Onconase (E. coli Asparaginase) is a chemotherapeutic drug that is used to treat patients with acute lymphoblastic leukemia and acute lymphoblastic lymphoma. It is used in combination with other chemotherapeutic drugs as a part of a multi-drug regimen and has little bone marrow toxic effects.

Onconase (E. coli Asparaginase) Uses:

• Acute lymphoblastic leukemia:

  • Used in the treatment of acute lymphoblastic leukemia (ALL) (in combination with other chemotherapy)

• Off Label Use of E. coli asparaginase in Adults:

  • Used in lymphoblastic lymphoma

Onconase (E. coli Asparaginase) Dose in Adults

Note: Frequency, number of doses,Dose and start date may vary by protocol and treatment phase.

Onconase (E. coli Asparaginase) Dose in the treatment of Acute lymphoblastic leukemia (ALL):

• Daily administration:

  • Induction: IM, IV: 200 to 1,000 units per kg per day for 28 consecutive days;
  • continue induction therapy for an additional 2 weeks if not in remission or begin maintenance therapy if in remission (Canadian labeling)

• Intermittent administration:

  • Induction: IM, IV: 400 units per kg on Monday and Wednesday and 600 units per kg on Friday;
  • repeat  every weak  for a time period of  4 weeks;
  • continue induction therapy for an additional 2 weeks if not in remission or begin maintenance therapy if in remission (Canadian labeling)

• CALGB-8811 regimen (off-label dosing):

  • SubQ: 6,000 units per m² per dose on days 5, 8, 11, 15, 18, and 22 (induction phase) and on days 15, 18, 22, and 25 (early intensification phase).

• Hyper-CVAD regimen (off-label dosing):

  • IV: 20,000 units every week for 4 doses (starting on day 2) during either month 7 and 19 or months 7 and 11 of the intensification phase.

• Linker regimen (off-label dosing): IM:

  • Remission induction:
    • 6,000 units per m² per dose on days 17 to 28;
  • if bone marrow on day 28 is positive for residual leukemia:
    • 6,000 units per m² per dose on days 29 to 35.
  • Consolidation (Treatment A; cycles 1, 3, 5, and 7):
    • 12,000 units per m²  per dose on days 2, 4, 7, 9, 11, and 14.

Onconase (E. coli Asparaginase) Dose in the treatment of Lymphoblastic lymphoma (off-label):

• Hyper-CVAD regimen:

  • IV: 20,000 units every week for 4 doses (starting on day 2) for 2 cycles (months 7 and 11) during the maintenance phase.

Onconase (E. coli Asparaginase) Dose in Childrens

Note: frequency, number of doses, dose, and start date may vary by protocol and treatment phase.

Onconase (E. coli Asparaginase) Dose in the treatment of Acute lymphoblastic leukemia (ALL):

• Children and Adolescents: Refer to adult dosing.

  • CCG 1922 protocol (off-label dosing):
    • IM: 6,000 units per m²  per dose 3 thrice in a week for 9 doses beginning either on day 2, 3, or 4 (induction phase) and 6,000 units per m²  per dose on Monday, Wednesday, and Friday for 6 doses beginning day 3 (delayed intensification phase).
  • DFCI-ALL Consortium protocol 00-01 (off-label dosing):
    • IM: 25,000 units per m² for 1 dose (induction phase) and 25,000 units per m²  per dose weekly for 30 weeks (intensification phase).
  • DFCI-ALL Consortium protocol 95-01 (off-label dosing):
    • IM: 25,000 units per m² for 1 dose on day 4 (induction phase) and 25,000 units per m² per dose in a week  for 20 weeks (intensification phase).

• Hyper-CVAD regimen (off-label dosing):

  • Adolescents ≥13 years: Refer to adult dosing.

Onconase (E. coli Asparaginase) Lymphoblastic lymphoma (off-label):

• Adolescents >15 years:

  • Refer to adult dosing.

Dosing adjustment for toxicity:

• Manufacturer labeling: Children and Adolescents:

  • Allergic reaction/hypersensitivity:
    • Discontinue for severe reactions.
  • Neurotoxicity (posterior reversible encephalopathy syndrome [PRES]):
    • Interrupt therapy for suspected PRES; control blood pressure and closely monitor for seizure activity.
  • Pancreatitis:
    • Discontinue permanently.
  • Thrombotic event:
    • Discontinue for serious reactions.

