ASPRAGINAZ 5000

Each vial contains:
L-Asparaginase …………..5000 I.U.
Glycine IP……………………q.s.
Water for Injection IP…………q.s.

ASPRAGINAZ 10000

Each vial contains:
L-Asparaginase …………..10000 I.U.
Glycine IP………………   …q.s.
Water for Injection IP…………q.s.

DOSAGE FORM
Lyophilized Powder for Injection.

 

ASPRAGINAZ (L-Asparaginase) is indicated in the therapy of patients with acute lymphocytic leukemia. This agent is useful primarily in combination with other chemotherapeutic agents in the induction of remissions of the disease in pediatric patients.

ASPRAGINAZ (L-Asparaginase) should not be used as the sole induction agent unless combination therapy is deemed inappropriate.

ASPRAGINAZ (L-Asparaginase) is not recommended for maintenance therapy.

This drug may have toxic properties and must be handled and administered with care Special handling procedures should be reviewed prior to handling and followed diligently during reconstitution and administration. Inhalation of dust or aerosols and contact with skin or mucous membranes, especially those of the eyes, must be avoided. (See DOSAGE AND METHOD OF ADMINISTRATION, Special Handling).

As a component of selected multiple agent induction regimens, ASPRAGINAZ (L-Asparaginase) may be administered by either the intravenous or the intramuscular route. When administered intravenously this enzyme should be given over a period of not less than thirty minutes through the side arm of an already running infusion of Sodium Chloride Injection or Dextrose Injection 5%. ASPRAGINAZ (L-Asparaginase) has lithe tendency to cause phlebitis when given intravenously. Anaphylactic reactions require the immediate use of epinephrine, oxygen, and intravenous steroids.

When administering ASPRAGINAZ (L-Asparaginase) intramuscularly, the volume at a single injection site should be limited to 2 ml. If a volume greater than 2 ml is to be administered, two injection sites should be used. Unfavorable interactions of ASPRAGINAZ (L-Asparaginase) with some antitumor agents have been demonstrated. It is recommended therefore, that ASPRAGINAZ (L-Asparaginase) be used in combination regimens only by physicians familiar with the benefits and risks of given regimen. During the period of its inhibition of protein synthesis and cell replication, Unfavorable interactions of ASPRAGINAZ (L-Asparaginase) may interfere all the action of drugs such as methotrexate which require cell replication for their lethal effect ASPRAGINAZ (L-Asparaginase) may interfere with the enzymatic detoxification of other drugs, particularly in the liver.

Recommended Induction Regimens: When using chemotherapeutic agents in combination for the induction of remissions in patients with acute lymphocytic leukemia, regimens are sought which provide maximum chance of success while avoiding excessive cumulative toxicity or negative drug interactions.

One of the following combination regimens incorporating ASPRAGINAZ (L-Asparaginase) is recommended for acute lymphocytic leukemia in pediatric patients.

In the Regimens below, Day 1 is considered to be the first day of therapy.

Regimen I

 

• Prednisone 40 mg/m2 per day orally in three divided doses for 15 days, followed by tapering of the dosage as follows: 20 mg/m’ for 2 days, 10 mg/m2 for 2 days, 5 mg/m2 for 2 days, 2.5 mg/m2 for 2 days, and then discontinue.

• Vincristine Sulfate, 2 mg/m2 of body surface area intravenously once weekly on Days1, 8, and 15 of the treatment period. The maximum single dose should not exceed 2.0 mg.
• L-Asparaginase 1,000 I.U./kg/day intravenously for ten successive days beginning on Day 22 of the treatment period.

 

Regimen II

 

• Prednisone 40 mg/m2 per day orally in three divided doses for 28 days (the total daily dose should be to the nearest 2.5 mg), following which the dosage of prednisone should be discontinued gradually over a 14 day period.

• Vincristine Sulfate 1.5 mg/m2 intravenously weekly for four doses, on Days 1,8,15 and 22 of the treatment period. The maximum single dose of Vincristine should not exceed 2.0 mg.

 

L-Asparaginase 6,0001U/square meter of body surface area intramuscularly on Day 4, 7, 10, 13, 16, 19, 22, 25 and 28 of the treatment period. When a remission is obtained with either of the above regimens, appropriate maintenance therapy must be instituted.

