Asparaginase Erwinia chrysanthemi is an asparagine specific enzyme indicated in combination with multi-agent chemotherapy in adult and pediatric patients who have developed hypersensitivity to Escherichia (E.) coli-derived asparaginase. Asparaginase Erwinia chrysanthemi (Erwinaze) was approved for use in patients aged 1 year and older with acute lymphoblastic leukemia (ALL); it may replace a dose of the modified version of E. coli L-asparaginase (pegaspargase) or a dose of native E. coli asparaginase (L-asparaginase). However, this product was discontinued from the US market in July 2021. Asparaginase Erwinia chrysanthemi (recombinant)-rwyn (Rylaze) is approved for use in patients aged 1 month and older with ALL or lymphoblastic lymphoma; it may replace a long-acting asparaginase product. Asparaginase Erwinia chrysanthemi is contraindicated in patients with severe hepatic impairment, a history of serious hypersensitivity reactions to Erwinia asparaginase , or who have a history of serious pancreatitis, serious thrombosis, or serious bleeding events with prior asparaginase therapy. Due to a critical shortage of FDA-approved Erwinaze, a non-FDA licensed product from the United Kingdom, Erwinase (crisantaspase), was made available in the United States in June 2020. Crisantaspase is British Approved Name (BAN) for asparaginase obtained from Erwinia chrysanthemi. It is indicated in combination with multi-agent chemotherapy in pediatric patients aged 4 months and older and adults who have developed hypersensitivity to E. coli-derived asparaginase There are differences in the FDA-approved Erwinaze and United Kingdom Erwinase product labeling.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Erwinase
Reconstitution:
-Slowly inject 1 or 2 mL of preservative free sterile 0.9% Sodium Chloride injection against the inner vial wall. Do not forcefully inject solution directly onto or into the powder.
-If 1 mL of 0.9% Sodium Chloride is used, the resultant concentration is 10,000 International Units per mL.
-If 2 mL of 0.9% Sodium Chloride is used, the resultant concentration is 5,000 International Units per mL.
-Dissolve contents by gentle mixing or swirling; do not shake or invert the vial.
-The reconstituted solution should be clear and colorless; discard if any visible particles or protein aggregates are present.
-Storage: Do not freeze or refrigerate the reconstituted solution. Withdraw the calculated dose within 15 minutes of reconstitution; discard any unused portion of the vial(s).
Dilution:
-Withdraw the calculated dose/volume from the reconstituted vial using a polypropylene syringe.
-Slowly inject the dose into an IV infusion bag containing 100 mL of 0.9% Sodium Chloride injection that has been acclimatized to room temperature; do not shake or squeeze the IV bag.
Intravenous infusion:
-Infuse the diluted solution over 1 to 2 hours; administer within 4 hours from vial reconstitution.
-Do not infuse other IV drugs through the same line.
Intramuscular Administration
-Limit the volume to 2 mL per injection site; multiple injection sites may be needed.
-Discard any unused portion of the vial(s).
-Divide the doses equally into multiple syringes if the volume to be administered is greater than 2 mL.
-Rotate injection sites and do not inject into scar tissue or areas that are reddened, inflamed, or swollen.
Erwinase
-Erwinase is available as a 10,000 International Units lyophilized powder that requires vial reconstitution prior to administration.
Reconstitution:
-Slowly inject 1 or 2 mL of preservative free sterile 0.9% Sodium Chloride injection against the inner vial wall. Do not forcefully inject solution directly onto or into the powder.
--If 1 mL of 0.9% Sodium Chloride is used, the resultant concentration is 10,000 International Units per mL.
-If 2 mL of 0.9% Sodium Chloride is used, the resultant concentration is 5,000 International Units per mL.
-Dissolve contents by gentle mixing or swirling; do not shake or invert the vial.
-The reconstituted solution should be clear and colorless; discard if any visible particles or protein aggregates are present.
-Storage: Do not freeze or refrigerate the reconstituted solution. Withdraw the calculated dose within 15 minutes of reconstitution; discard any unused portion of the vial(s).
Intramuscular injection:
-Withdraw the calculated dose/volume from the reconstituted vial using a polypropylene syringe.
-Inject the dose intramuscularly; administer within 4 hours from vial reconstitution.
Rylaze
-Rylaze is available as a 10 mg per 0.5 mL single-dose solution vial; do not shake the vial.
Intramuscular injection:
-Withdraw the calculated dose/volume from the solution vial(s) into a syringe.
-Storage: Use immediately or store the syringe at room temperature (15 to 25 degrees C; 59 to 77 degrees F) for up to 8 hours or refrigerated (2 to 8 degrees C; 36 to 46 degrees F) for up to 24 hours.
-Inject the dose intramuscularly.
Anti-drug antibodies developed in 47% of patients who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) in a clinical study (n = 166). Antibody formation occurred in 11% and 13.3% of patients who received asparaginase Erwinia chrysanthemi (Erwinaze) IM (n = 56) and IV (n = 30), respectively. Hypersensitivity reactions occurred in 1 patient (2%) who developed antibodies after IM administration and in 3 patients (10%) who developed antibodies after IV administration. None of the patients developed neutralizing antibodies.
Gastrointestinal adverse events including abdominal pain (25/25/25 arm: 21%; 25/25/50 arm: 25%; grade 3 or 4, 2%), anorexia/decreased appetite (25/25/25 arm: 21%; grade 3 or 4, 6%; 25/25/50 arm: 27%; grade 3 or 4, 6%), diarrhea (25/25/25 arm: 18%; grade 3 or 4, 6%; 25/25/50 arm: 25%; grade 3 or 4, 4%) including colitis, nausea (25/25/25 arm: 45%; grade 3 or 4, 9%; 25/25/50 arm: 47%; grade 3 or 4, 8%) including vomiting, and stomatitis (25/25/25 arm: 24%; grade 3 or 4, 12%; 25/25/50 arm: 27%; grade 3 or 4, 4%) were reported in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (25/25/25 arm, n = 33) or 50 mg/m2 (25/25/50 arm, n = 51) IM on Friday for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen. Additionally, abdominal discomfort, abdominal distension, constipation, and gastritis each occurred in less than 15% of patients who received recombinant asparaginase Erwinia chrysanthemi in combination with chemotherapy. Abdominal pain/discomfort (1%; grade 3 or 4, 0.3%), diarrhea (1%), mucositis (1%), nausea (2%; grade 3 or 4, 0.3%), and vomiting (3%; grade 3 or 4, 0.3%) occurred in patients with ALL or LBL who received IV or IM asparaginase Erwinia chrysanthemi (Erwinaze) in a clinical trial (n = 940).
