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PEGASPARGASE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pegaspargase is L-asparaginase (a tetrameric enzyme) that is covalently conjugated to monomethoxypolyethylene glycol (mPEG). L-asparaginase is derived from cultures of either Escherichia coli, Erwinia carotovora, or Vibrio succinogenes. It is used as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL).

Specific Substances

    1) PEG-L-asparaginase
    2) Pegaspargasa
    3) Pegaspargasum
    4) CAS 130167-69-0

Available Forms Sources

    A) FORMS
    1) Pegaspargase is available as 3750 International Units/5 mL solution for IV and IM routes (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    B) SOURCES
    1) Pegaspargase is L-asparaginase (a tetrameric enzyme) that is covalently conjugated to monomethoxypolyethylene glycol (mPEG) (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014). L-asparaginase is derived from cultures of either Escherichia coli, Erwinia carotovora, or Vibrio succinogenes (AMA Department of Drugs, 1991; MacEwen et al, 1987; Abuchowski et al, 1984).
    C) USES
    1) Pegaspargase is used as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Pegaspargase is used as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL).
    B) PHARMACOLOGY: Pegaspargase is L-asparaginase (a tetrameric enzyme) that is covalently conjugated to monomethoxypolyethylene glycol (mPEG). L-asparaginase is derived from cultures of either Escherichia coli, Erwinia carotovora, or Vibrio succinogenes. L-asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid by a reaction catalyzed by the enzyme L-asparagine synthetase. The ability to synthesize asparagine is notably lacking in malignancies of lymphoid origin; therefore, leukemic cells are dependent on an exogenous source of asparagine for survival. Asparaginase catalyzes the conversion of L-asparagine to aspartic acid and ammonia. The enzyme does not enter cells; instead, it degrades circulating asparagine to aspartic acid, which cannot be converted to asparagine by the leukemic cells. Rapid depletion of asparagine, which results from treatment with the enzyme L-asparaginase, kills the leukemic cells. However, normal cells are less affected by the rapid depletion due to their ability to synthesize asparagine. This therapeutic approach is based on a specific metabolic defect in some leukemic cells that do not produce asparagine synthetase.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON: Allergic reaction (including anaphylaxis), hyperglycemia, pancreatitis, CNS thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. OTHER ADVERSE EFFECTS include nausea, vomiting, abdominal pain, diarrhea, anorexia, rash, confusion, and seizures.
    E) WITH POISONING/EXPOSURE
    1) Overdose data is limited. After receiving 10,000 International Units/m(2) IV infusion of pegaspargase, one patient developed a slight increase in liver enzymes and another patient developed a rash about 10 minutes after the start of the infusion; no adverse effects developed in a third patient.
    0.2.20) REPRODUCTIVE
    A) Pegaspargase is classified as FDA category C. Due to lack of animal or human data, it is unknown whether pegaspargase can cause fetal harm or affect reproductive capacity. Therefore, pegaspargase should be used in pregnant women only if clearly necessary. It is unknown whether pegaspargase is excreted into human milk. Because of the possibility of infant risk, a decision should be made to discontinue pegaspargase or discontinue nursing after considering the importance of the drug to the nursing mother.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, human carcinogenicity studies have not been conducted.

Laboratory Monitoring

    A) Serum concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    B) Monitor vital signs, serum electrolytes, liver enzymes, CBC with differential, and coagulation parameters after an overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor blood glucose concentration and serum amylase in symptomatic patients.
    E) Monitor patients for sign and symptoms of thrombosis (eg, severe headache, arm or leg swelling, dyspnea, chest pain).

