Asparaginase 5000iu Injection

What is asparaginase?

Asparaginase is a cancer medication that interferes with the growth of cancer cells and slows their growth and spread in the body.

Asparaginase is used to treat acute lymphocytic lymphoma.
Asparaginase may also be used for other purposes not listed in this medication guide.

What are the possible side effects of asparaginase?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

• severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;
• easy bruising or bleeding, unusual weakness;
• fever, chills, body aches, flu symptoms;
• sudden headache, confusion, problems with vision, speech, or balance;
• increased thirst or urination;
• agitation, hallucinations, seizure (convulsions);
• tremors, muscle stiffness; or
• urinating more or less than usual, or not at all.

Less serious side effects may include:

• mild skin rash or itching;
• depression, drowsiness;
• swelling in your hands, ankles, or feet;
• nausea, vomiting, loss of appetite, weight loss;
• stomach cramps; or
• headache, feeling tired or irritable.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 0-000-FDA-0000.

What is the most important information I should know about asparaginase?

Do not receive this medication if you are allergic to asparaginase or pegaspargase (Oncaspar), or if you have a history of liver disease or pancreas problems. Tell your doctor about all other cancer medications you are receiving.

Get emergency medical help if you think you have received too much of this medicine, or if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of the following side effects during your treatment with asparaginase:

• severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;
• easy bruising or bleeding, unusual weakness;
• fever, chills, body aches, flu symptoms;
• sudden headache, confusion, problems with vision, speech, or balance;
• agitation, hallucinations, seizure (convulsions); or
• urinating less than usual or not at all.

Asparaginase is highly toxic and both the powder and solution must be handled with care. Avoid inhaling vapors from the medicine, or allowing the medicine to come into contact with your skin, eyes, nose, or mouth. If the medicine gets on your skin, wash the area right away with soap and water. If the medicine gets into your eyes, rinse them for at least 15 minutes with water, saline, or other irrigating solution and seek emergency medical attention.

Avoid being near people who have colds, the flu, or other contagious illnesses. Contact your doctor at once if you develop signs of infection.

What should I discuss with my health care provider before receiving asparaginase?

Do not receive this medication if you are allergic to asparaginase or pegaspargase (Oncaspar), or if you have a history of pancreas problems.

If you have any of these other conditions, you may need a dose adjustment or special tests to safely use this medication:

• liver disease;
• gout;
• diabetes (asparaginase can raise blood sugar); or
• if you are being treated with other cancer medications.

FDA pregnancy category C. It is not known whether asparaginase is harmful to an unborn baby. Before using this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether asparaginase passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How is asparaginase given?

Asparaginase is given as an injection through an IV needle placed into a vein, or as a shot into a muscle. You will receive this injection in a clinic or hospital setting. The IV medicine must be given slowly, and it can take up to 30 minutes to complete.

Before you receive your first treatment with this medication, you may need a skin test to make sure you are not allergic to asparaginase.

Asparaginase can lower the blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. To be sure your blood cells do not get too low, your blood will need to be tested on a regular basis. Do not miss any scheduled visits to your doctor.

This medication can cause you to have unusual results with certain thyroid tests. Tell any doctor who treats you that you are receiving asparaginase.

What happens if I miss a dose?

Contact your doctor if you miss an appointment for your asparaginase injection.

What happens if I overdose?

Seek emergency medical attention if you think you have received too much of this medicine. Overdose symptoms may include easy bruising or bleeding, unusual weakness, fever, chills, flu symptoms, confusion, agitation, hallucinations, urinating less than usual or not at all, and seizure (convulsions).

What should I avoid while receiving asparaginase?

Asparaginase is highly toxic and both the powder and solution must be handled with care. Avoid inhaling vapors from the medicine, or allowing the medicine to come into contact with your skin, eyes, nose, or mouth. If the medicine gets on your skin, wash the area right away with soap and water. If the medicine gets into your eyes, rinse them for at least 15 minutes with water, saline, or other irrigating solution and seek emergency medical attention.

Avoid being near people who have colds, the flu, or other contagious illnesses. Contact your doctor at once if you develop signs of infection.

What other drugs will affect asparaginase?