Increased glucose level has been reported with asparaginase Erwinia chrysanthemi use. Monitor glucose levels prior to treatment every 2 to 3 weeks and as clinically indicated during asparaginase Erwinia chrysanthemi therapy. If increased blood glucose occurs, monitor patients until recovery from the therapy cycle. Hyperglycemia occurred in 21% (grade 3 or 4, 3%) and 12% (grade 3 or 4, 4%) of patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (n = 33) or 50 mg/m2 (n = 51) IM on Friday, respectively, for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen. Additionally, hypoglycemia was reported in less than 15% of patients in this trial. Hyperglycemia occurred in 3.7% (grade 3 or 4, 3.5%) of patients with ALL or LBL who received IV or IM asparaginase Erwinia chrysanthemi (Erwinaze) in a clinical trial (n = 940). In all clinical trials, the overall incidence of glucose intolerance was 5%. Irreversible glucose intolerance may occur; treat patients who develop hyperglycemia with insulin if necessary.
Bleeding and prolonged bleeding time have been reported with asparaginase Erwinia chrysanthemi use. Evaluate patients who develop bleeding for coagulopathy. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy. An interruption of therapy may be necessary in patients who develop severe bleeding. Bleeding (25%; grade 3 or 4, 2%) including bruising (12%) and nosebleed/epistaxis (9%) occurred in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) in combination with chemotherapy in a multi-cohort trial (n =167). The term bleeding included rectal/GI bleeding, catheter-site hemorrhage, petechiae, hematochezia, menorrhagia, and mouth hemorrhage. Decreased fibrinogen level/hypofibrinogenemia and prolonged activated partial thromboplastin time (PTT) each occurred in less than 15% of patients who received Rylaze in combination with chemotherapy. Bleeding disorder occurred in 1% (grade 3 or 4, 0.1%) of patients with ALL or LBL who received IV or IM asparaginase Erwinia chrysanthemi (Erwinaze) in a clinical trial (n = 940). Fibrinogen levels decreased in most patients after a 2-week course of Erwinaze.
Hepatotoxicity has been reported with asparaginase Erwinia chrysanthemi use. Veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) was reported in postmarketing surveillance of recombinant asparaginase Erwinia chrysanthemi. Severe, life-threatening, and potentially fatal cases of hepatic VOD have occurred in patients treated with asparaginase class products in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy. In patients who develop elevated hepatic enzymes during therapy, increase the frequency monitoring of liver function tests and for clinical signs and symptoms of VOD/SOS. Therapy interruption or permanent discontinuation may be necessary in patients who develop hepatotoxicity; provide supportive care as indicated. Elevated hepatic enzymes (4%; grade 3 or 4, less than 1%), hyperbilirubinemia (0.9%; grade 3 or 4, 0.1%), and hyperammonemia (0.7%) occurred in patients with ALL or LBL who received IV or IM asparaginase Erwinia chrysanthemi (Erwinaze) in a clinical trial (n = 940).
Thromboembolism/thromboembolic events have been reported with asparaginase Erwinia chrysanthemi use. Evaluate patients who develop clotting for coagulopathy. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy. Therapy interruption or permanent discontinuation may be necessary in patients who develop clotting. Treat thromboembolic events with appropriate antithrombotic therapy. Serious thrombotic events including sagittal sinus thrombosis and pulmonary embolism (PE) (1%) and decreased antithrombin III level (less than 15%) occurred in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) in combination with chemotherapy in a multi-cohort trial (n =167). Thrombosis (e.g., cerebrovascular accident/stroke and PE) occurred in 2% (grade 3 or 4, less than 1%) of patients with ALL or LBL who received IV or IM asparaginase Erwinia chrysanthemi (Erwinaze) in a clinical trial (n = 940). Asparaginase-related clotting factor deficiency may occur. Protein C activity, protein S activity, and antithrombin III were decreased in most patients after a 2-week course of Erwinaze.
Peripheral neuropathy (25/25/25 arm: 15%; 25/25/50 arm: 6%) and headache (25/25/25 arm: 36%; 25/25/50 arm: 22%) were reported in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (25/25/25 arm, n = 33) or 50 mg/m2 (25/25/50 arm, n = 51) on Friday for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen. Additionally, paresthesias, dizziness, gait disturbance, and hyperammonemic encephalopathy were each reported in less than 15% of patients who received recombinant asparaginase Erwinia chrysanthemi in combination with chemotherapy.
Pancreatitis has been reported with asparaginase Erwinia chrysanthemi use. Evaluate patients who have signs or symptoms of pancreatitis and obtain serum amylase and lipase levels. Therapy interruption or permanent discontinuation may be necessary in patients who develop pancreatitis. Pancreatitis (20%; grade 3 or 4, 8%) including symptomatic pancreatitis (7%; grade 3 or 4, 6%) and elevated amylase level/hyperamylasemia or elevated lipase level without symptomatic pancreatitis (13%) occurred in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) in combination with chemotherapy in a multi-cohort trial (n =167). Pancreatitis occurred in 12% and 22% (grade 3 or 4, 10%) of patients who received Rylaze 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (n = 33) or 50 mg/m2 (n = 51) IM on Friday, respectively, for 6 doses to replace a single dose of pegaspargase in this trial. Hemorrhagic or necrotizing pancreatitis have been reported with asparaginase class products. Pancreatitis occurred in 4% (grade 3 or 4, less than 1%) of patients with ALL or LBL who received IV or IM asparaginase Erwinia chrysanthemi (Erwinaze) in a clinical trial (n = 940). In all clinical trials, the overall incidence of pancreatitis was also 4%.
Dehydration occurred in 15% (grade 3 or 4, 9%) and 12% (grade 3 or 4, 6%) of patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (n = 33) or 50 mg/m2 (n = 51) IM on Friday, respectively, for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen.