• Following adjustments have also been recommended: Older Adolescents:

  • Hyperammonemia-related fatigue:
    • Continue therapy for grade 2 toxicity.
    • If grade 3 toxicity occurs, reduce dose by 25 percent; resume full dose when toxicity ≤ grade 2 (make up for missed doses).
    • If grade 4 toxicity appears, reduce dose by 50 percent; resume full dose when toxicity ≤ grade 2 (make up for missed doses).
  • Hyperglycemia:
    • Starts therapy for uncomplicated hyperglycemia.
    • If hyperglycemia needed insulin therapy, hold asparaginase (and any concomitant corticosteroids) until blood glucose controlled; resume dosing at prior dose level.
    • For life-threatening hyperglycemia or toxicity needs urgent intervention, hold asparaginase (and corticosteroids) until blood glucose is controlled with insulin; resume asparaginase and do not make up for missed doses.
  • Hypersensitivity reactions:
    • Starts dosing for urticaria without hypotension, edema, bronchospasm, or requirement for parenteral intervention.
    • If wheezing or another symptomatic bronchospasm with or without angioedema, hypotension, urticaria, and life-threatening hypersensitivity reactions appears, stop asparaginase.
  • Hypertriglyceridemia:
    • If serum triglyceride level less than 1,000 mg per dL, continue asparaginase but monitor closely for pancreatitis.
    • If triglyceride level more than 1,000 mg per dL, hold asparaginase and monitor; resume therapy at prior dose level after triglyceride level returns to baseline.
  • Pancreatitis:
    • Asymptomatic amylase or lipase more than thrice times  ULN (chemical pancreatitis) or radiologic abnormalities only:
      • starts asparaginase and monitor levels closely.
    • Symptomatic amylase or lipase more than thrice times ULN:
      • Hold asparaginase until enzyme levels stabilize or are declining.
    • Clinical pancreatitis or symptomatic pancreatitis (abdominal pain with amylase or lipase more than thrice times  ULN for more than thrice days or development of pancreatic pseudocyst):
      • Permanently stops asparaginase.
  • Thrombosis and bleeding, CNS:
    • Thrombosis:
      • Starts therapy for abnormal laboratory findings without a clinical correlate.
      • If grade 3 toxicity occurs, stops the therapy; if CNS signs and symptoms are fully resolved and further asparaginase doses are needed, may resume therapy at a lower dose and/or longer intervals between doses.
      • Discontinue therapy for grade 4 toxicity.
    • Hemorrhage:
      • Discontinue therapy; do not retain therapy for abnormal laboratory findings without a clinical correlate.
      • If grade 3 toxicity occurs, discontinue therapy; if CNS signs and symptoms are fully resolved and further asparaginase doses are required, may resume therapy at a lower dose and/or longer intervals between doses.
      • Discontinue therapy for grade 4 toxicity.
  • Thrombosis and bleeding, non-CNS:
    • Thrombosis:
      • Starts therapy for abnormal laboratory findings without a clinical correlate.
      • If grade 3 or 4 toxicity appears, withhold therapy until acute toxicity and clinical signs resolve and anticoagulant therapy is stable or completed.
      • Do not withhold therapy for abnormal laboratory findings without clinical correlation.
    • Hemorrhage:
      • If bleeding of grade 2 in conjunction with hypofibrinogenemia appears, withhold therapy until bleeding grade 1 or less than grade 1.
      • Do not retain therapy for abnormal laboratory findings without clinical correlate.
      • For grade 3 or 4 bleeding, retain therapy until bleeding grade 1 or less than grade 1 and until acute toxicity and clinical signs resolve and coagulant replacement therapy is stable or completed.

Onconase (E. coli Asparaginase) Pregnancy Risk Category: C

• Based on animal reproduction studies, it is possible for fetal harm to be caused by in utero asparaginase (E. coli derived).
• According to the manufacturer, pregnant females with reproductive potential should limit their pregnancy while undergoing chemotherapy.
• Males should refrain from having children during chemotherapy or for a time after receiving the last dose of E.coli-derived asparaginase.

Use of E.coli asparaginase during breastfeeding

• Manufacturers do not recommend breastfeeding.

Onconase (E. coli Asparaginase) Dose in Kidney Disease:

The manufacturer’s labeling doesn't provide any dosage adjustments.

Onconase (E. coli Asparaginase) Dose in Liver disease:

• Its use is contraindicated in patients with hepatic insufficiency.

