(peg AS par jase)
Acute lymphoblastic leukemia and hypersensitivity to asparaginase: Treatment of acute lymphoblastic leukemia (ALL) in patients with hypersensitivity to native forms of L-asparaginase (as a component of a multiagent chemotherapy regimen)
Acute lymphoblastic leukemia, first-line: First-line treatment of ALL (as a component of a multiagent chemotherapy regimen)
History of serious allergic reactions to pegaspargase or any component of the formulation; history of any of the following with prior L-asparaginase treatment: serious thrombosis, pancreatitis, and/or serious hemorrhagic events
Acute lymphoblastic leukemia (ALL): IM, IV: 2500 units/m2 (as part of a combination chemotherapy regimen), do not administer more frequently than every 14 days
Refer to adult dosing.
Acute lymphoblastic leukemia (ALL): IM, IV: Refer to adult dosing.
There are no dosage adjustments provided in the manufacturer 's labeling.
There are no initial dosage adjustments provided in the manufacturer 's labeling. The following adjustments have been recommended (Stock 2011):
ALT/AST >3 to 5 times ULN: Continue therapy.
ALT/AST >5 to 20 times ULN: Delay next dose until transaminases <3 times ULN.
ALT/AST >20 times ULN: Discontinue therapy if it takes longer than 1 week for transaminases to return to < 3 times ULN.
Direct bilirubin <3 mg/dL: Continue therapy.
Direct bilirubin 3.1 to 5 mg/dL: Hold pegaspargase and resume when direct bilirubin <2 mg/dL; consider switching to alternate asparaginase product.
Direct bilirubin >5 mg/dL: Discontinue pegaspargase; do not substitute other asparaginase products; do not make up for missed doses.
IV: Dilute in 100 mL NS or D5W.
Have available appropriate agents for maintenance of an adequate airway and treatment of a hypersensitivity reaction (antihistamine, epinephrine, oxygen, IV corticosteroids). Be prepared to treat anaphylaxis at each administration.
IM: Must only be administered as a deep intramuscular injection into a large muscle. Do not exceed 2 mL per injection site; use multiple injection sites for IM injection volume >2 mL.
IV: Administer over 1 to 2 hours through a running IV infusion line; do not administer IV push.
Store intact vials at 2 ‚ °C to 8 ‚ °C (36 ‚ °F to 46 ‚ °F); do not freeze. Do not shake; protect from light. Discard vial if previously frozen, stored at room temperature for >48 hours, excessively shaken/agitated, or if cloudy, discolored, or if precipitate is present. If not used immediately, solutions diluted for infusion in NS or D5W should be protected from light, refrigerated at 2 ‚ °C to 8 ‚ °C (36 ‚ °F to 46 ‚ °F) and used within 48 hours (including administration time).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection [preservative free]:
Oncaspar: 750 units/mL (5 mL)
Stable in NS, D5W.
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Pegloticase: May diminish the therapeutic effect of Pegaspargase. Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination
CBC with differential, platelets, amylase/lipase, liver function tests (baseline and periodically during treatment), fibrinogen, PT, PTT (coagulation parameters [baseline and periodically during and after treatment]), renal function tests; urine glucose, blood glucose; triglycerides; vital signs during administration; monitor for onset of abdominal pain; observe for allergic reaction (for 1 hour after administration); signs/symptoms of thrombosis or bleeding
>10%:
Hepatic: Increased serum transaminases (ALT, AST; grades 3/4: 3% to 11%)
Hypersensitivity: Hypersensitivity reaction (grades 3/4: 1%, includes anaphylaxis, bronchospasm, erythema, hives, hypotension, laryngeal edema, skin rash, swelling, urticaria; relapsed acute lymphoblastic leukemia [ALL] with no prior asparaginase hypersensitivity: 10%; relapsed ALL with prior asparaginase hypersensitivity: 32%)
1% to 10%:
Cardiovascular: Thrombosis (4%)
Central nervous system: Cerebral thrombosis (or hemorrhage of the brain: 2%; grades 3/4: 3%)
Endocrine & metabolic: Hyperglycemia (3% [some patients required insulin therapy]; grades 3/4: 5%)
Gastrointestinal: Pancreatitis (1%; grades 3/4: 2% [includes 3 deaths])
Hematologic: Blood coagulation disorder (grades 3/4: 2% to 7%; includes prolonged prothrombin time or partial thromboplastin time or decreased serum fibrogen)
Hepatic: Abnormal hepatic function tests (grades 3/4: 5%), hyperbilirubinemia (grades 3/4: 1% to 2%)
Immunologic: Hypersensitivity to L-asparaginase (grades 3/4: 2%)
<1%(Limited to important or life-threatening): Abdominal pain, anemia, arthralgia, bronchospasm, chest pain, coagulation time increased, colitis, confusion, constipation, deep vein thrombosis, disseminated intravascular coagulation, dizziness, dyspnea, emotional lability, endocarditis, facial edema, gastrointestinal pain, headache, hemorrhagic cystitis, hepatic failure, hyperuricemia, hypoglycemia, increased thirst, lip edema, liver steatosis, myalgia, night sweats, ostealgia, pancytopenia, paresthesia, purpura, renal failure, sagittal sinus thrombosis, seizure, septic shock, superficial venous thrombosis
Concerns related to adverse effects:
- Allergic reactions: Anaphylaxis and serious allergic reactions (eg, bronchospasm, hypotension, laryngeal edema, local erythema or swelling, systemic rash, urticaria) may occur; discontinue in patients with serious allergic reaction. The risk of serious allergic reactions is increased in patients with a history of hypersensitivity reactions to other L-asparaginase products. Observe patients for 1 hour after administration; equipment and immediate treatment for hypersensitivity reactions should be available during administration.