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Severe nausea and vomiting may respond to a combination of agents from different drug classes. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. If significant hyperglycemia occurs, careful blood glucose monitoring and insulin therapy might be required. Treat patients with severe or symptomatic coagulopathy with fresh-frozen plasma to replace coagulation factors.
    C) INTRATHECAL INJECTION
    1) No clinical reports of intrathecal injection with pegaspargase are available. This information was derived from experience with other antineoplastics. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative-free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative-free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    E) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions or persistent seizures.
    F) ANTIDOTE
    1) None
    G) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    H) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management.
    2) OBSERVATION CRITERIA: Patients who are symptomatic need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    J) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of pegaspargase. Patients taking pegaspargase may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects.
    K) PHARMACOKINETICS
    1) Vd: 2.1 L/m(2). Metabolism: Metabolism of pegaspargase appears to be similar to that of L-asparaginase, an agent that is inactivated by serum proteases, as well as immune and reticuloendothelial systems. Excretion: Pegaspargase was not detected in urine for up to 4 days following intravenous infusions to cancer patients. Elimination half-life: 3.2 to 5.8 days.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause seizures, hepatotoxicity, thrombosis, or coagulopathy.

Range Of Toxicity

    A) TOXICITY: After receiving 10,000 International Units/m(2) IV infusion of pegaspargase, one patient developed a slight increase in liver enzymes and another patient developed a rash about 10 minutes after the start of the infusion; no adverse effects developed in a third patient.
    B) THERAPEUTIC DOSE: ADULT AND PEDIATRIC: 2500 International Units/m(2) IM or IV, administered no more frequently than every 14 days.

