Asparaginase

Name: Asparaginase

Description

Elspar (asparaginase) contains the enzyme L-asparagine amidohydrolase, type EC-2, derived from Escherichia coli. Elspar activity is expressed in terms of International Units according to the recommendation of the International Union of Biochemistry. One International Unit of asparaginase is defined as that amount of enzyme required to generate 1 μmol of ammonia per minute at pH 7.3 and 37°C. The specific activity of Elspar is at least 225 International Units per milligram of protein.

Elspar is provided as a sterile, white lyophilized plug or powder. Each vial contains 10,000 International Units of asparaginase and 80 mg of mannitol.

Indications

Elspar is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL).

Clinical pharmacology

Mechanism of Action

The mechanism of action of Elspar is thought to be based on selective killing of leukemic cells due to depletion of plasma asparagine. Some leukemic cells are unable to synthesize asparagine due to a lack of asparagine synthetase and are dependent on an exogenous source of asparagine for survival. Depletion of asparagine, which results from treatment with the enzyme Lasparaginase, kills the leukemic cells. Normal cells, however, are less affected by the depletion due to their ability to synthesize asparagine.

Pharmacodynamics

The relationship between asparaginase activity and asparagine levels has been studied in clinical trials. In previously untreated, standard-risk ALL patients treated with native asparaginase in whom plasma enzyme activity was greater than 0.1 International Units/mL, plasma asparagine levels decreased from a pretreatment average level of 41 μM to less than 3 μM. In this study, cerebrospinal fluid asparagine levels in patients treated with asparaginase decreased from 2.8 μM (pretreatment) to 1.0 μM and 0.3 μM at day 7 and day 28 of induction, respectively.

Pharmacokinetics

In a study in patients with metastatic cancer and leukemia, daily intravenous administration of L-asparaginase resulted in a cumulative increase in plasma levels. Plasma half-life varied from 8 to 30 hours. Apparent volume of distribution was slightly greater than the plasma volume. Asparaginase levels in cerebrospinal fluid were less than 1% of concurrent plasma levels.

In a study in which patients with leukemia and metastatic cancer received intramuscular L-asparaginase, peak plasma levels of asparaginase were reached 14 to 24 hours after dosing. Plasma half-life was 34 to 49 hours.

Animal Toxicology

Edema and necrosis of pancreatic islets were observed in rabbits following a single, intravenous injection of 12,500 to 50,000 International Units Elspar/kg (approximately equivalent to 25 to 100fold the recommended human dose, when adjusted for total body surface area). These changes were not reflective of pancreatitis, and were not observed in rabbits following a single intravenous injection of 1000 International Units/kg (approximately equivalent to two times the recommended human dose, when adjusted for total body surface area).

Clinical Studies

Elspar was evaluated in an open-label, multi-center, single-arm study in which 823 patients less than 16 years of age with previously untreated acute lymphoblastic or acute undifferentiated leukemia received Elspar as a component of multi-agent chemotherapy for induction of first remission. Elspar was administered at a dose of 6,000 International Units/m² intramuscularly 3 times a week for a total of 9 doses. Of 815 evaluable patients, 758 (93%) achieved a complete remission. In a previous study, in a similar patient population, which utilized an initial induction chemotherapy regimen containing the same agents without Elspar, 429 of 499 (86%) patients achieved a complete remission.

What are some things I need to know or do while I take Asparaginase?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • Very bad bleeding and blood clots in the brain have happened with asparaginase and other drugs like it. Talk with the doctor.
  • Talk with your doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • If you have high blood sugar (diabetes), talk with your doctor. This medicine may raise blood sugar.
  • Check your blood sugar as you have been told by your doctor.
  • A very bad and sometimes deadly pancreas problem (pancreatitis) has happened with asparaginase. Talk with your doctor.
  • This medicine may stop menstrual periods in females and affect sperm in males. Talk with the doctor.
  • This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking this medicine, call your doctor right away.

How is this medicine (Asparaginase) best taken?

Use asparaginase as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • It is given as a shot into a muscle or vein.