Before receiving asparaginase, tell your doctor if you are using any of the following drugs:

• vincristine (Oncovin, Vincasar);
• prednisone (Deltasone, Meticorten, Orasone, and others); or
• methotrexate (Folex, Rheumatrex, Trexall).

This list is not complete and there may be other drugs that can interact with asparaginase. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Asparaginase 5000iu Injection

Indications and Usage

Asparaginase Erwinia chrysanthemi is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E.coli-derived asparaginase.

DOSAGE AND ADMINISTRATION

Recommended Dose

To substitute for a dose of pegaspargase:
The recommended dose is 25,000 International Units/m² administered intramuscularly three times a week (Monday/Wednesday/Friday) for six doses for each planned dose of pegaspargase.

To substitute for a dose of native E. coli asparaginase:
The recommended dose is 25,000 International Units/m² administered intramuscularly for each scheduled dose of native E. coli asparaginase within a treatment.

Preparation Instructions

• Visually inspect the Asparaginase powder for foreign particulate matter and discoloration prior to reconstitution. Discard vial if present.
• Reconstitute the contents of each vial by slowly injecting 1 or 2 mL of preservative free sterile sodium chloride (0.9%) injection (USP) 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 International Units per mL. When reconstituted with 2 mL the resultant concentration is 5,000 International Units per mL.
• Dissolve contents by gentle mixing or swirling. Do not shake or invert vial.
• When reconstituted, Asparaginase should be a clear, colorless solution. Discard 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. Do not freeze or refrigerate reconstituted solution and administer within 4 hours or discard.

Administration Instructions

• Inject Asparaginase solution intramuscularly.
• Limit the volume of reconstituted Asparaginase at a single injection site to 2 mL; if reconstituted dose to be administered is greater than 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.

DOSAGE FORMS AND STRENGTHS

Lyophilized powder 10,000 International Units per vial

CONTRAINDICATIONS

• History of serious hypersensitivity reactions to Asparaginase, 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

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions

Grade 3 and 4 hypersensitivity reactions after the use of Asparaginase have occurred in 5% of patients in clinical trials. Anaphylaxis after the use of Asparaginase has occurred in 0.8% of patients in clinical trials.

Administer this product in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. If a serious hypersensitivity reaction occurs, discontinue Asparaginase and initiate appropriate therapy.

Pancreatitis

Pancreatitis has been reported with Asparaginase therapy in 4% of patients in clinical trials.

Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis. Discontinue Asparaginase for severe or hemorrhagic pancreatitis manifested by abdominal pain > 72 hours and amylase elevation ≥ 2.0 x ULN. Severe pancreatitis is a contraindication to additional asparaginase administration. In the case of mild pancreatitis, hold Asparaginase until the signs and symptoms subside and amylase levels return to normal. After resolution, treatment with Asparaginase may be resumed.

Glucose Intolerance

Glucose intolerance has been reported with Asparaginase therapy in 4% of patients in clinical trials and, in some cases, may be irreversible. Monitor glucose levels in patients at baseline and periodically during treatment. Administer insulin therapy as necessary in patients with hyperglycemia.

Thrombosis and Hemorrhage

Serious thrombotic events, including sagittal sinus thrombosis have been reported with both E. coli and Erwinia-derived L-asparaginase therapy. The following coagulation proteins were decreased in the majority of patients after a 2-week course of Asparaginase: fibrinogen, protein C activity, protein S activity, and anti-thrombin III. Discontinue Asparaginase for a thrombotic or hemorrhagic event until symptoms resolve; after resolution, treatment with Asparaginase may be resumed.

ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Hypersensitivity reactions
• Pancreatitis
• Glucose intolerance
• Thrombosis and hemorrhage

The most common adverse reactions (incidence 1% or greater) with Asparaginase treatment are systemic hypersensitivity, hyperglycemia, abnormal transaminases, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.

Clinical Studies

Because clinical trials are conducted under controlled, but widely varying conditions, adverse reaction rates observed in clinical trials of Asparaginase cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

The data presented below are based on information collected from Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial and the Asparaginase Master Treatment Protocol (EMTP), an expanded access program. Study 1 enrolled 58 patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. Patients received 6 doses of Asparaginase 25,000 International Units/m² intramuscularly on a Monday, Wednesday, and Friday schedule as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol. The Study 1 population included patients with a median age of 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino. In Study 1, the number of Asparaginase courses ranged from 1 to 9. In this study, 76% (44 of 58) completed all planned therapy. Fourteen (24%) patients stopped therapy prior to completion; seven due to allergic reactions, five due to physician or patient choice, one due to disease progression, and one due to discontinuation during frontline protocol. All other chemotherapy was continued according to the patient’s prescribed treatment regimen.

