrexate, the efficacy of methotrexate is decreased. This could be due to inhibition of protein synthesis preventing progression to the S-phase of the cell cycle. Alternatively, L-asparaginase pretreatment may inhibit methotrexate polyglutamation, which is required for intracellular retention of methotrexate. Cells are refractory to methotrexate for up to 10 days following a single dose of L-asparaginase. During the period following L-asparaginase protein inhibition, there is a period of increased DNA synthesis that leads to increased sensitivity to methotrexate. Since the active component of pegaspargase is L-asparaginase, the same drug-drug interactions reported with L-asparaginase would be expected with pegaspargase. It is recommended to give L-asparaginase or pegaspargase at least 10-14 days prior to methotrexate or shortly after methotrexate administration.
    Methylprednisolone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Mometasone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Nabumetone: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Sumatriptan: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Oxaprozin: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentosan: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Piroxicam: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Platelet Inhibitors: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Prasugrel: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Prednisolone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Prednisone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Reteplase, r-PA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Rivaroxaban: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Rofecoxib: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Streptokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Sulindac: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Tenecteplase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Thrombolytic Agents: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Ticagrelor: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Ticlopidine: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Tinzaparin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Tirofiban: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Tolmetin: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Triamcinolone: (Moderate) Concomitant use of pegaspargase with corticosteroids can result in additive hyperglycemia. Insulin therapy may be required in some cases.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Urokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Valdecoxib: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Vincristine Liposomal: (Major) Administration of pegaspargase concurrently or prior to vincristine may result in decreased hepatic metabolism of vincristine and cause additive neurotoxicity. Administration of L-asparaginase after vincristine may lessen this effect; vincristine should be given 12 to 24 hours prior to L-asparaginase or pegaspargase.
    Vincristine: (Major) Administration of pegaspargase concurrently or prior to vincristine may result in decreased hepatic metabolism of vincristine and cause additive neurotoxicity. Administration of L-asparaginase after vincristine may lessen this effect; vincristine should be given 12 to 24 hours prior to L-asparaginase or pegaspargase.
    Vorapaxar: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Warfarin: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.

    PREGNANCY AND LACTATION

    Pregnancy

    Pegaspargase is classified as FDA pregnancy-risk category C. Animal reproductive studies have not been performed with pegaspargase. It is also not known if pegaspargase can cause fetal harm when administered to a pregnant woman or can affect fertility. Pegaspargase should be given to a pregnant woman only if clearly needed.

    It is uncertain if pegaspargase is distributed into breast milk. The potential for serious adverse effects on the infant indicates that breast-feeding should be discontinued during pegaspargase therapy.

    MECHANISM OF ACTION

    Mechanism of Action: The active moiety of pegaspargase is L-asparaginase. L-Asparaginase hydrolyzes L-asparagine to aspartic acid and ammonia, resulting in a rapid and complete depletion of L-asparagine; circulating glutamine levels are also reduced. L-asparagine is a nonessential amino acid synthesized from aspartic acid and glutamine by the enzyme asparagine synthetase. The E. coli enzyme is highly specific for L-asparagine and has < 10% activity for the D-isomer, N-acylated derivatives, or L-asparagine in peptide linkage. L-asparagine synthetase is constitutively expressed in many tissues but is lacking in certain malignancies, especially those of lymphoid origin. Cells lacking L-asparagine synthetase can only obtain asparagine by diffusion from extracellular fluids. The cytotoxicity of L-asparaginase results from inhibition of protein synthesis. Decreases in RNA and DNA synthesis are secondary to protein synthesis inhibition. Cell death is due to apoptosis, programmed cell death.Resistance to L-asparaginase is due to an increase in L-asparagine synthetase activity in the tumor cells. This is due to selection of a subpopulation of cells that contain L-asparaginase synthetase or by an increase in L-asparagine synthetase due to a decrease in intracellular levels of L-asparagine.

    PHARMACOKINETICS

    Pegaspargase is given intramuscularly (IM) or intravenously (IV). It is distributed mainly in the intravascular space, with minimal blood-brain barrier penetration. Despite poor penetration into the CNS, the concentration of L-asparagine within the CSF falls rapidly and an antileukemic effect is seen. The CNS effect is most likely due to rapid depletion of plasma L-asparagine. In one series of patients, investigators compared the effects of pegaspargase and E. coli L-asparaginase on CSF concentrations of asparagine. Among patients who did not have antibodies to asparaginase, those who received E. coli L-asparaginase had lower mean CSF asparagine concentrations as compared to those receiving pegaspargase. Similar results were also noted for plasma asparagine concentrations. A later study also examined asparagine concentrations following treatment with pegaspargase and this evaluation determined the treatment intensity of pegaspargase (2500 IU/m2 IV) achieved acceptable activity. However, complete depletion of CSF asparagine was not achieved. The authors note that the minimum asparagine concentration for leukemic cell growth has not been determined.
     
    The metabolism of L-asparaginase is unknown. L-Asparaginase was measurable for at least 15 days following initial treatment with pegaspargase. The enzyme was not detected in the urine. In pharmacokinetic studies, the half-life of pegaspargase was 3.24 +/- 1.83 days in 9 patients who were previously hypersensitive to native L-asparaginase and 5.69 +/- 3.25 days in 28 non-hypersensitive patients following IM administration.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  none

    Intramuscular Route

    In pharmacokinetic studies of pegaspargase, the area under the curve (AUC) values were similar between the two groups of patients: 9 patients who were previously hypersensitive to native L-asparaginase and 28 non-hypersensitive patients following IM administration.