 

ASPRAGINAZ (L-Asparaginase) should not be used as part of a maintenance regimen, The above regimens do not preclude a need f or special therapy directed toward the prevention of central nervous system leukemia.

It should be noted that ASPRAGINAZ (L-Asparaginase) has been used in combination regimens other than those recommended above. It is important to keep in mind that ASPRAGINAZ (L-Asparaginase) administered intravenously concurrently with or immediately before a course of vincristine and prednisone may be associated with increased toxicity. Physicians using a given regimen should be thoroughly familiar with its benefits and risks. 

Clinical data are insufficient for a recommendation concerning the use of combination regimens in adults. L-Asparaginase toxicity is reported to be greater in adults than in pediatric patients. 

Use of ASPRAGINAZ (L-Asparaginase)as the sole induction agent should be undertaken only in an unusual situation when a combined regimen is inappropriate because of toxicity or other specific patient-related factors or in cases refractory to other therapy.

 

When ASPRAGINAZ (L-Asparaginase) is to be used as the sole induction agent for pediatric patients or adults, the recommended dosage regimen is 200 IU /kg/day intravenously for 28 days. When complete remissions were obtained with this regimen, they were of short duration, 1 to 3 months, ASPRAGINAZ (L-Asparaginase) has been used as the sole induction agent in other regimens. Physicians using a given regimen should be thoroughly familiar with its benefits and risks.

Patients undergoing induction therapy must be carefully monitored and the therapeutic regimen adjusted according to response and toxicity.

Such adjustments should always involve decreasing dosages alone or more agents or discontinuation depending on the degree of toxicity. Patents, who have received a course of ASPRAGINAZ (L-Asparaginase), if retreated, have an increased risk of hypersensitivity reactions. Therefore, the treatment should be undertaken only when the benefit of such therapy is weighed against the increased risk.

Intradermal Skin Test: Because of the occurrence of allergic reactions, an intradermal skin test should be performed prior to the initial administration of ASPRAGINAZ (L-Asparaginase) and when ASPRAGINAZ (L-Asparaginase) is given after an interval of a week or more has elapsed between doses. The Skin test solution may be prepared as follows: Reconstitute the contents of a 10,0001.U. vial with 5.0 mL of diluent. From this solution (2,000 I.U./mL) withdraw 0.1 mL and inject it into another vial containing 9.9 mL of diluent, yielding a skin test solution of approximately 20.0 I.U./ml. Use 0.1 mL of this solution (about 2.0 I.U.) for the intradermal skin test. The skin test site should be observed for at least one hour for the appearance of a wheal or erythema either of which indicates a positive reaction. An allergic reaction even to the skin test dose in certain sensitized individuals may rarely occur.

A negative skin test reaction does not preclude the possibility of the development of an allergic reaction every 3 weeks. 

Directions for Reconstitution

This drug may have toxic properties and must be handled and administered with care, inhalation of dust of aerosols and contact with skin or mucous membranes, especially those of the eyes, must be avoided, Appropriate protective equipment should be worn when handling ASPRAGINAZ (L-Asparaginase). (See Special Handling).

Parenteral drug products should be inspected visually for particulate matter and cloudiness or discoloration prior to administration whenever solution and container permit. When reconstituted, ASPRAGINAZ (L-Asparaginase) should be a clear colorless solution. If the solution becomes cloudy, discard.

Occasionally, a very small number of gelatinous fiber-like particles may develop on standing. Filtration through a 5.0 micron filter during administration will remove the particles with no resultant loss in potency. Some loss of potency has been observed with the use of a 0.2 micron Site.

 

For Intravenous Use

Reconstitute with Sterile Water for Injection or with Sodium Chloride Injection. The volume recommended for reconstitution is 5 mL for the 10,000 unit vials. Ordinary shaking during reconstitution does not inactivate the enzyme. This solution may be used for direct intravenous administration within an eight hour period following restoration. For administration by infusion, solutions should be diluted with the isotonic solutions, Sodium Chloride Injection or Dextrose Injection 5%. These solutions should be infused within eight hours and only if clean

 

For Intramuscular Use

When ASPRAGINAZ (L-Asparaginase) is administered intramuscularly according to the schedule cited in the inductors regimen, reconstitution is carded out by adding 2 mL Sodium Chloride Injection to the 10,000 unit vial. The resulting solution should be used within eight hours and only if clear.