Infection (25/25/25 arm: 36%; grade 3 or 4, 15%; 25/25/50 arm: 27%; grade 3 or 4, 17%), fever (25/25/25 arm: 30%; grade 3 or 4, 6%; 25/25/50 arm: 20%), and febrile neutropenia (25/25/25 arm: grade 3 or 4, 30%; 25/25/50 arm: grade 3 or 4, 27%) were reported in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (25/25/25 arm, n = 33) or 50 mg/m2 (25/25/50 arm, n = 51) on Friday for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen. Additionally, viral, bacterial, and fungal infections were each reported in less than 15% of patients in thi trial. One patient died due to infection. The term infection included sepsis, upper respiratory tract infection, infectious enterocolitis, skin infection, bacteremia, paronychia, pneumonia, otitis externa, soft tissue infection, abdominal infection, conjunctivitis, device-related infection, folliculitis, lymph gland infection, necrotizing fasciitis, perirectal abscess, peritonsillar abscess, sinusitis, subcutaneous abscess, and wound infection. Fever occurred in 4% of patients with ALL or LBL who received IV or IM asparaginase Erwinia chrysanthemi (Erwinaze) in a clinical trial (n = 940).
Musculoskeletal pain occurred in 45% (grade 3 or 4, 6%) and 35% (grade 3 or 4, 4%) of patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (n = 33) or 50 mg/m2 (n = 51) IM on Friday, respectively, for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen. Pain, bone pain, muscular weakness, and muscle cramps/spasm each occurred in less than 15% of patients in this trial. The term musculoskeletal pain included arthralgia, back pain, musculoskeletal chest pain, myalgia, and extremity pain.
Fatigue including asthenia occurred in 36% (grade 3 or 4, 18%) and 22% (grade 3 or 4, 18%) of patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (n = 33) or 50 mg/m2 (n = 51) IM on Friday, respectively, for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen.
Insomnia occurred in 15% and 4% of patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (n = 33) or 50 mg/m2 (n = 51) IM on Friday, respectively, for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen. Additionally, agitation, anxiety, and irritability each occurred in less than 15% of patients in this trial.
Cough occurred in 15% and 14% of patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (n = 33) or 50 mg/m2 (n = 51) IM on Friday, respectively, for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen. Additionally, acute respiratory distress syndrome (ARDS) and pulmonary edema each occurred in less than 15% of patients in this trial.
Tachycardia/sinus tachycardia occurred in 18% and 16% (grade 3 or 4, 2%) of patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (n = 33) or 50 mg/m2 (n = 51) IM on Friday, respectively, for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen. Additionally, hypotension and hypertension were each reported in less than 15% of patients in this trial.
Metabolic acidosis occurred in less than 15% of patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) in combination with chemotherapy in a multi-cohort trial.
Infusion-related reactions and injection site reaction were each reported in less than 15% of patients (median age, 10 [range, 1 to 25] years) with acute lymphocytic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) in combination with chemotherapy in a multi-cohort trial.
Nephrotoxicity, specifically acute kidney injury, was reported in less than 15% of patients (median age, 10 [range, 1 to 25] years) with acute lymphocytic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) in combination with chemotherapy in a multi-cohort trial.
Pruritus occurred in less than 15% of patients with acute lymphocytic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) in combination with chemotherapy in a multi-cohort trial.
Hypokalemia occurred in 9% (grade 3 or 4, 3%) and 22% (grade 3 or 4, 8%) of patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) 25 mg/m2 IM on Monday and Wednesday and either 25 mg/m2 (n = 33) or 50 mg/m2 (n = 51) IM on Friday, respectively, for 6 doses to replace a single dose of pegaspargase in a multi-cohort trial. All patients received Rylaze in combination with a multi-agent chemotherapy regimen. Additionally, hyperphosphatemia was reported in less than 15% of patients in this trial.
Hypersensitivity reactions have been reported with asparaginase Erwinia chrysanthemi use. Treat life-threatening anaphylaxis/anaphylactoid reactions (e.g., epinephrine, oxygen, corticosteroids, antihistamines) promptly. Permanently discontinue therapy if a severe hypersensitivity reaction occurs; initiate appropriate treatment. Premedicate patients with acetaminophen, an H-1 receptor blocker (e.g., diphenhydramine), and an H-2 receptor blocker (e.g., famotidine) prior to the Rylaze intramuscular injection to decrease the risk and severity of hypersensitivity reactions. Provide symptomatic treatment in patients who develop a grade 2 hypersensitivity reaction. Hypersensitivity reaction (29%; grade 3 or 4, 6%) including anaphylactoid reaction (2%) and rash (19%; grade 3 or 4, 1%) occurred in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) in combination with chemotherapy in a multi-cohort trial (n =167). The term hypersensitivity reaction included rash, maculopapular rash, infusion-related reactions, lip swelling, periorbital edema, throat irritation, urticaria, dry skin/xerosis, eczema, erythema, and hand dermatitis. Other reactions that have occurred with asparaginase class products include angioedema, eye swelling, hypotension, bronchospasm, dyspnea, and pruritus. In clinical trials, the median number of Rylaze doses prior to the onset of the first hypersensitivity reaction was 12 (range, 1 to 64) doses. Systemic hypersensitivity reactions (16%; grade 3 and 4, 4%) including anaphylactoid reactions (less than 1%) and local reactions (3%) occurred in patients with ALL or lymphoblastic lymphoma LBL who received IV or IM asparaginase Erwinia chrysanthemi (Erwinaze) in a clinical trial (n = 940). In all clinical trials, the overall incidence of grade 3 or 4 hypersensitivity reactions was 5%.
Increased cholesterol level/hypercholesterolemia and hypertriglyceridemia each occurred in less than 15% of patients (median age, 10 [range, 1 to 25] years) with acute lymphocytic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi (Rylaze) in combination with chemotherapy in a multi-cohort trial.
Asparaginase Erwinia chrysanthemi (Erwinaze) is contraindicated for use in patients with a history of serious hypersensitivity reactions to Erwinaze including anaphylaxis. Recombinant asparaginase Erwinia chrysanthemi (Rylaze) is contraindicated for use in patients with a history of serious hypersensitivity reactions to Erwinia Asparaginase including anaphylaxis. Provide symptomatic treatment in patients who develop a grade 2 hypersensitivity reaction. Premedicate patients with acetaminophen, an H-1 receptor blocker (e.g., diphenhydramine), and an H-2 receptor blocker (e.g., famotidine) prior to the intramuscular injection to decrease the risk and severity of hypersensitivity reactions. Administration requires a specialized care setting which has resuscitation equipment and treatment necessary in case anaphylaxis occurs (e.g., oxygen, epinephrine, corticosteroids, and antihistamines). Permanently discontinue therapy if a severe hypersensitivity reaction occurs; initiate appropriate treatment.