• The following adjustments have been recommended for hepatotoxicity during treatment (Stock 2011):

  • ALT/AST >3 to 5 times ULN:
    • starts therapy.
  • ALT/AST >5 to 20 times ULN:
    • Delay next dose until transaminases less than thrice times ULN.
  • ALT/AST >20 times ULN:
    • Discontinue therapy if takes longer than 7 days for transaminases to return to less than thrice times ULN.
  • Direct bilirubin <3 mg/dL:
    • Continue therapy.
  • Direct bilirubin 3.1 to 5 mg/dL:
    • Hold asparaginase and resume when direct bilirubin less than 2 mg per dL; consider switching to alternate asparaginase product.
  • Direct bilirubin >5 mg/dL:
    • stops asparaginase; do not make up for missed doses; do not substitute other asparaginase products.

Onconase (E. coli Asparaginase) Side effects:

• Cardiovascular:

  • Cerebrovascular accident (hemorrhagic stroke and thrombotic stroke, thrombosis (including cerebral thrombosis)

• Central Nervous System:

  • Cerebral hemorrhage
  • Cerebrovascular hemorrhage
  • Central nervous system disease (disorientation, mild depression, delusion,  Parkinsonian-like syndrome, personality disorder, and seizure)

• Endocrine & metabolic:

  • Amenorrhea
  • Hyperglycemia
  • Hypertriglyceridemia
  • Hypoalbuminemia
  • Hypocholesterolemia
  • Increased uric acid
  • Decreased glucose tolerance
  • Hyperammonemia (with clinical signs of metabolic encephalopathy such as impaired consciousness with confusion, coma, and stupor])
  • Hypercholesterolemia
  • Weight loss

• Gastrointestinal:

  • Cholestatic injury
  • Diarrhea (infrequent)
  • Intestinal perforation (rare)
  • Nausea (frequent, but rarely severe; nauses may be due to increased blood urea nitrogen and increased uric acid)
  • Abdominal pain (infrequent)
  • Acute pancreatitis (may be fatal)
  • Vomiting (frequent, but rarely severe; may be due to increased blood urea nitrogen and increased uric acid)

• Genitourinary:

  • Azoospermia

• Hematologic:

  • Antithrombin III deficiency
  • Prolonged partial thromboplastin time
  • Blood coagulation disorder (change in hemostatic function)
  • Bone marrow depression
  • Decreased clotting factors (factors VII, VIII, IX, and X)
  • Decreased plasminogen
  • Hypofibrinogenemia
  • Prolonged prothrombin time

• Hepatic:

  • Hyperbilirubinemia
  • Increased serum alkaline phosphatase
  • Increased serum ALT
  • Increased serum AST (mild)
  • Jaundice
  • Hepatic injury
  • Hepatotoxicity (usually mild and regressive, but may be fatal rarely)
  • Liver steatosis

• Hypersensitivity:

  • Allergic reactions (includes  bronchospasm, edema, hypotension, laryngeal edema, skin rash, urticaria, anaphylactic shock, and anaphylaxis;
    • allergic reactions usually occur within one hour of administration and the risk increases with the increasing number of exposures)

• Immunologic:

  • Increased serum globulins (beta and gamma)

• Infection:

  • Septicemia (during bone marrow depression)

• Renal:

  • Renal failure
  • Increased blood urea nitrogen

• Respiratory:

  • Respiratory distress (with retrosternal pressure)

• Miscellaneous:

  • Fever

Contraindications to Onconase (E. coli Asparaginase):

• Known hypersensitivity to asparaginase or any component of formulation
• Asparaginase and severe pancreatitis in the past.
• Grave hepatic impairment
• Pancreatitis (current).
• Recent yellow fever vaccination
• Concurrent use of phenytoin

Warnings and precautions

• Allergic reactions: [Canadian Boxed Warn]

  • Patients with hypersensitivity to L-asparaginase or other forms may experience allergic reactions.
  • Watch for any reactions after administration. Reactions usually occur between 30 and 60 minutes (although they may occur later).
  • It is important to seek treatment as soon as possible for hypersensitivity reactions.
  • If you experience severe allergic reactions, discontinue use.
  • Asparaginase can cause allergic reactions if it is not used within 24 hours. IV administration, as opposed to SubQ or IM administration, may also be a risk.
  • Patients with an allergy to E.coli asparaginase could also be allergic to pegaspargase and asparaginase. (Erwinia).

• Coagulopathy

  • Hypofibrinogenemia, partial thromboplastin times, and increased prothrombin times may occur.
  • Monitor coagulation parameters at baseline, periodically during, and after therapy; hemorhage and cerebrovascular thrombosis have been reported.
  • Patients with underlying coagulopathy should be cautious.
  • If fibrinogen is below 1g/L, ATIII is below 60 percent, replacement therapy should be initiated.
  • Treatment should not be stopped if the laboratory parameters are normal.