 

Special Handing

L-Asparaginase may be irritating to eyes, skin and the upper respiratory tract. It has also been shown to be embryotoxic and teratogenic by the intravenous route in animal studies. due to the drug’s potential toxic properties appropriate precautions including the use of appropriate safely equipment are recommended for the preparation of ASPRAGINAZ (L- Asparaginase) for administration. Inhalation of duster aerosols and contact with skin or mucous membranes, especially those of the eyes, must be avoided. The National Institutes of Health presently recommends that the preparation of injectable antineoplastic drugs should be performed in a Class II laminar flow biological safety cabinet. Personnel preparing drugs of this class should wear chemical resistant, impervious gloves, safety goggles, outer garments and shoe covers.

Additional body garments should be used based upon the task being performed (e.g. sleevelets, apron, gauntlets, disposable suits) to avoid exposed skin surfaces and inhalation of vapors and dust Appropriate techniques should be used to remove potentially contaminated clothing.

Several other guidelines for proper handling and disposal of antineoplastic drugs have been published and should be considered.

Accidental Contact Measures

If accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. If accidental skin contact occurs, the affected part should be washed immediately with soap and water. Medical attention should be sought If inhaled remove from exposure and seek medical attention, (See WARNINGS AND PRECAUTIONS AND DOSE AND METHOD OF ADMINISTRATION)

USE IN SPECIAL POPULATIONS

Pregnancy

Pregnancy Category C

Asparaginase administered in mice and rats has been shown to retard the weight gain of mothers and fetuses when given in doses of more than 1000 International Units/kg (approximately equivalent to the recommended human dose, when adjusted for total body surface area).

Resorptions, gross abnormalities and skeletal abnormalities were observed. In pregnant rabbits, the intravenous administration of 50 or 100 International Units/kg (approximately equivalent to 10 to 20’% of the recommended human dose, when adjusted for total body surface area) on Day 8 and 9 of gestation resulted in dose dependent embryotoxicity and gross abnormalities. In pregnant women there are no adequate and well-controlled studies. L-Asparaginase should be administered to pregnant woman only lithe potential benefit justifies the potential risk to the fetus, or clearly needed.

 

Nursing Mothers

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

 

Pediatric use

The study was carded out in 823 patients less than 16years of age with previously untreated acute lymphoblastic or acute undifferentiated leukemia who received L-Asparaginase as a component of multi-agent chemotherapy for induction of first remission. The dose of L-Asparaginase administered was 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, 429 of 499 (86%) patients achieved a complete remission, in a similar patient population, which utilized an initial induction chemotherapy regimen containing the same agents without L-Asparaginase.

Toxicity of L-Asparaginase has been reported to be greater in adults than the pediatrics.

 

Geriatric use

Clinical studies of L-Asparaginase did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

ASPRAGINAZ (L-Asparaginase) is contraindicated in:

• Patients with serious allergic reactions to L-Asparaginase or other Escherichia coli-derived L- asparaginase

• Patients with serious thrombosis with prior L-asparaginase therapy

• Patients with pancreatitis with prior L-asparaginase therapy

• Patients with serious hemorrhagic events with prior L-asparaginase therapy

Anaphylaxis and Serious Allergic Reactions

The patients receiving L-asparaginase can show serious allergic reactions. The patients with prior exposure to asparaginase or other Escherichia coli-derived L-Asparaginase are at higher risk of serious allergic reactions. Observe patients for one hour after administration of L-asparaginase in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines). In patients with serious allergic reactions discontinue L-asparaginase.

Thrombosis

In patients receiving L-asparaginase, serious thrombotic events, including sagittal sinus thrombosis can occur. Patients with serious thrombotic events should discontinue L-asparaginase.

Pancreatitis

In patients receiving L-asparaginase in some cases fulminate or fatal Pancreatitis can occur in some cases. For evidence of pancreatitis evaluate patients with abdominal pain. In patients with pancreatitis discontinue L-asparaginase. 