Clinical Effects

Summary Of Exposure

    A) USES: Pegaspargase is used as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL).
    B) PHARMACOLOGY: Pegaspargase is L-asparaginase (a tetrameric enzyme) that is covalently conjugated to monomethoxypolyethylene glycol (mPEG). L-asparaginase is derived from cultures of either Escherichia coli, Erwinia carotovora, or Vibrio succinogenes. L-asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid by a reaction catalyzed by the enzyme L-asparagine synthetase. The ability to synthesize asparagine is notably lacking in malignancies of lymphoid origin; therefore, leukemic cells are dependent on an exogenous source of asparagine for survival. Asparaginase catalyzes the conversion of L-asparagine to aspartic acid and ammonia. The enzyme does not enter cells; instead, it degrades circulating asparagine to aspartic acid, which cannot be converted to asparagine by the leukemic cells. Rapid depletion of asparagine, which results from treatment with the enzyme L-asparaginase, kills the leukemic cells. However, normal cells are less affected by the rapid depletion due to their ability to synthesize asparagine. This therapeutic approach is based on a specific metabolic defect in some leukemic cells that do not produce asparagine synthetase.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON: Allergic reaction (including anaphylaxis), hyperglycemia, pancreatitis, CNS thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. OTHER ADVERSE EFFECTS include nausea, vomiting, abdominal pain, diarrhea, anorexia, rash, confusion, and seizures.
    E) WITH POISONING/EXPOSURE
    1) Overdose data is limited. After receiving 10,000 International Units/m(2) IV infusion of pegaspargase, one patient developed a slight increase in liver enzymes and another patient developed a rash about 10 minutes after the start of the infusion; no adverse effects developed in a third patient.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) In a randomized (1:1), active-controlled study (median age of 4.7 years; age range 1.1 to 9.9 years), CNS thrombosis developed in 2 (3%) of 58 patients receiving pegaspargase and 2 (3%) of 59 patients receiving native E. coli L-asparaginase. In an ongoing, multi-factorial design study with interim safety data for 2770 patients (median age of 4 years; age range 1 to 10 years), 2% of patients developed CNS thrombosis/hemorrhage after receiving pegaspargase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    B) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) In a phase II trial, severe confusion and disorientation resulting in discontinuation developed in 10% of patients with non-Hodgkin lymphoma receiving pegaspargase (2000 international units/m(2) IM every 2 weeks) (Muss et al, 1990)
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Grand mal seizures, without evidence of hemorrhagic or thrombotic event, occurred in a 33-year-old woman receiving pegaspargase for lymphoblastic lymphoma. Two days after completing the 2nd week of pegaspargase therapy (6000 Units/(m)2 IM 3 times weekly), she experienced a generalized seizure and brief loss of consciousness without loss of sphincter control; while hospitalized, she had another grand mal seizure with postictal drowsiness but no focal signs. She was treated with phenytoin for 1 month and pegaspargase was removed from the chemotherapy regimen (Hamdan et al, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) In a randomized (1:1), active-controlled study (median age of 4.7 years; age range 1.1 to 9.9 years), pancreatitis developed in 1 (2%) of 58 patients receiving pegaspargase and 1 (2%) of 59 patients receiving native E. coli L-asparaginase. In an ongoing, multi-factorial design study with interim safety data for 2770 patients (median age of 4 years; age range 1 to 10 years), 2% of patients developed pancreatitis after receiving pegaspargase. Three patients died after developing pancreatitis (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In a phase II trial, nausea developed in 50% of patients with non-Hodgkin lymphoma receiving pegaspargase (2000 international units/m(2) IM every 2 weeks) (Muss et al, 1990).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In a phase II trial, loss of appetite developed in 28% of patients with non-Hodgkin lymphoma receiving pegaspargase (2000 international units/m(2) IM every 2 weeks) (Muss et al, 1990).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a phase II trial, diarrhea developed in 38% of patients with non-Hodgkin lymphoma receiving pegaspargase (2000 international units/m(2) IM every 2 weeks) (Muss et al, 1990).
    E) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a phase II trial, abdominal pain developed in 33% of patients with non-Hodgkin lymphoma receiving pegaspargase (2000 international units/m(2) IM every 2 weeks) (Muss et al, 1990).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HYPERBILIRUBINEMIA
    1) WITH THERAPEUTIC USE
    a) In a randomized (1:1), active-controlled study (median age of 4.7 years; age range 1.1 to 9.9 years), hyperbilirubinemia developed in 1 (2%) of 58 patients receiving pegaspargase and 1 (2%) of 59 patients receiving native E. coli L-asparaginase. In an ongoing, multi-factorial design study with interim safety data for 2770 patients (median age of 4 years; age range 1 to 10 years), 1% of patients developed hyperbilirubinemia after receiving pegaspargase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    B) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) In a randomized (1:1), active-controlled study (median age of 4.7 years; age range 1.1 to 9.9 years), abnormal liver tests developed in 3 (5%) of 58 patients (aged 1.1 to 9.9 years) receiving pegaspargase and 5 (8%) of 59 patients receiving native E. coli L-asparaginase. Elevated transaminases developed in 2 (3%) of 58 patients receiving pegaspargase and 4 (7%) of 59 patients receiving native E. coli L-asparaginase. In an ongoing, multi-factorial design study with interim safety data for 2770 patients (median age of 4 years; age range 1 to 10 years), 11% of patients developed elevated transaminases after receiving pegaspargase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    2) WITH POISONING/EXPOSURE
    a) After receiving 10,000 International Units/m(2) IV infusion of pegaspargase, one patient developed a slight increase in liver enzymes (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLOOD COAGULATION DISORDER
    1) WITH THERAPEUTIC USE
    a) In a randomized (1:1), active-controlled study (median age of 4.7 years; age range 1.1 to 9.9 years), coagulopathy (prolonged prothrombin time or partial thromboplastin time, or hypofibrinogenemia) developed in 1 (2%) of 58 patients receiving pegaspargase and 3 (5%) of 59 patients receiving native E. coli L-asparaginase. In an ongoing, multi-factorial design study with interim safety data for 2770 patients (median age of 4 years; age range 1 to 10 years), 7% of patients developed coagulopathy after receiving pegaspargase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    B) THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) Serious thrombotic events, including sagittal sinus thrombosis, have occurred in patients receiving pegaspargase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014)
    C) GRANULOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Granulocytopenic disorder has been reported in patients with non-Hodgkin lymphoma receiving pegaspargase 2000 international units/m(2) every 2 weeks (Muss et al, 1990)