Asparaginase Erwinia chrysanthemi is contraindicated for use by patients with a history of serious pancreatitis with prior asparaginase therapy. Pancreatitis has been noted during clinical trials. In patients with signs or symptoms of pancreatitis, evaluate for a diagnosis of pancreatitis and obtain serum amylase and lipase levels. Therapy interruption or permanent discontinuation may be necessary in patients who develop pancreatitis.
Asparaginase Erwinia chrysanthemi is contraindicated for use in patients with a history of a serious bleeding event or thrombosis with prior asparaginase therapy. Evaluate patients who develop bleeding or clotting for coagulopathy. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy. Therapy interruption or permanent discontinuation may be necessary in patients who develop bleeding or clotting. Treat thromboembolic events with appropriate antithrombotic therapy.
Recombinant asparaginase Erwinia chrysanthemi is contraindicated for use in patients with severe hepatic impairment/hepatic disease. Evaluate liver function tests (LFTs) prior to each cycle of therapy, at least weekly during treatment cycles that include recombinant asparaginase Erwinia chrysanthemi, and for 4 weeks after the last dose. Frequently monitor patients for signs and symptoms of hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS), including rapid weight gain, fluid retention with ascites, hepatomegaly, and rapid increased bilirubin levels. In patients who develop elevated hepatic enzymes during therapy, increase the frequency monitoring of LFTs and for clinical signs and symptoms of VOD/SOS.Therapy interruption or permanent discontinuation may be necessary in patients who develop hepatotoxicity; provide supportive care as indicated.
Monitor glucose levels prior to treatment every 2 to 3 weeks and as clinically indicated during asparaginase Erwinia chrysanthemi therapy. If hyperglycemia occurs, monitor patients until recovery from the therapy cycle. Irreversible glucose intolerance may occur; treat patients who develop severe hyperglycemia with insulin if necessary.
Asparaginase Erwinia chrysanthemi may cause fetal harm if used during pregnancy, based on data from animal studies. Females of reproductive potential should avoid pregnancy during asparaginase Erwinia chrysanthemi therapy. Advise pregnant women of the potential risk to the fetus. An increased incidence of partially undescended thymic tissue was observed in the offspring of pregnant rats who received IM asparaginase Erwinia chrysanthemi at doses that were 0.5 times the maximum recommended human dose. Additionally, fetal malformation (i.e., absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) occurred in the offspring of pregnant rabbits who received IM asparaginase Erwinia chrysanthemi at doses that were 0.005 times the maximum recommended human dose.
Counsel patients about the reproductive risk and contraception requirements during asparaginase Erwinia chrysanthemi treatment. Pregnancy testing is recommended for females of reproductive potential prior to starting asparaginase Erwinia chrysanthemi. Advise these patients to use effective contraception during treatment and for 3 months after the final dose. The manufacturer of Erwinaze recommends using a contraceptive method other than oral contraceptives because an indirect interaction between asparaginase Erwinia chrysanthemi and oral contraceptives cannot be ruled out.
Breast-feeding is not recommended during asparaginase Erwinia chrysanthemi (Erwinaze) or recombinant asparaginase Erwinia chrysanthemi (Rylaze) treatment and for 3 months (Erwinaze) or 1 week (Rylaze) after the last dose due to the potential for serious adverse reactions in the breast-fed child. There are no data on the presence of asparaginase Erwinia chrysanthemi in human milk, the effects on the breast-fed child, or the effects on milk production.
For the treatment of acute lymphocytic leukemia (ALL):
-for the treatment of ALL in patients who have developed hypersensitivity to E. coli-derived asparaginase, in combination with a multi-agent chemotherapy regimen:
NOTE: Due to a critical shortage of FDA-approved Erwinaze, a non-FDA licensed product from the United Kingdom, Erwinase (crisantaspase), was made available in the United States in June 2020. There are differences in the FDA-approved Erwinaze and United Kingdom Erwinase product labeling.
Intravenous or Intramuscular dosage (Erwinaze):
NOTE: Consider monitoring nadir serum asparaginase activity (NSAA) concentrations when administering asparaginase Erwinia chrysanthemi IV and switching to IM administration if desired NSAA concentrations are not achieved.
Adults: To substitute for a dose of pegaspargase: 25,000 International Units/m2 IV or IM 3 times a week (Monday/Wednesday/Friday) for 6 doses. To substitute for native E. coli asparaginase: 25,000 International Units/m2 IV or IM for each scheduled dose of native E. coli asparaginase within a treatment.
Children and Adolescents: To substitute for a dose of pegaspargase: 25,000 International Units/m2 IV or IM 3 times a week (Monday/Wednesday/Friday) for 6 doses. To substitute for native E. coli asparaginase: 25,000 International Units/m2 IV or IM for each scheduled dose of native E. coli asparaginase within a treatment.
Intramuscular dosage (Rylaze only; every 48 hours regimen):
Adults: 25 mg/m2 intramuscularly (IM) every 48 hours to replace a long-acting asparaginase product. Premedicate patients with acetaminophen, an H-1 receptor blocker (e.g., diphenhydramine), and an H-2 receptor blocker (e.g., famotidine) at 30 to 60 minutes prior to the IM injection to decrease the risk and severity of hypersensitivity reactions. Replace a single dose of calaspargase pegol with 11 doses of recombinant asparaginase Erwinia chrysanthemi; replace a single dose of pegaspargase with 7 doses of recombinant asparaginase Erwinia chrysanthemi. Continue therapy based on the duration of therapy for the replaced long-acting asparaginase product. Intramuscular administration of different dosing regimens of recombinant asparaginase Erwinia chrysanthemi on Monday, Wednesday, and Friday for 6 doses to replace a single dose of pegaspargase were evaluated in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma in a multi-cohort, open-label (JZP458-201) trial (n = 225). Based on simulation using 2,000 virtual subjects, 96% (95% CI, 94.4% to 97.2%) of patients who receive recombinant asparaginase Erwinia chrysanthemi 25 mg/m2 IM every 48 hours would achieve a nadir serum asparaginase activity (NSAA) level of at least 0.1 units/mL at 48 hours after the dose. In this trial, 83% of patients had developed a grade 3 or higher allergic reaction to and 7% of patients had silent inactivation after receiving a pegylated E. coli-derived asparaginase product.