Glucose Intolerance

Administration of L-asparaginase in patients can cause glucose intolerance. In some cases, glucose intolerance is irreversible. Monitor serum glucose.

Coagulopathy

In patients receiving L-asparaginase increased prothrombin lime, increased partial thromboplastin time, and hypofibrinogenemia can occur, CNS hemorrhages have been observed. Monitor coagulation parameters. A baseline and periodically monitoring of coagulation parameters should be done during and after treatment. Inflate treatment with fresh-frozen plasma to replace coagulation factors in patients with severe or symptomatic coagulopathy.

General

This drug may have toxic properties and must be handled and administered with care. L-asparaginase may be irritating to eyes, skin, and the upper respiratory tract. Inhalation of dust or aerosols and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Asparaginase has been reported to have Immunosuppressive activity in animal experiments. Accordingly, the possibility that use of the drug in man may predispose to infection should be considered.

Asparaginase toxicity is reported to be greater in adults than in pediatric patents.

In view of the unpredictability of the adverse reactions to L-asparaginase, it is recommended that this product be used in a hospital setting.

Asparaginase has an adverse effect on liver function in the majority of patients. Therapy with L-asparaginase may increase pre-existing liver impairment caused by prior therapy or the underlying disease. Because of this there is a possibility that L-asparaginase may increase the toxicity of other medications.

The administration of L-asparaginase intravenously concurrently with or immediately before a course of vincristine and prednisone may be associated with increased toxicity.

 

Laboratory Tests

The fall in circulating lymphoblasts often is quite marked, normal or below normal leukocyte counts are noted frequently within the first several days after initiating therapy. This may be accompanied by a marked rise in serum uric acid. The possible development of uric acid nephropathy should be borne in mind. Appropriate preventive measures should be taken, e.g., allopurinol, increased fluid Intake alkalization of urine. As a guide to the effects of therapy, the patient’s peripheral blood count and bone marrow should be monitored frequently.

Frequent serum amylase determinations should be obtained to detect early evidence of pancreatitis. If pancreatitis occurs, therapy should be stopped and not reinstituted. Blood sugar should be monitored during therapy with L-asparaginase because hyperglycemia may occur.

Tissue culture and animal studies indicate that L-asparaginase can diminish or abolish the effect of methotrexate on malignant cells. This effect on methotrexate activity persists as long as plasma asparagine levels are suppressed. These results would seem to dictate against the clinical use of methotrexate with L-Asparaginase, or during the period following L-Asparaginase therapy when plasma asparagine levels are below normal.

 

Drug/Laboratory Test Interactions

L-Asparaginase has been reported to interfere with the interpretation of thyroid function tests by producing a rapid and marked reduction in serum concentrations of thyroxine-binding globulin within two day after the first dose. Serum concentrations of thyroxine-binding globulin returned to pretreatment values within four weeks of the last dose of L-Asparaginase.

The acute intravenous LD of L-Asparaginase was about 500000 I.U./kg and f or rabbits about 22000 I.U./kg.

The following adverse events have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

Body as whole diffuse pain, chest pain, radiation recall phenomenon

Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction

Cutaneous : rare cases of buttons eruption such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. Multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported.

Gastrointestinal: in some cases fulminant or fatal abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, intestinal obstruction, liens, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported.

Hematologic : serious thrombosis, including sagittal sinus thrombosis, bleeding, episodes, coagulopathy, including increased prothrombin time, increased partial thromboplastin time, and decreased fibrinogen, protein C, protein S and antithrombin III, CNS hemorrhages have been reported.

Hepatic : rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, hyperbilirubinemia have been reported.

Neurologic coma, confusion, hallucination and rare cases of seizures or transient loss of consciousness have been observed, sometimes appealing during the infusion of the drug.

Ophthalmologic : conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (gashes, flashing lights, scotomate) typically occurring during drugs infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion.

Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome, interstitial pneumonia. Pulmonary fibrosis has been rarely reported.

Urogenital : renal insufficiency azotemia.