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) After receiving 10,000 International Units/m(2) IV infusion of pegaspargase, a rash developed in one patient about 10 minutes after the start of the infusion (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) In a randomized (1:1), active-controlled study (median age of 4.7 years; age range 1.1 to 9.9 years), hyperglycemia developed in 3 (5%) of 58 patients receiving pegaspargase and 2 (3%) of 59 patients receiving native E. coli L-asparaginase. In an ongoing, multi-factorial design study with interim safety data for 2770 patients (median age of 4 years; age range 1 to 10 years), 5% of patients developed hyperglycemia after receiving pegaspargase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reactions, including anaphylaxis, are among the most common adverse reactions reported following the use of pegaspargase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014)
    b) Allergic reaction may include bronchospasm, hypotension, laryngeal edema or swelling, local erythema, systemic rash, or urticaria (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014)
    c) Risk of serious allergic reaction is higher in patients with known hypersensitivity to other forms of L-asparaginase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    d) In a randomized (1:1), active-controlled study (median age of 4.7 years; age range 1.1 to 9.9 years), acute allergic reaction to asparaginase developed in 1 (2%) of 58 patients receiving pegaspargase and 0 of 59 patients receiving native E. coli L-asparaginase. In an ongoing, multi-factorial design study with interim safety data for 2770 patients (median age of 4 years; age range 1 to 10 years), 1% of patients developed acute allergic reaction after receiving pegaspargase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Pegaspargase is classified as FDA category C. Due to lack of animal or human data, it is unknown whether pegaspargase can cause fetal harm or affect reproductive capacity. Therefore, pegaspargase should be used in pregnant women only if clearly necessary. It is unknown whether pegaspargase is excreted into human milk. Because of the possibility of infant risk, a decision should be made to discontinue pegaspargase or discontinue nursing after considering the importance of the drug to the nursing mother.
    3.20.2) TERATOGENICITY
    A) BONE MARROW HYPOPLASIA
    1) Asparaginase use during pregnancy has been reported in 6 cases. All cases involved other chemotherapeutic agents in addition to asparaginase. Of the 7 infants born (one set of twins), 2 infants had transient bone marrow hypoplasia (Okun et al, 1979; Khurshid & Saleem, 1978), and 1 infant had chromosomal gaps and a ring chromosome (Schleuning & Clemm, 1987).
    B) ANIMAL STUDIES
    1) Pegaspargase is an analog of asparaginase, which is teratogenic in animals (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013). No animal studies have been performed with pegaspargase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Pegaspargase is classified as FDA category C (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    2) Due to lack of animal or human data, it is unknown whether pegaspargase can cause fetal harm or affect reproductive capacity. Therefore, pegaspargase should be used in pregnant women only if clearly necessary (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    B) ANTINEOPLASTIC AGENTS
    1) In general, antineoplastic agents when given during the first trimester are believed to cause increases in the risk of congenital malformations, but when given during the second or third trimesters are believed to only increase the risk of growth retardation (Glantz, 1994; Doll et al, 1988).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether pegaspargase is excreted into human milk. Because of the possibility of infant risk, a decision should be made to discontinue pegaspargase or discontinue nursing after considering the importance of the drug to the nursing mother (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) Studies on the effects of pegaspargase on fertility have not been conducted (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, human carcinogenicity studies have not been conducted.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, animal carcinogenicity studies have not been conducted (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

Genotoxicity

    A) In tests against Salmonella typhimurium strains in the Ames assay, pegaspargase did not produce any mutagenic effects (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    B) Monitor vital signs, serum electrolytes, liver enzymes, CBC with differential, and coagulation parameters after an overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor blood glucose concentration and serum amylase in symptomatic patients.
    E) Monitor patients for sign and symptoms of thrombosis (eg, severe headache, arm or leg swelling, dyspnea, chest pain).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no role for home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients who are symptomatic need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Serum concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    B) Monitor vital signs, serum electrolytes, liver enzymes, CBC with differential, and coagulation parameters after an overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor blood glucose concentration and serum amylase in symptomatic patients.
    E) Monitor patients for sign and symptoms of thrombosis (eg, severe headache, arm or leg swelling, dyspnea, chest pain).

