Allopathy
Prescription Required
DCGI (Drugs Controller General of India)
Schedule H
Asparaginase is an antineoplastic agent belonging to the pharmacological class of bacterial enzymes.
Asparaginase is also known as Asparaginase Erwinia chrysanthemi, an asparaginase-specific enzyme derived from Erwinia chrysanthemi.
The FDA approves Asparaginase to treat acute lymphoblastic leukaemia (ALL).
Asparaginase is administered intramuscularly or intravenously to prevent systemic absorption. About 20% of its distribution occurs in the lymphatic system, with the intravascular space accounting for the majority. It is primarily metabolized in the liver, where it is thought that catabolic pathways break down the material into smaller peptides. Urine contains trace amounts that are excreted.
The most common side effects of Asparaginase include breathlessness, rash, vomiting, angioedema (swelling of deeper layers of skin), and nausea.
Asparaginase is available as a powder for injections.
The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.
Asparaginase is an antineoplastic agent belonging to the pharmacological class of bacterial enzymes.
Asparaginase catalyzes the amino acid's deamidation to aspartic acid and ammonia, lowering the amount of L-asparagine in the blood. Leukemic cells, which lack asparagine synthetase and are dependent on an exogenous source of asparagine for survival, endure an inhibition of their cellular proliferation. It is derived from Erwinia chrysanthemi as crisantaspase or E. Coli as colaspase (unconjugated) and pegaspargase (conjugated with polyethene glycol).
As crisantaspase, the peak plasma concentration for Asparaginase is 1-2 hours.
Injectable solutions: To be administered parenterally as applicable.
The physician recommends taking this medication once daily, with or without food.
Patients with acute lymphoblastic leukaemia (ALL) who have developed a hypersensitivity to Asparaginase derived from Escherichia coli should be treated with an asparagine-specific enzyme as part of a multiagent chemotherapy regimen.
Parenterally: Asparaginase should be injected intramuscularly (IM) or intravenously (IV). Inject the drug into the muscle for intramuscular delivery and directly infuse it into a vein for intravenous delivery. Examine the powder visually for foreign particles and discolouration before reconstitution; if the vial is present, do not use it. Give Asparaginase a one to two-hour infusion in 100 millilitres of normal saline. Do not inject any other medication via the same IV line when administering Asparaginase. To maximize the therapeutic benefits of treating some types of leukaemia, especially Acute Lymphocytic Leukemia (ALL), ensure the dosage is precisely calculated and the recommended treatment schedule is followed.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
3750IU/vial, 5000 IU/ vial, 10,000 IU/vial
Asparaginase is available as a powder for injections.
Dose Adjustment in Adult Patients:
Acute Lymphoblastic Leukemia
Pegaspargase substitute: 25,000 IU/m² IM/IV For each scheduled dosage of pegaspargase, administer six doses three times a week on Monday, Wednesday, and Friday.
The recommended substitution for native E. coli asparaginase is 25,000 IU/m² IM/IV for each scheduled dose.
Avoid foods high in asparagine when taking Asparaginase, such as protein-rich sources like meat, dairy, and nuts. To prevent dehydration, patients are advised to prioritize staying hydrated, maintaining a well-balanced diet, and drinking certain fluids daily. It is crucial to check blood cell counts regularly and report any unusual bleeding or bruises immediately. Effective contraception is recommended due to the possibility of fetal harm. When treating patients who already have kidney or liver problems, use caution.
The dietary restriction should be individualized as per patient requirements.
- History of severe pancreatitis,
- hypersensitivity,
- history of hemorrhagic extreme events,
- Pre-existing known coagulopathy (e.g. haemophilia),
- serious thrombotic (e.g. sagittal sinus thrombosis, pulmonary embolism) and haemorrhagic events related to asparaginase therapy,
- lactation,
- severe hepatic impairment (as colaspase),
- Monitor closely for severe hypersensitivity reactions, such as anaphylaxis. Give in an environment with resuscitation equipment. If a hypersensitivity reaction happens, stop taking the medication immediately.
- Maintain a watch for signs of potentially irreversible glucose intolerance. At the beginning of treatment, regularly check your serum glucose levels.
- L-asparaginase therapy derived from Erwinia and E. coli has been associated with severe thrombotic events, such as sagittal sinus thrombosis. After a 2-week course, most patients showed decreased levels of coagulation proteins, including fibrinogen, protein C activity, protein S activity, and anti-thrombin III. If one experiences a thrombotic or hemorrhagic episode, stop taking the medication until the symptoms go away and then resume the course of therapy.
- Monitor closely for symptoms of pancreatitis. Discontinue the medication if the symptoms of severe or hemorrhagic pancreatitis include amylase elevation ≥2.0 times the upper limit of normal (ULN) and abdominal pain that lasts longer than 72 hours. If you have mild pancreatitis, stop taking the medication until the symptoms disappear and your amylase levels return to normal. Treatment can then be restarted. Quickly focusing on potential pancreatic complications needs vigilant monitoring.
Alcohol Warning
Breast Feeding Warning
Pregnancy Warning
Food Warning
The adverse reactions related to Asparaginase can be categorized as:
- Common Adverse Effects: Hypersensitivity reactions, including anaphylaxis
- Less Common Adverse Effects: Hypersensitivity reactions (grades 3/4), pancreatitis, fever, hyperglycemia, headache, hyperbilirubinemia, abnormal transaminases, and gastrointestinal symptoms like nausea and vomiting.