• Hepatotoxicity: [Canadian Boxed Warn]

  • There may be adverse effects on the liver, including an exacerbation or worsening of liver disease (due to previous therapy)
  • Physicians must carefully weigh therapeutic benefits against toxicity risks.
  • Alterations in liver function tests, such as increased AST, ALT and alkaline phosphatase or decreased plasma fibrinogen, may occur.
  • Fulminant hepatic dysfunction has also been reported.
  • A biopsy may show fatty liver.
  • Take care and keep your liver function test at the minimum once a week during treatment. If you notice any changes, discontinue therapy.

• Hyperammonemia

  • This may cause excessive ammonia production. Monitor for signs of metabolic disorder (confusion, stupor and coma).

• Hyperglycemia

  • Hyperglycemia/glucose inlerance may occur (may not be reversible); diabetic ketoacidosis has been reported.
  • As clinically required, monitor blood glucose.

• Neurotoxicity:

  • Patients treated with asparaginase in combination with other chemotherapy agents have been known to develop posterior reversible syndrome (PRES).
  • Monitor for signs and symptoms of PRES (eg altered mental state, headaches, hypertensions, seizures, visual disturbances) and interrupt therapy if suspected.
  • Keep your blood pressure under control and watch out for seizures.

• Pancreatitis: [Canadian-Boxed Warning]

  • Patients with abdominal pain may develop severe and potentially fatal pancreatitis.
  • You may consider continuing therapy for symptomatic chemical pancreatitis (amylase/lipase >3x ULN) or radiologic abnormalities only; closely monitor for elevated amylase/lipase levels.
  • For clinical pancreatitis (eg vomiting, severe abdominal pain), with amylase/lipase elevation >3x ULN for >3 Days, and/or the development of a pseudocyst, discontinue use permanently
  • Avoid drinking alcohol.

• Thrombotic events

  • If serious thrombotic events happen, discontinue treatment.
  • Anticoagulation prophylaxis might be offered to some patients during therapy.
  • The risk of thrombosis in adult patients is higher for those who are older.

• Tumor lysis syndrome

  • To limit tumor lysis syndrome, uric acid neuropathy, and subsequent hyperuricemia, it is important to take appropriate measures.

coli asparaginase: Drug Interaction

Note: Drug Interaction Categories:

• • Risk Factor C: Monitor When Using Combination
  • Risk Factor D: Consider Treatment Modification
  • Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• CBC with differential,
• amylase,
• lipase,
• triglycerides,
• liver function prior to and weekly during therapy,
• coagulation parameters (baseline and prior to each injection),
• blood glucose,
• uric acid.
• Monitor for allergic reactions;
• monitor for the onset of abdominal pain and mental status changes.
• Monitor vital signs during administration.

How to administer Onconase (E. coli Asparaginase)?

• May be administered IV (preferred for intermittent consideration), or IM (preferred to be administered IM).
• This route has been considered SubQ (offlabel route) in certain protocols.
• To prevent hypersensitivity reaction, you may be given corticosteroids for up to two days before starting reinduction therapy.
• After consideration, monitor patients for one hour; provide diphenhydramine and epinephrine at the bedside. Accessible to a physician.

IM:

• Doses should only be administered intramuscularly into large muscles. Volumes greater than 2 mL should not be divided.

IV:

• Allow to infuse for at least 30 minutes using the sidearm of a D5W or NS infusion.

Mechanism of action of Onconase (E. coli Asparaginase):

• Asparaginase hydrolyzes L'asparagine into ammonia and L'aspartic acids in leukemic cells.
• This causes depletion. Exogenous asparagine is required for lymphoblasts and Leukemia cells.
• Normal cells can synthesize it. In leukemic cells, asparagine depletion leads to inhibition in protein synthesis and apoptosis. 
• The G phase of asparaginase has a cycle-specific structure.

Distribution: IV:

• Slightly higher than plasma volume;
• less than 1 percent CSF penetration

Metabolism:

• Systemically degraded

Half-life elimination:

• IM: 34 to 49 hours;
• IV: 8 to 30 hours

Time to peak, plasma:

• IM: 14 to 24 hours

International Brands of E. coli asparaginase:

• Kidrolase
• Asparaginase medac
• Colaspase
• Crasnitin
• Elspar
• Kidrolase
• L-aspase
• Laspar
• Leucoginase
• Leunase
• Oncaspar
• Onconase
• Paronal
• Spectrila

E. coli asparaginase Brands Names in Pakistan:

There is no brand available in Pakistan.