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Refer to the PARENTERAL EXPOSURE section for treatment recommendations.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: After receiving 10,000 International Units/m(2) IV infusion of pegaspargase, one patient developed a slight increase in liver enzymes and another patient developed a rash about 10 minutes after the start of the infusion; no adverse effects developed in a third patient.
    B) THERAPEUTIC DOSE: ADULT AND PEDIATRIC: 2500 International Units/m(2) IM or IV, administered no more frequently than every 14 days.

Therapeutic Dose

    7.2.1) ADULT
    A) 2,500 International units/m(2) IM/IV administered no more frequently than every 14 days (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    1) IM ROUTE: Single IM injection volume should not exceed 2 mL per injection site. Multiple injection sites should be used if the injection volume is greater than 2 mL (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    2) IV ROUTE: Infused over a period of 1 to 2 hours in 100 mL of normal saline (sodium chloride 0.9%) or D5W (dextrose 5% water) into a flowing IV line (Prod Info ONCASPAR(R) IM injection, 2006).
    7.2.2) PEDIATRIC
    A) 2,500 International units/m(2) IM/IV administered no more frequently than every 14 days (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    1) IM ROUTE: Single IM injection volume should not exceed 2 mL per injection site. Multiple injection sites should be used if the injection volume is greater than 2 mL (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).
    2) IV ROUTE: Infused over a period of 1 to 2 hours in 100 mL of normal saline (sodium chloride 0.9%) or D5W (dextrose 5% water) into a flowing IV line (Prod Info ONCASPAR(R) IM injection, 2006).

Maximum Tolerated Exposure

    A) After receiving 10,000 International Units/m(2) IV infusion of pegaspargase, one patient developed a slight increase in liver enzymes and another patient developed a rash about 10 minutes after the start of the infusion; no adverse effects developed in a third patient (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Pegaspargase is L-asparaginase (a tetrameric enzyme) that is covalently conjugated to monomethoxypolyethylene glycol (mPEG) (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014). L-asparaginase is derived from cultures of either Escherichia coli, Erwinia carotovora, or Vibrio succinogenes (AMA Department of Drugs, 1991; MacEwen et al, 1987; Abuchowski et al, 1984). L-asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid by a reaction catalyzed by the enzyme L-asparagine synthetase. The ability to synthesize asparagine is notably lacking in malignancies of lymphoid origin (De Vita et al, 1997; Plesnicar et al, 1976); therefore, leukemic cells are dependent on an exogenous source of asparagine for survival (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014; De Vita et al, 1997). Asparaginase catalyzes the conversion of L-asparagine to aspartic acid and ammonia. The enzyme does not enter cells; instead, it degrades circulating asparagine to aspartic acid, which cannot be converted to asparagine by the leukemic cells (De Vita et al, 1997). Rapid depletion of asparagine, which results from treatment with the enzyme L-asparaginase, kills the leukemic cells. However, normal cells are less affected by the rapid depletion due to their ability to synthesize asparagine (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014). This therapeutic approach is based on a specific metabolic defect in some leukemic cells that do not produce asparagine synthetase (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014; Burnham, 1994).

Physicochemical

Physical Characteristics

    A) A clear, colorless, preservative-free, isotonic sterile solution in phosphate-buffered saline (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

Molecular Weight

    A) L-asparaginase consists of identical 35 kDa subunits, covalently conjugated to about 69 to 82 molecules of monomethoxypolyethylene glycol (mPEG), with molecular weight of each molecule being about 5 kDa (Prod Info Oncaspar(R) intramuscular injection, intravenous injection, 2014).

References

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    42) Product Information: promethazine hcl rectal suppositories, promethazine hcl rectal suppositories. Perrigo, Allegan, MI, 2007.
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