The EMTP trial had enrolled 1368 patients with ALL or lymphoblastic lymphoma who received Asparaginase after developing systemic hypersensitivity to an E. coli-derived asparaginase. Of these 1368 patients, safety data were received for 940 patients with a median age of 9 years (1 to 76 years), 63% were male, 91% with leukemia, and 3% with lymphoma, and 6% with unknown disease information. Patients received Asparaginase according to several schedules, and treatment center specifications with doses that ranged from 20,000 to 25,000 International Units/m². In the EMTP trial, the planned number of doses of Asparaginase ranged from 3 to 48 doses. Seventy-eight percent of patients (693 of 893) were able to receive all planned doses to complete their prescribed treatment regimen.

In Study 1, safety information included all reported adverse events with systematic collection of the following adverse events of special interest: allergy, pancreatitis, coagulopathy (hemorrhage, thrombosis or infarct), hyperbilirubinemia, hyperglycemia, hyperlipidemia, ketoacidosis, and CNS events (hemorrhage, thrombosis or infarction, cerebral venous thrombosis). EMTP safety data were derived from case report forms that collected adverse event information. The forms specifically requested information on occurrence of allergic reactions, thrombotic events, hemorrhagic events, hepatobiliary disorders, pancreatic disorders, and hyperglycemia.

The combined incidence of non-hematologic, non-infectious, adverse reactions (all Grades) occurring with Asparaginase in Study 1 and the EMTP trial is provided in Table 1. The incidence of Grade 3 or greater non-hematologic, non-infectious adverse reactions occurring with Asparaginase in each individual Study is provided in Table 2.

Immunogenicity

There is a potential for immunogenicity with therapeutic proteins such as Asparaginase. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Asparaginase with the incidence of antibodies to other products may be misleading.

There is insufficient information to characterize the incidence of antibodies to Asparaginase.

DRUG INTERACTIONS

No formal drug interaction studies between Asparaginase and other drugs have been performed.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy category C

Risk Summary
There are no adequate and well-controlled studies of Asparaginase in pregnant women. In embryofetal development studies in rats and rabbits, asparaginase Erwinia chrysanthemi produced embryofetal toxicities and fetal abnormalities. Asparaginase should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data
In embryofetal development studies, asparaginase Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats (at 500, 1000, or 2000 IU/kg) and rabbits (at 10, 25, and 40 IU/kg). In rats given 2000 IU/kg (approximately 50% of the recommended human dose, adjusted for body surface area), maternal toxicity of decreased body weight gain was observed, as well as a fetal finding of increased incidence of partially undescended thymic tissue.

In rabbits, maternal toxicity consisting of decreased body weight was observed at 40 IU/kg (approximately 2% of the recommended human dose, adjusted for body surface area). Increased post-implantation loss, a decrease in the number of live fetuses, and gross abnormalities (e.g., absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) were observed at doses of ≥10 IU/kg (approximately 0.5% of the recommended human dose, adjusted for body surface area).

Nursing Mothers

It is not known whether Asparaginase is secreted in human milk. Because many drugs are secreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Asparaginase, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

[seeClinical Studies  (14)].

Geriatric Use

The safety and efficacy of Asparaginase has not been studied in geriatric patients.

OVERDOSAGE

There are no known cases of overdose with Asparaginase.

DESCRIPTION

Asparaginase (asparaginase Erwinia chrysanthemi) contains an asparagine specific enzyme derived from Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme consisting of four identical subunits, each having a molecular weight of about 35 kDa. The activity of Asparaginase is expressed in terms of International Units.

Asparaginase is supplied as a sterile, lyophilized, white powder in vials. Each vial contains 10,000 International Units of asparaginase Erwinia chrysanthemi, and the following inactive ingredients: glucose monohydrate (5.0 mg), sodium chloride (0.5 mg).