Infants, Children, and Adolescents: 25 mg/m2 intramuscularly (IM) every 48 hours to replace a long-acting asparaginase product. Premedicate patients with acetaminophen, an H-1 receptor blocker (e.g., diphenhydramine), and an H-2 receptor blocker (e.g., famotidine) at 30 to 60 minutes prior to the IM injection to decrease the risk and severity of hypersensitivity reactions. Replace a single dose of calaspargase pegol with 11 doses of recombinant asparaginase Erwinia chrysanthemi; replace a single dose of pegaspargase with 7 doses of recombinant asparaginase Erwinia chrysanthemi. Continue therapy based on the duration of therapy for the replaced long-acting asparaginase product. Intramuscular administration of different dosing regimens of recombinant asparaginase Erwinia chrysanthemi on Monday, Wednesday, and Friday for 6 doses to replace a single dose of pegaspargase were evaluated in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma in a multi-cohort, open-label (JZP458-201) trial (n = 225). Based on simulation using 2,000 virtual subjects, 96% (95% CI, 94.4% to 97.2%) of patients who receive recombinant asparaginase Erwinia chrysanthemi 25 mg/m2 IM every 48 hours would achieve a nadir serum asparaginase activity (NSAA) level of at least 0.1 units/mL at 48 hours after the dose. In this trial, 83% of patients had developed a grade 3 or higher allergic reaction to and 7% of patients had silent inactivation after receiving a pegylated E. coli-derived asparaginase product.
Intramuscular dosage (Rylaze only; 25/25/50 mg/m2 Mon-Wed-Fri regimen):
Adults: 25 mg/m2 intramuscularly (IM) on Monday (in the morning) and Wednesday (in the morning), and then 50 mg/m2 IM on Friday (in the afternoon) to replace a long-acting asparaginase product. Administer the Friday afternoon dose at 53 to 58 hours after the Wednesday morning dose (e.g., 8 am on Monday and Wednesday, and 1 pm to 6 pm on Friday). Premedicate patients with acetaminophen, an H-1 receptor blocker (e.g., diphenhydramine), and an H-2 receptor blocker (e.g., famotidine) at 30 to 60 minutes prior to the IM injection to decrease the risk and severity of hypersensitivity reactions. Replace a single dose of calaspargase pegol with 9 doses of recombinant asparaginase Erwinia chrysanthemi; replace a single dose of pegaspargase with 6 doses of recombinant asparaginase Erwinia chrysanthemi. Continue therapy based on the duration of therapy for the replaced long-acting asparaginase product. Intramuscular administration of 3 different dosing regimens of recombinant asparaginase Erwinia chrysanthemi on Monday, Wednesday, and Friday for 6 doses to replace a single dose of pegaspargase were evaluated in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma in a multi-cohort, open-label (JZP458-201) trial (n = 225). In patients who receive recombinant asparaginase Erwinia chrysanthemi 25 mg/m2 IM on Monday and Wednesday and 50 mg/m2 IM on Friday, a nadir serum asparaginase activity (NSAA) level of at least 0.1 units/mL is expected in 91.6% (95% CI, 90.4% to 92.8%) of patients at 58 hours after the Wednesday morning dose and 91.4% (95% CI, 90.1% to 92.6%) of patients at 67 hours after the Friday afternoon dose based on simulation using 2,000 virtual subjects. In this trial, 83% of patients had developed a grade 3 or higher allergic reaction to and 7% of patients had silent inactivation after receiving a pegylated E. coli-derived asparaginase product.
Infants, Children, and Adolescents: 25 mg/m2 intramuscularly (IM) on Monday (in the morning) and Wednesday (in the morning), and then 50 mg/m2 IM on Friday (in the afternoon) to replace a long-acting asparaginase product. Administer the Friday afternoon dose at 53 to 58 hours after the Wednesday morning dose (e.g., 8 am on Monday and Wednesday, and 1 pm to 6 pm on Friday). Premedicate patients with acetaminophen, an H-1 receptor blocker (e.g., diphenhydramine), and an H-2 receptor blocker (e.g., famotidine) at 30 to 60 minutes prior to the IM injection to decrease the risk and severity of hypersensitivity reactions. Replace a single dose of calaspargase pegol with 9 doses of recombinant asparaginase Erwinia chrysanthemi; replace a single dose of pegaspargase with 6 doses of recombinant asparaginase Erwinia chrysanthemi. Continue therapy based on the duration of therapy for the replaced long-acting asparaginase product. Intramuscular administration of 3 different dosing regimens of recombinant asparaginase Erwinia chrysanthemi on Monday, Wednesday, and Friday for 6 doses to replace a single dose of pegaspargase were evaluated in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma in a multi-cohort, open-label (JZP458-201) trial (n = 225). In patients who receive recombinant asparaginase Erwinia chrysanthemi 25 mg/m2 IM on Monday and Wednesday and 50 mg/m2 IM on Friday, a nadir serum asparaginase activity (NSAA) level of at least 0.1 units/mL is expected in 91.6% (95% CI, 90.4% to 92.8%) of patients at 58 hours after the Wednesday morning dose and 91.4% (95% CI, 90.1% to 92.6%) of patients at 67 hours after the Friday afternoon dose based on simulation using 2,000 virtual subjects. In this trial, 83% of patients had developed a grade 3 or higher allergic reaction to and 7% of patients had silent inactivation after receiving a pegylated E. coli-derived asparaginase product.