Anaphylaxis and serious allergic reactions : allergic reactions have occurred with the first dose AND WITH SUBSEQUENT DOSES OF L-Asparaginase. The risk of serious allergic reactions appears to be higher in patients with prior exposure to L-Asparaginase or other Escherichia coli-derived L-asparaginase.

Glucose intolerance, in some cases irreversible.

Immunogenicity : As with all therapeutics proteins, there is potential for immunogenicity, defined as development of binding and/or neutralizing antibodies to the product.

L-Asparaginase can elicit antibodies in patients treated with the drug. The results of two prospectively designed clinical trials (N=59 and 24) showed that, approximately one quarter of the patients developed antibodies that bound to L- Asparaginase as measured by enzyme-linked immunosorbent assays (ELISA). Clinical hypersensitivity reactions to L-Asparaginase in studies were common ranging from 32.5% to 75%. In these studies, concomitant medications and dosing schedules varied. Patients with hypersensitivity reactions were more likely to have antibodies than those without hypersensitivity reactions. Hypersensitivity reactions have been associated with increased clearance of L-Asparaginase. Upon first administration of L-Asparaginase incidence of antibody formation was lower than second administration. The frequency of antibody formation in adults relative to children is unknown. There is insufficient information to comment on neutralizing antibodies, however, higher levels of antibody correlated with a decrease in asparaginase activity.

The sensitivity and specificity of the assay determines the detection of antibody formation. The observed incidence of antibody positivity in an assay maybe influenced by several factors including sample handling, concomitant medications and underlying disease. Therefore, comparison of the incidence of antibodies to L-Asparaginase with the incidence of antibodies to other products may be misleading.

Mechanism of Action

 

Some leukemic cells are dependent on exogenous source of asparaginase for survival, as these cells are unable to synthesize asparagine due to a lack of Asparagine synthetase. Asparaginase is an enzyme that destroys asparagine external to the cell. Normal cells are able to make elite asparagine they need internally whereas tumor cells become depleted rapidly and die. The mechanism of action of asparaginase is thought to be based on selective killing of leukemic cells due to depletion of plasma asparagine. 

 

Pharmacokinetics

 

The initial plasma levels of L-Asparaginase following intravenous administration were correlated with dose in patients with metastatic cancer and leukemia. A cumulative increase in plasma levels was observed after daily administration of L-Asparaginase. Plasma half-life varied from 8 to 30 hours. Single or repetitive dosage did not influence plasma half-life. The plasma half-life could not be influenced by dosage, either, and could not be correlated with age, sex, surface area, renal or hepatic function, diagnosis or extent of disease. Apparent volume of distribution was approximately 70-80% of estimated plasma volume. The movement of asparaginase from vascular to extravascular extracellular space was slow. L-Asparaginase was detected in the lymph. The concentration of asparaginase in cerebrospinal fluid were less than 1% of concurrent plasma levels. Only trace amounts appeared in the urine. Intramuscular L-Asparaginase was administered in patients with leukemia and metastatic cancer. The peak plasma levels of asparaginase were reached 14 to 24 hours after dosing with plasma half-life was 39 to 49 hours. No asparaginase was detected in the urine.

ASPRAGINAZ must not be mixed with any other drugs prior to administration. Reconstitute only as mentioned under Dosage and Method of Administration.

SHELF LIFE

Not more than 24 months. Please see details of Mfg. Date/Exp. Date printed on pack. Do not use the product after the expiry date which is slated on the packaging. The expiry date refers to the last day of that month.

ASPRAGINAZ 5000 IU

Single-dose vial containing 5000 IU of L-Asparaginase

 

ASPRAGINAZ 10000 IU

Single-dose vial containing 10000 IU of L-Asparaginase

ASPRAGINAZ Injection (as packages for sale) should be stored under refrigeration between 2°C to 8°C (36°-46°F) 

RECONSTITUTED SOLUTION: 

ASPRAGINAZ does not contain a preservative. In keeping with good clinical and pharmaceutical practice, the reconstituted solution should be administered as a freshly prepared solution. On the few occasions where changing circumstances makes this impossible or impractical, reconstituted solution should be stored at 2 to 8°C and should be used within 8 hours of preparation. The reconstituted solution should be discarded after eight hours or sooner if it becomes cloudy. Do not freeze.