- Rare Adverse Effects: Irreversible glucose intolerance, thrombotic events, and coagulation abnormalities.
Reports from postmarketing
stomach ache or discomfort
diarrhoea
local reactions
The clinically relevant drug interactions of Asparaginase are briefly summarized here.
An increased risk of neurotoxicity and anaphylaxis when using vincristine. It may make coagulation abnormalities more likely when combined with corticosteroids (e.g., prednisone). May lessen methotrexate's effects on malignant cells. It could increase the level of dexamethasone in the blood.
The common side effects of Asparaginase include
- Breathlessness
- Rash
- Nausea
- Fatigue
- Emesis
- Hives
- Angioedema (swelling of the skin's deeper layers)
- Edema or swelling
- Elevated hepatic enzymes
- Diarrhea
- Lower blood pressure
- Warmth in the face, neck, ears, and trunk is known as flushing.
- Reduced blood albumin levels
- Elevated blood glucose levels
- Pregnancy
Pregnancy Category C (FDA): Use caution if the benefits outweigh the risks.
Pregnant women who receive therapy may experience fetal harm based on findings from animal reproduction studies; there is no data available to assess the drug's association with a risk of significant congenital disabilities, miscarriage, or other unfavourable outcomes for the mother or fetus; pregnant women should be advised of this potential risk.
For females who are capable of reproducing, pregnancy testing should be done before beginning treatment.
It is advised that women of reproductive potential use effective contraception during treatment and for atleast three months after the final dose. Since there is no guarantee that oral contraceptives and drugs won't interact indirectly, women of childbearing potential should use a method of contraception other than oral contraceptives.
Animal data
The intramuscular administration of drugs at doses approximately 0.005-0.5 times the maximum recommended human dose during organogenesis in pregnant rats and rabbits during animal reproduction studies resulted in structural abnormalities and embryo-fetal mortality.
- Nursing Mothers
It is advised to patients that breastfeeding is not recommended during treatment and for three months following the last dose due to the possibility of severe adverse reactions in breastfed children. There is no data regarding the presence of this substance in human or animal milk, its effects on milk production, or its effects on the child.
- Pediatric Use
As per the FDA, long-term use and clinical trials have proved the safety and effectiveness of Asparaginase in pediatric patients. It helps with pediatric outcomes and remission rates by specifically depleting asparagine.
Dose Adjustments
Acute Lymphoblastic Leukemia
≥1 year: 25,000 IU/m³ IM/IV as a pegaspargase substitute. For every scheduled dosage of pegaspargase, administer six doses three times a week on Monday, Wednesday, and Friday.
For each scheduled dose of native E. coli asparaginase, substitute 25,000 IU/m² IM/IV.
Dose Adjustment in Kidney Impairment Patients:
Renal impairment: No dose adjustment is needed.
Dose Adjustment in Hepatic Impairment Patients:
Mild - moderate hepatic impairment, there is no need for a modification in dosage.
Severe hepatic impairment: Not recommended
Pharmacodynamics
Asparaginase Erwinia chrysanthemi is an enzyme that causes leukaemia cells to become cytotoxic by reducing the availability of asparagine. This amino acid is essential for malignant cell survival, proliferation, and protein metabolism.
Pharmacokinetics
- Absorption: Asparaginase is not absorbed systemically when injected intramuscularly or intravenously. The medication acts only at the site of administration, where it catalyzes asparagine's hydrolysis.
- Distribution: Approximately 20% of the drug is found in the lymphatic system, with the intravascular space making up most of its distribution.
- Metabolism: Asparaginase is influenced by metabolic processes, primarily in the liver. Catabolic pathways are believed to be responsible for the breakdown into small peptides, even though specific metabolic pathways are still not fully understood.
- Excretion: Urine contains trace amounts of the drug. The elimination half-life of Colaspase varies from 14.2 to 44.2 hours. The elimination half-lives of crizantaspase are roughly 7.5 hours when administered intravenously and 16 hours when administered intramuscularly.
- Maese L, Rau RE. Current Use of Asparaginase in Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma. Front Pediatr. 2022 Jun 30;10:902117. doi: 10.3389/fped.2022.902117. PMID: 35844739; PMCID: PMC9279693.
- Chand S, Mahajan RV, Prasad JP, Sahoo DK, Mihooliya KN, Dhar MS, Sharma G. A comprehensive review on microbial l-asparaginase: Bioprocessing, characterization, and industrial applications. Biotechnol Appl Biochem. 2020 Jul;67(4):619-647. doi: 10.1002/bab.1888. Epub 2020 Feb 18. PMID: 31954377.
- Maese L, Rau RE. Current Use of Asparaginase in Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma. Front Pediatr. 2022 Jun 30;10:902117. doi: 10.3389/fped.2022.902117. PMID: 35844739; PMCID: PMC9279693.
- Avramis VI, Tiwari PN. Asparaginase (native ASNase or pegylated ASNase) in the treatment of acute lymphoblastic leukemia. Int J Nanomedicine. 2006;1(3):241-54. PMID: 17717965; PMCID: PMC2426805.
- KD Tripathi. [link]. Seventh Edition. New Delhi, India: Jaypee Brothers Medical Publishers; 2013: Page No 868-869
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125359s088lbl.pdf
- https://www.ncbi.nlm.nih.gov/books/NBK548488/
- April Hazard Vallerand, Cynthia A. Sanoski. [link]. Sixteenth Edition. Philadelphia, China: F. A. Davis Company; 2019: Page No 190-191