For the treatment of non-Hodgkin's lymphoma (NHL):
-for the treatment of lymphoblastic lymphoma (LBL) in patients who have developed hypersensitivity to E. coli-derived asparaginase, in combination with a multi-agent chemotherapy regimen:
Intramuscular dosage (Rylaze only; every 48 hours regimen):
Adults: 25 mg/m2 intramuscularly (IM) every 48 hours to replace a long-acting asparaginase product. Premedicate patients with acetaminophen, an H-1 receptor blocker (e.g., diphenhydramine), and an H-2 receptor blocker (e.g., famotidine) at 30 to 60 minutes prior to the IM injection to decrease the risk and severity of hypersensitivity reactions. Replace a single dose of calaspargase pegol with 11 doses of recombinant asparaginase Erwinia chrysanthemi; replace a single dose of pegaspargase with 7 doses of recombinant asparaginase Erwinia chrysanthemi. Continue therapy based on the duration of therapy for the replaced long-acting asparaginase product. Intramuscular administration of different dosing regimens of recombinant asparaginase Erwinia chrysanthemi on Monday, Wednesday, and Friday for 6 doses to replace a single dose of pegaspargase were evaluated in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma in a multi-cohort, open-label (JZP458-201) trial (n = 225). Based on simulation using 2,000 virtual subjects, 96% (95% CI, 94.4% to 97.2%) of patients who receive recombinant asparaginase Erwinia chrysanthemi 25 mg/m2 IM every 48 hours would achieve a nadir serum asparaginase activity (NSAA) level of at least 0.1 units/mL at 48 hours after the dose. In this trial, 83% of patients had developed a grade 3 or higher allergic reaction to and 7% of patients had silent inactivation after receiving a pegylated E. coli-derived asparaginase product.
Infants, Children, and Adolescents: 25 mg/m2 intramuscularly (IM) every 48 hours to replace a long-acting asparaginase product. Premedicate patients with acetaminophen, an H-1 receptor blocker (e.g., diphenhydramine), and an H-2 receptor blocker (e.g., famotidine) at 30 to 60 minutes prior to the IM injection to decrease the risk and severity of hypersensitivity reactions. Replace a single dose of calaspargase pegol with 11 doses of recombinant asparaginase Erwinia chrysanthemi; replace a single dose of pegaspargase with 7 doses of recombinant asparaginase Erwinia chrysanthemi. Continue therapy based on the duration of therapy for the replaced long-acting asparaginase product. Intramuscular administration of different dosing regimens of recombinant asparaginase Erwinia chrysanthemi on Monday, Wednesday, and Friday for 6 doses to replace a single dose of pegaspargase were evaluated in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma in a multi-cohort, open-label (JZP458-201) trial (n = 225). Based on simulation using 2,000 virtual subjects, 96% (95% CI, 94.4% to 97.2%) of patients who receive recombinant asparaginase Erwinia chrysanthemi 25 mg/m2 IM every 48 hours would achieve a nadir serum asparaginase activity (NSAA) level of at least 0.1 units/mL at 48 hours after the dose. In this trial, 83% of patients had developed a grade 3 or higher allergic reaction to and 7% of patients had silent inactivation after receiving a pegylated E. coli-derived asparaginase product.
Intramuscular dosage (Rylaze only; 25/25/50 mg/m2 Mon-Wed-Fri regimen):
Adults: 25 mg/m2 intramuscularly (IM) on Monday (in the morning) and Wednesday (in the morning), and then 50 mg/m2 IM on Friday (in the afternoon) to replace a long-acting asparaginase product. Administer the Friday afternoon dose at 53 to 58 hours after the Wednesday morning dose (e.g., 8 am on Monday and Wednesday, and 1 pm to 6 pm on Friday). Premedicate patients with acetaminophen, an H-1 receptor blocker (e.g., diphenhydramine), and an H-2 receptor blocker (e.g., famotidine) at 30 to 60 minutes prior to the IM injection to decrease the risk and severity of hypersensitivity reactions. Replace a single dose of calaspargase pegol with 9 doses of recombinant asparaginase Erwinia chrysanthemi; replace a single dose of pegaspargase with 6 doses of recombinant asparaginase Erwinia chrysanthemi. Continue therapy based on the duration of therapy for the replaced long-acting asparaginase product. Intramuscular administration of 3 different dosing regimens of recombinant asparaginase Erwinia chrysanthemi on Monday, Wednesday, and Friday for 6 doses to replace a single dose of pegaspargase were evaluated in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma in a multi-cohort, open-label (JZP458-201) trial (n = 225). In patients who receive recombinant asparaginase Erwinia chrysanthemi 25 mg/m2 IM on Monday and Wednesday and 50 mg/m2 IM on Friday, a nadir serum asparaginase activity (NSAA) level of at least 0.1 units/mL is expected in 91.6% (95% CI, 90.4% to 92.8%) of patients at 58 hours after the Wednesday morning dose and 91.4% (95% CI, 90.1% to 92.6%) of patients at 67 hours after the Friday afternoon dose based on simulation using 2,000 virtual subjects. In this trial, 83% of patients had developed a grade 3 or higher allergic reaction to and 7% of patients had silent inactivation after receiving a pegylated E. coli-derived asparaginase product.
Infants, Children, and Adolescents: 25 mg/m2 intramuscularly (IM) on Monday (in the morning) and Wednesday (in the morning), and then 50 mg/m2 IM on Friday (in the afternoon) to replace a long-acting asparaginase product. Administer the Friday afternoon dose at 53 to 58 hours after the Wednesday morning dose (e.g., 8 am on Monday and Wednesday, and 1 pm to 6 pm on Friday). Premedicate patients with acetaminophen, an H-1 receptor blocker (e.g., diphenhydramine), and an H-2 receptor blocker (e.g., famotidine) at 30 to 60 minutes prior to the IM injection to decrease the risk and severity of hypersensitivity reactions. Replace a single dose of calaspargase pegol with 9 doses of recombinant asparaginase Erwinia chrysanthemi; replace a single dose of pegaspargase with 6 doses of recombinant asparaginase Erwinia chrysanthemi. Continue therapy based on the duration of therapy for the replaced long-acting asparaginase product. Intramuscular administration of 3 different dosing regimens of recombinant asparaginase Erwinia chrysanthemi on Monday, Wednesday, and Friday for 6 doses to replace a single dose of pegaspargase were evaluated in patients (median age, 10 [range, 1 to 25] years) with acute lymphoblastic leukemia or lymphoblastic lymphoma in a multi-cohort, open-label (JZP458-201) trial (n = 225). In patients who receive recombinant asparaginase Erwinia chrysanthemi 25 mg/m2 IM on Monday and Wednesday and 50 mg/m2 IM on Friday, a nadir serum asparaginase activity (NSAA) level of at least 0.1 units/mL is expected in 91.6% (95% CI, 90.4% to 92.8%) of patients at 58 hours after the Wednesday morning dose and 91.4% (95% CI, 90.1% to 92.6%) of patients at 67 hours after the Friday afternoon dose based on simulation using 2,000 virtual subjects. In this trial, 83% of patients had developed a grade 3 or higher allergic reaction to and 7% of patients had silent inactivation after receiving a pegylated E. coli-derived asparaginase product.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Erwinaze
Bleeding
Hemorrhagic event: Hold Erwinaze; may resume therapy when symptoms resolve.