What do I do if I miss a dose?

  • Call your doctor to find out what to do.

What are some other side effects of Asparaginase?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Upset stomach or throwing up.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about asparaginase, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about asparaginase. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using asparaginase.

Review Date: October 4, 2017

For the Consumer

Applies to asparaginase escherichia coli: injection solution reconstituted

For Healthcare Professionals

Applies to asparaginase escherichia coli: injectable powder for injection

Hematologic

Hematologic side effects have included a marked decrease in circulating lymphoblasts, with normal or below normal leukocyte counts, within the first days after initiating therapy. This is sometimes accompanied by a marked rise in serum uric acid. Pre-renal azotemia has also been reported.

Hypofibrinogenemia has been reported. Depression of other clotting factors including factors V and VIII (marked decreases) and factors VII and IX (variable decreases) have also been reported. A low incidence of decrease in circulating platelets has been reported. Bleeding has been reported in a minority of patients with a demonstrable coagulopathy. Intracranial hemorrhage and fatal bleeding associated with low fibrinogen levels have been reported. Compensatory increased fibrinolytic activity has also been reported.

Transient bone marrow depression has rarely been observed as evidenced by a delay in return of hemoglobin or hematocrit levels to normal in patients undergoing hematologic remission of leukemia. Marked leukopenia has also been reported.

Hypertriglyceridemia has been reported.[Ref]

Gastrointestinal

Gastrointestinal side effects have included nausea, vomiting, and anorexia. Acute hemorrhagic pancreatitis (sometimes fatal) has also been reported.[Ref]

General

General side effects include chills, fever, abdominal cramps, weight loss, and headache. Fatal hyperthermia has also been reported.[Ref]

Hepatic

Most hepatic abnormalities are usually reversible upon discontinuation of therapy and some reversal has been reported during the course of therapy.[Ref]

Hepatic side effects have included elevations of SGOT, SGPT, alkaline phosphatase, bilirubin, and depression of serum albumin, cholesterol, and plasma fibrinogen. Both increases and decreases in total blood lipids have been reported. Marked hypoalbuminemia associated with peripheral edema has been reported. Fatty changes in the liver have been documented by biopsy. Malabsorption syndrome has also been reported.[Ref]

Nervous system

Nervous system side effects have usually reversed spontaneously upon discontinuation of asparaginase.[Ref]

Nervous system side effects have included somnolence, fatigue, seizures, coma, and confusion. A Parkinson-like syndrome with tremor and a progressive increase in muscle tone has been reported rarely.[Ref]

Cardiovascular

Cardiovascular side effects have included one reported case of acute myocardial infarction.[Ref]

Dermatologic

Dermatologic side effects have included skin rashes and urticaria.[Ref]

Musculoskeletal

Musculoskeletal side effects have included arthralgia.[Ref]

Respiratory

Respiratory side effects have included respiratory distress.[Ref]

Metabolic

Metabolic side effects have included a low incidence of hyperglycemia with glycosuria and polyuria.[Ref]

The syndrome resembles hyperosmolar nonketonic hyperglycemia. While the syndrome usually responds to discontinuation of asparaginase, judicious use of IV fluid, and insulin, it has occasionally been fatal.[Ref]

Psychiatric

Psychiatric side effects have included depression, agitation, confusion, paranoia, and hallucinations.[Ref]

Renal

Renal side effects include acute renal shut down and fatal renal insufficiency. Proteinuria has been reported infrequently.[Ref]

Other

Serum concentrations of thyroxine-binding globulin have been reported to return to pretreatment values within four weeks of the last dose.[Ref]

Other side effects have included interference with the interpretation of thyroid function tests by production of a rapid and marked reduction in serum concentrations of thyroxine-binding globulin within days after the first dose.[Ref]

Oncologic

Oncologic side effects have included reports of small increases in pulmonary adenomas in animal studies..[Ref]

Immunologic

Immunosuppressive activity has been reported in animal experiments.[Ref]

Some side effects of asparaginase escherichia coli may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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