asparaginase Erwinia chrysanthemi (Rx)

>10%

Hypersensitivity reactions, including anaphylaxis (17%)

1-10%

Hypersensitivity, grades 3/4 (5%)

Glucose intolerance (5%)

Pancreatitis (4%)

Fever (3%)

Coagulation abnormalities (3%)

Thrombosis (2%)

Hyperglycemia (2%)

Headache (1%)

Hyperbilirubinemia (1%)

Abnormal transaminases (>1%)

Coagulation abnormalities including thrombosis and hemorrhage (>1%)

Nausea (>1%)

Vomiting (>1%)

Postmarketing reports

Abdominal pain/discomfort

Diarrhea

Local reactions

Contraindications

History of serious hypersensitivity reactions to asparaginase Erwinia chrysanthemi, including anaphylaxis

History of serious pancreatitis with prior L-asparaginase therapy

History of serious thrombosis with prior L-asparaginase therapy

History of serious hemorrhagic events with prior L-asparaginase therapy

Cautions

Serious hypersensitivity reactions, including anaphylaxis have occurred; administer in setting with resuscitation equipment; discontinue drug if hypersensitivity reaction occurs

Glucose intolerance reported and in some cases, may be irreversible; monitor serum glucose levels at baseline and periodically during treatment

Serious thrombotic events, including sagittal sinus thrombosis reported with both E. coli and Erwinia-derived L-asparaginase therapy; coagulation proteins were decreased in the majority of patients after a 2-week course (eg, fibrinogen, protein C activity, protein S activity, and anti-thrombin III); discontinue for a thrombotic or hemorrhagic event until symptoms resolve; after resolution, treatment may resume

Pancreatitis

• Pancreatitis reported during clinical trials
• Discontinue drug for severe or hemorrhagic pancreatitis manifested by abdominal pain >72 hr and amylase elevation 2.0 x ULN or more
• Mild pancreatitis: hold drug until signs and symptoms subside, and amylase levels return to normal; after resolution, treatment may resume

Pregnancy

Based on findings from animal reproduction studies, therapy can cause fetal harm when administered to a pregnant woman; there are no available data use in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes; advise pregnant women of potential risk to fetus

Pregnancy testing is recommended for females of reproductive potential before starting treatment

Contraception

• Therapy can cause embryo-fetal harm when administered to pregnant women; advise females of reproductive potential to use effective contraception during treatment and for 3 months after final dose; since an indirect interaction between oral contraceptives and ddrug cannot be ruled out, a method of contraception other than oral contraceptives should be used in women of childbearing potential

Animal data

• In animal reproduction studies, intramuscular administration of drug to pregnant rats and rabbits during organogenesis at doses approximately 0.005-0.5 times maximum recommended human dose resulted in structural abnormalities and embryo-fetal mortality

Lactation

There are no data on presence in human or animal milk, effects on breastfed child, or on milk production; because of potential for serious adverse reactions in breastfed child, advise patients that breastfeeding is not recommended during treatment and for 3 months after last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Catalyzes deamidation of asparagine to aspartic acid and ammonia, thereby reducing circulating levels of asparagine

The mechanism of action is thought to be based on the inability of leukemic cells to synthesize asparagine due to lack of asparagine synthetase activity

The lack of asparagine synthetase activity results in cytotoxicity specific for leukemic cells that depend on an exogenous source of the amino acid asparagine for their protein metabolism and survival

Pharmacokinetics

Serum trough concentration: 0.1 IU/mL or greater at 48-72 hr

Serum activity levels 0.4 IU/mL or greater shown in 80% at 48 hr and in 38% at 72 hr

Half-life: 16 hr (IM)

IM Preparation

Visually inspect the powder for foreign particulate matter and discoloration prior to reconstitution; do use vial if present

Reconstitute vial contents by slowly injecting 1 or 2 mL of preservative free sterile sodium chloride (0.9%) injection against the inner vial wall

Do not forcefully inject solution for reconstitution directly onto or into the powder

When reconstituted with 1 mL the resultant concentration is 10,000 IU/mL

When reconstituted with 2 mL the resultant concentration is 5,000 IU/mL

Dissolve contents by gentle mixing or swirling; do not shake or invert vial When reconstituted, solution should be a clear and colorless

Do not use the reconstituted solution if any visible particles or protein aggregates are present

Calculate the dose needed and the volume needed to obtain the calculated dose

Withdraw the volume containing the calculated dose from the vial into a polypropylene syringe within 15 minutes of reconstitution

Administer within 4 hr or discard

IM Administration

Limit volume of single injection site to 2 mL; if volume of dose exceeds 2 mL, use multiple injection sites

If a partial vial is used, do not save or reuse the unused drug for later administration; discard unused portions

IV Preparation

Slowly inject the reconstituted asparaginase into an IV infusion bag containing 100 mL of 0.9%NaCl acclimatized to room temperature

Do not shake or squeeze IV bag

If partial vial is used, do not save or reuse the unused drug for later administration; discard unused portions

IV Administration

Infuse asparaginase in 100 mL of normal saline over 1-2 hr

Do not infuse other drugs through same IV line while administering asparaginase

Storage

Store unused or unopened vials and cartons at 36-46°F (2-8°C) and protect from light

Do not freeze or refrigerate reconstituted solution