Hypersensitivity Reactions
Serious reaction: Discontinue Erwinaze; initiate appropriate therapy.
Pancreatitis
Mild pancreatitis: Hold Erwinaze; may resume therapy when the signs and symptoms subside and amylase levels return to normal.
Severe or hemorrhagic pancreatitis (abdominal pain lasting longer than 72 hours and elevated amylase level of 2 times the ULN or more): Discontinue Erwinaze; severe pancreatitis is a contraindication to additional asparaginase administration.
Thrombosis
Thrombotic event: Hold Erwinaze; may resume therapy when symptoms resolve.
Rylaze
Bleeding
Grade 3 or 4 toxicity: Hold Rylaze and evaluate the patient for coagulopathy; consider clotting factor replacement as necessary. Resume Rylaze at the next scheduled dose if bleeding is controlled.
Hypersensitivity Reactions
Grade 2 toxicity: Provide symptomatic treatment.
Grade 3 or 4 toxicity: Permanently discontinue Rylaze.
Pancreatitis
Grade 2, 3, or 4 toxicity: Hold Rylaze for elevated lipase or amylase levels greater than 2 times the ULN occur or for symptomatic pancreatitis; resume therapy when lipase or amylase levels decrease to less than 1.5 time the ULN and symptom have resolved. Permanently discontinue Rylaze if clinical necrotizing or hemorrhagic pancreatitis is confirmed.
Thrombosis
Uncomplicated thrombosis: Hold Rylaze and treat with appropriate antithrombotic therapy. Consider resuming therapy when symptoms resolve; continue antithrombotic therapy.
Severe or life-threatening thrombosis: Permanently discontinue Rylaze; treat with appropriate antithrombotic therapy.
Maximum Dosage Limits:
-Adults
Erwinaze: 25,000 International Units/m2 IV or IM.
Rylaze: 50 mg/m2 IM.
-Geriatric
Erwinaze: 25,000 International Units/m2 IV or IM.
Rylaze: 50 mg/m2 IM.
-Adolescents
Erwinaze: 25,000 International Units/m2 IV or IM.
Rylaze: 50 mg/m2 IM.
-Children
Erwinaze: 25,000 International Units/m2 IV or IM.
Rylaze: 50 mg/m2 IM.
-Infants
Erwinaze: Safety and efficacy not established.
Rylaze: 50 mg/m2 IM.
-Neonates
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Mild or moderate hepatic impairment: Specific guidelines for dosage adjustments are not available; it appears that no initial dosage adjustments are needed.
Severe hepatic impairment: Avoid use.
Treatment-Related Hepatotoxicity (Rylaze)
Total bilirubin level greater than 3 to 10 times the ULN: Hold Rylaze; resume therapy when the total bilirubin levels decrease to 1.5 times the ULN or less.
Total bilirubin level greater than 10 times the ULN: Discontinue Rylaze; do not make up for missed doses.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Albuterol; Budesonide: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Azelastine; Fluticasone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Beclomethasone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Betamethasone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Budesonide: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Budesonide; Formoterol: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciclesonide: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Corticosteroids: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Cortisone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
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. In addition, L-asparaginase may have schedule-dependent synergy and antagonism with high-dose cytarabine.
Deflazacort: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dexamethasone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Fludrocortisone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Flunisolide: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Fluticasone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Fluticasone; Salmeterol: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Fluticasone; Vilanterol: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Formoterol; Mometasone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Hydrocortisone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Levothyroxine: (Moderate) Some hypothyroid patients receiving asparaginase may require reduced doses of thyroid hormone. Other patients may remain euthyroid during combined treatment. Monitor TSH levels and monitor for symptoms of hyperthyroidism; a free-T4 concentration may be useful to assess euthyroidism. Asparaginase may decrease the serum TBG (thyroxine-binding globulin) concentration. Decreased amounts of TBG may result in an increased clinical response to thyroid hormones.
Levothyroxine; Liothyronine (Porcine): (Moderate) Some hypothyroid patients receiving asparaginase may require reduced doses of thyroid hormone. Other patients may remain euthyroid during combined treatment. Monitor TSH levels and monitor for symptoms of hyperthyroidism; a free-T4 concentration may be useful to assess euthyroidism. Asparaginase may decrease the serum TBG (thyroxine-binding globulin) concentration. Decreased amounts of TBG may result in an increased clinical response to thyroid hormones.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Some hypothyroid patients receiving asparaginase may require reduced doses of thyroid hormone. Other patients may remain euthyroid during combined treatment. Monitor TSH levels and monitor for symptoms of hyperthyroidism; a free-T4 concentration may be useful to assess euthyroidism. Asparaginase may decrease the serum TBG (thyroxine-binding globulin) concentration. Decreased amounts of TBG may result in an increased clinical response to thyroid hormones.
Liothyronine: (Moderate) Some hypothyroid patients receiving asparaginase may require reduced doses of thyroid hormone. Other patients may remain euthyroid during combined treatment. Monitor TSH levels and monitor for symptoms of hyperthyroidism; a free-T4 concentration may be useful to assess euthyroidism. Asparaginase may decrease the serum TBG (thyroxine-binding globulin) concentration. Decreased amounts of TBG may result in an increased clinical response to thyroid hormones.
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 to 24 hours prior to L-asparaginase, 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.
Methylprednisolone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Mometasone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Olopatadine; Mometasone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Prednisolone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Prednisone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Thyroid hormones: (Moderate) Some hypothyroid patients receiving asparaginase may require reduced doses of thyroid hormone. Other patients may remain euthyroid during combined treatment. Monitor TSH levels and monitor for symptoms of hyperthyroidism; a free-T4 concentration may be useful to assess euthyroidism. Asparaginase may decrease the serum TBG (thyroxine-binding globulin) concentration. Decreased amounts of TBG may result in an increased clinical response to thyroid hormones.