CLINICAL PHARMACOLOGY

Mechanism of Action

Asparaginase Erwinia chrysanthemi catalyzes the deamidation of asparagine to aspartic acid and ammonia, resulting in a reduction in circulating levels of asparagine. The mechanism of action of Asparaginase is thought to be based on the inability of leukemic cells to synthesize asparagine due to lack of asparagine synthetase activity, resulting in cytotoxicity specific for leukemic cells that depend on an exogenous source of amino acid asparagine for their protein metabolism and survival.

Pharmacokinetics

The pharmacokinetics of Asparaginase has not been characterized. The serum trough concentrations of asparaginase Erwinia chrysanthemi were determined in 48 ALL patients aged ≥ 2 year to ≤ 18 years enrolled in Study 1 [see Clinical Studies (14)]. Following administration of Asparaginase 25,000 International Units/m² intramuscularly on a Monday, Wednesday, and Friday schedule for 6 doses, 100% of patients in course 1 achieved serum trough asparaginase concentrations ≥ 0.1 International Units/mL at either 48-hour (n=35) or 72-hour (n=13) post dose 3. Eighty percent (28/35) of those evaluated at 48 hours and 38% (5/13) evaluated at 72 hours had serum asparaginase activity levels ≥ 0.4 International Units/mL.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term carcinogenicity studies in animals have been performed with asparaginase Erwinia chrysanthemi. No studies that assess the mutagenic potential of asparaginase Erwinia chrysanthemi have been conducted.

In a fertility and early embryonic development study in rats, asparaginase Erwinia chrysanthemi had no effect on male or female fertility when administered intramuscularly at doses of up to 2000 IU/kg (approximately 50% of the recommended human dose, when adjusted for total body surface area) every other day for a total of 35 doses. Findings in males included decreased sperm count at doses of more than 500 IU/kg (approximately 12% of the recommended human dose).

CLINICAL STUDIES

The safety and efficacy of Asparaginase was established in Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial.  Additional safety data was obtained in the Asparaginase Master Treatment Protocol (EMTP), an expanded access program. Study 1 enrolled patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions.  The main outcome measure was determination of the proportion of patients who achieved a serum trough asparaginase level greater than or equal to 0.1 International Units/ mL.  Serum trough asparaginase activity ≥ 0.1 International Units/ mL has been demonstrated to correlate with asparagine depletion (asparagine < 0.4 mcg/mL or 3 µM) and to serum levels that predict clinical efficacy.   Patients received Asparaginase 25,000 International Units/m² intramuscularly for two weeks (total 6 doses) as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol.

Fifty-eight patients were enrolled in Study 1, of these 48 were evaluable for the main outcome measure based on availability of pharmacokinetic samples in course 1.  The median age was 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino.   

Study 1 met its main outcome measure of demonstrating that greater than 50% of the patients achieved the pre-specified trough asparaginase activity level of ≥ 0.1 International Units/ mL at 48 or 72 hours following the third dose. Results for the main outcome measure and for an exploratory analysis using a higher cut-off (trough serum asparaginase activity levels ≥ 0.4 International Units/mL are presented in Table 3. 

16 HOW SUPPLIED/STORAGE AND HANDLING

Asparaginase is a sterile, white lyophilized powder supplied in a clear 3 mL glass vial. Each carton of Asparaginase (NDC 57902-249-05) contains 5 vials. Each single vial (NDC 57902-249-01) contains 10,000 International Units asparaginase Erwinia chrysanthemi.

Store unused or unopened vials and cartons at 36°F to 46°F (2°C to 8°C). Protect from light. Do not use Asparaginase after the expiration date on the vial.

17 PATIENT COUNSELING INFORMATION

• Instruct patients on the risk of allergic reactions, including anaphylaxis. Describe the symptoms of allergic reactions, including anaphylaxis, and instruct the patient to seek medical advice immediately if they experience such symptoms.
• Instruct patients on the risk of pancreatitis and to seek medical advice immediately if they experience abdominal pain.
• Instruct patients on the risk of hyperglycemia and glucose intolerance. Advise patients to seek medical advice if they experience excessive thirst or any increase in the volume or frequency of urination.
• Instruct patients on the risk of thrombosis and hemorrhage and to seek medical advice immediately if they experience headache, arm or leg swelling, shortness of breath, and chest pain.