- Coagulopathy: Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia may occur. Severe or symptomatic coagulopathy may require treatment with fresh-frozen plasma. Use cautiously in patients with an underlying coagulopathy or previous hematologic complications from asparaginase. Monitor coagulation parameters at baseline and periodically during and after therapy.
- Glucose intolerance: May cause glucose intolerance; irreversible in some cases. Use with caution in patients with diabetes mellitus and hyperglycemia. Monitor serum glucose.
- Hepatotoxicity: Altered liver function tests (eg, increased AST, ALT, alkaline phosphatase, bilirubin [direct and indirect], and decreased serum albumin, plasma fibrinogen) may occur with therapy. Use with caution in patients with pre-existing hepatic impairment. Monitor liver function tests at baseline and periodically during treatment.
- Pancreatitis: May occur; promptly evaluate patients with abdominal pain. The manufacturer recommends discontinuing pegaspargase if pancreatitis occurs during treatment. May consider continuing therapy for asymptomatic chemical pancreatitis (amylase or lipase >3 times ULN) or only radiologic abnormalities; monitor closely for rising amylase and/or lipase levels (Stock 2011). Discontinue permanently for clinical pancreatitis (eg, vomiting, severe abdominal pain) with amylase/lipase elevation >3 times ULN for >3 days and/or development of a pancreatic pseudocyst. Avoid alcohol use (Stock 2011).
- Thrombotic events: Serious thrombotic events, including sagittal sinus thrombosis may occur; discontinue with serious thrombotic event. Anticoagulation prophylaxis during therapy may be considered in some patients (Farge 2013).
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Other warnings/precautions:
- Administration route: In a study comparing IV pegaspargase to IM native E. coli asparaginase for post-induction treatment in children with ALL, 5-year disease-free survival did not differ and the overall frequency of asparaginase-related toxicities (including allergy, pancreatitis, and thrombotic or bleeding complications) did not differ between the IV pegaspargase and IM native E. coli apsaraginase groups. The median nadir serum asparaginase activity was significantly higher in the IV pegaspargase group. Reported treatment-related anxiety was significantly lower (for both patients and guardians) in the group that received IV pegaspargase (Place 2015).
- Medication error prevention: Do not interchange pegaspargase for asparaginase (E. coli) or asparaginase (Erwinia); ensure the proper asparaginase formulation, route of administration, and dose prior to administration.
C
Animal reproduction studies have not been conducted with pegaspargase.
Pegaspargase is a modified version of L-asparaginase, conjugated with polyethylene glycol. In leukemic cells, asparaginase hydrolyzes L-asparagine to ammonia and L-aspartic acid, leading to depletion of asparagine. Leukemia cells, especially lymphoblasts, require exogenous asparagine; normal cells can synthesize asparagine. Asparagine depletion in leukemic cells leads to inhibition of protein synthesis and apoptosis. Asparaginase is cycle-specific for the G1 phase of the cell cycle.
Not absorbed from the GI tract; therefore, requires parenteral administration; IM: Slow
Apparent Vd: Plasma volume: IM: Children: 1.5 L/m2; IV: Adults (asparaginase naive): 2.4 L/m2 (Douer 2007)
Systemically degraded
Clearance is unaffected by age, renal function, or hepatic function; not detected in urine
Asparagine depletion: IM: Within 4 days
IM: 3 to 4 days
Asparagine depletion: IV (in asparaginase naive adults): 2 to 4 weeks (Douer 2007); IM: ~21 days
IM: Children: 5.8 days; Adults: 5.5-6 days; 3.2 ‚ ± 1.8 days in patients who previously had a hypersensitivity reaction to native L-asparaginase
IV: Adults (asparaginase naive): 7 days (Douer 2007)
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Have patient report immediately to prescriber signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), injection site irritation, angina, coughing up blood, shortness of breath, severe headache, bruising, bleeding, vision changes, or confusion (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.