Triamcinolone: (Moderate) Concomitant use of L-asparaginase with corticosteroids can result in additive hyperglycemia. L-Asparaginase transiently inhibits insulin production contributing to hyperglycemia seen during concurrent corticosteroid therapy. Insulin therapy may be required in some cases. Administration of L-asparaginase after rather than before corticosteroids reportedly has produced fewer hypersensitivity reactions.
Vincristine Liposomal: (Moderate) Use L-asparaginase and vincristine together with caution; increased vincristine-related toxicity may occur. L-asparaginase administered before or concurrently with vincristine may reduce the hepatic clearance of vincristine. If these drugs are used together, administer vincristine 12 to 24 hours before L-asparaginase to minimize toxicity.
Vincristine: (Moderate) Use L-asparaginase and vincristine together with caution; increased vincristine-related toxicity may occur. L-asparaginase administered before or concurrently with vincristine may reduce the hepatic clearance of vincristine. If these drugs are used together, administer vincristine 12 to 24 hours before L-asparaginase to minimize toxicity.
Zonisamide: (Moderate) Concomitant use of zonisamide with asparaginase may increase the risks of hyperammonemia and encephalopathy. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
Asparaginase Erwinia chrysanthemi is an asparagine specific enzyme derived from Erwinia chrysanthemi. This enzyme catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia, resulting in a reduced circulating asparagine levels. Leukemic cells have an inability to synthesize asparagine due to a lack of asparagine synthetase activity. Asparaginase Erwinia chrysanthemi therapy deprives leukemic cells of an exogenous source of asparagine which eventually leading to cell death. Asparaginase erwinia chrysanthemi (recombinant)-rywn is produced by fermentation of a genetically engineered Pseudomonas fluorescens bacterium containing the DNA which encodes for asparaginase Erwinia chrysanthemi. It's amino acid sequence is identical to native asparaginase Erwinia chrysanthemi, also known as crisantaspase.
Asparaginase Erwinia chrysanthemi (Erwinaze) is administered intravenously (IV) and intramuscularly (IM). Nadir serum asparaginase activity (NSAA) of 0.1 units/mL or more correlates with asparagine depletion and serum concentrations that predict clinical efficacy.
Recombinant asparaginase Erwinia chrysanthemi (Rylaze) is administered IM. Achieving and maintaining a NSAA greater than 0.1 unit/mL predicts clinical efficacy. The geometric mean volume of distribution was 1.37 L/m2 (coefficient of variation (CV), 47%), apparent half-life was 15.9 hours (CV, 11%), and geometric mean clearance was 0.17 L/hour/m2 (CV, 42%) in pediatric and young adult patients with acute lymphocytic leukemia or lymphoblastic lymphoma who received recombinant asparaginase Erwinia chrysanthemi. Metabolism into small peptides occurs via catabolic pathways.
-Route-Specific Pharmacokinetics
Intravenous Route
Based on a population pharmacokinetic model in patients aged 1 to 17 years, the mean half-life of asparaginase Erwinia chrysanthemi after IV administration was 7.51 hours (coefficient of variation (CV), 23.9%). Following asparaginase Erwinia chrysanthemi 25,000 International Units/m2 IV 3 days per week for 6 doses, a nadir serum asparaginase activity (NSAA) concentration of 0.1 International Units/mL or more was achieved in 83% of patients at 48 hours post dose 5 (n = 20 of 24) and 43% of patients at 72 hours post dose 6 (n = 9 of 21); a NSAA concentration of 0.4 International Units/mL or more was achieved in 29% and 0% of patients, respectively.
Intramuscular Route
Based on a population pharmacokinetic (PK) model in patients aged 1 to 18 years, the mean half-life of asparaginase Erwinia chrysanthemi after IM administration was 15.6 hours (coefficient of variation (CV), 20%). Following asparaginase Erwinia chrysanthemi 25,000 International Units/m2 IM 3 days per week for 6 doses, a nadir serum asparaginase activity (NSAA) concentration of 0.1 International Units/mL or more was achieved in 100% of patients at 48 hours (n = 35) or 72 hours (n = 13) post dose 3; a NSAA concentration of 0.4 International Units/mL or more was achieved in 80% and 38% of patients, respectively.
In a virtual population, the simulated geometric mean Ctrough value was 0.46 units/mL (coefficient of variation (CV), 75%), based on serum asparaginase activity (SAA), after the last dose of recombinant asparaginase Erwinia chrysanthemi 25 mg/m2 IM every 48 hours. Following the administration of recombinant asparaginase Erwinia chrysanthemi 25 mg/m2 IM on Monday and Wednesday and 50 mg/m2 IM on Friday, the simulated geometric mean Ctrough values were 0.3 units/mL (CV, 75%) at a maximum interval of 58 hours after the last Wednesday morning dose and 0.39 units/mL (CV, 87%) at a maximum interval of 67 hours after the last Friday afternoon dose in a virtual population. The median Tmax is 12 (range, 8 to 24) hours.
-Special Populations
Pediatrics
Age (range, 1.4 to 25 years) has no clinically significant impact on the pharmacokinetic parameters of recombinant asparaginase Erwinia chrysanthemi. There were no clinically meaningful differences in nadir serum asparaginase activity across age groups in 139 pediatric patients (age: 1 month to less than 2 years, n = 2; 2 to 11 years, n = 99; and 12 to 16 years, n = 38).
Gender Differences
Gender has no clinically significant impact on the pharmacokinetic parameters of recombinant asparaginase Erwinia chrysanthemi.
Ethnic Differences
Black or African American patients had a 29% lower recombinant asparaginase Erwinia chrysanthemi clearance compared with White and Asian patients. There were no clinically significant differences in clearance between Hispanic and non-Hispanic patients who received recombinant asparaginase Erwinia chrysanthemi.
Obesity
Body weight (range, 9 to 131 kg) has no clinically significant impact on the pharmacokinetic parameters of recombinant asparaginase Erwinia chrysanthemi. The volume of distribution and clearance of recombinant asparaginase Erwinia chrysanthemi increase with increasing body surface area (0.44 to 2.53 m2).