Asparaginase Medac

Release form, composition and packing

Valium for a solution for IV and IM administration in the form of powder or a mass of white or nearly white.

1 vial. L-asparaginase 5 thousand IU.

Valium for a solution for IV and IM administration in the form of powder or a mass of white or nearly white.

1 vial. L-asparaginase 10 thousand IU.

Clinico-pharmacological group: Anti-tumor drug.

Pharmacological action

Antitumor drug. L-asparaginase catalyzes the cleavage of asparagine, which is necessary for cell activity. The maximum effect of L-asparaginase on the suppression of proliferation observed in postmitotic G1-phase of the cell cycle. It is believed that the antitumor effect of the drug due to reduced levels of asparagine in the leukemic tumor cells, which unlike normal cells can not synthesize their own asparagine due to a lack asparaginsintetazy. As a result of disturbed protein synthesis, and synthesis of DNA and RNA.

Pharmacokinetics

Distribution

At iv administration Cmax in plasma achieved during the first minute, when i / m administration - through 14-24 h. Binding to plasma proteins is 30%. Asparaginase penetrates into the reticuloendothelial system and is slowly broken down to inactive substances.

Breeding

T1 / 2 at / in the introduction of 14-22 h, T1 / 2 for i / m administration - 39-49 h. With daily use of the drug able to maintain its adequate level in the blood, and traces of the enzyme can be detected in plasma as early as Within 10 days after completion of treatment. Path Withdrawal is not installed. The urine drug appears only in trace amounts.

Statement
as part of combination therapy to induce remission in acute lymphoblastic leukemia, as well as for the treatment of lymphoblastic non-Hodgkin's lymphoma (lymph and reticulosarcoma). Not recommended for use in the preparation of schemes of maintenance therapy due to the rapid development of resistance to the drug.

Dosing regimen

The first administration of the drug recommended by a physician who has experience in cancer chemotherapy.

The drug is administered IV bolus, as a slow intravenous infusion (at least 30 minutes) or V / m. Asparaginase is used as a monotherapy and in a number of schemes in combination with other cytostatic agents, in connection with which the selection of individual dose should be guided by the data of the medical literature.

The drug is prescribed to adults and children in a dose of 6 000-10 000 ME/m2 body surface iv or im every other day or daily basis to achieve a total dose of not more than 400 000 ME. When i / m administration in one place should be given no more than 2 ml.

If necessary, the introduction of higher doses simultaneously to do a few injections. Before the introduction of the drug is recommended intracutaneous test, despite the fact that the results of intradermal tests are not fully reliable in predicting allergic reactions to asparaginase.

It is recommended to test before the first injection and in those cases where between injections is 1 week or longer. To carry out sample preparation should be dissolved in water for injection to achieve a concentration of asparaginase 100 ME / ml. Intradermally injected 0.1 mL (about 10 ME) of the resulting solution and observe the reaction for 1 h.

Development of congestion or papules over 1 cm in diameter indicates a positive reaction, so the asparaginase treatment should be avoided.

When I / O application is recommended, in addition, the introduction of a test dose of IV (1000 ME / O in the form of short-term infusion for 1 hour before treatment).

Preparation of solutions

Powder at a dose of 5000 IU was dissolved in 2 mL at a dose of 10,000 IU - 4 ml water for injection. In order to avoid foam formation, a jet of water should be slowly pour in the inner wall of the vial, the dissolution does not stir, and rotate the bottle.

The prepared solution may be slightly opalestsirovat. For IM administration prepared solution need not be diluted. For continuous IV infusion after dilution, according to the instruction, a calculated amount of asparaginase should be diluted in 250-500 ml of saline or 5% glucose for iv injection jet - in 20-40 ml.

Side effect

Allergic reactions: 20-35% of cases may develop hypersensitivity reactions (rash and / or blisters), and sometimes - anaphylactic shock with fatal outcome, respiratory failure.

Risk of anaphylaxis is increased by repeated application of the drug. However, the development of anaphylactic shock and possibly the first introduction.

Keep in mind that after 2-5 hours after drug administration may develop febrile reactions such as fever and chills. Usually these events are themselves. In rare cases life-threatening high fever (hyperpyrexia).
From the digestive system: disorders of the pancreas, acute pancreatitis, a rare - hemorrhagic pancreatitis.

In some cases, noted the formation of psevdotsist (within 4 months after treatment). Therefore, the patient should be observed within 4 months after the last injection by means of appropriate techniques (eg, ultrasound).

In case of increase of amylase in serum, the use of the drug should be discontinued (increase in serum amylase and possibly after asparaginase therapy). Also observed liver function abnormalities (increased serum transaminases, alkaline phosphatase, LDH, and serum bilirubin). In the course of treatment may decrease the level of serum albumin. In some cases, marked cholestasis, and there were reports of one case of jaundice and one case of necrosis of liver cells. It is also possible nausea, vomiting and anorexia.
From a metabolism: impaired glucose tolerance, lower insulin levels, and often - hyperglycemia, requiring use of insulin may develop ketoacidosis.
From the coagulation system: reduction of fibrinogen, factor X and XI, antithrombin III, protein C and plasminogen, thromboembolism, and in some cases noted the development of hemolytic anemia.
With the urinary system: rarely - impaired renal function.
Increased nitrogen in the blood serum usually reflects prerenal metabolic imbalance. Can be marked hyperuricemia.
CNS: CNS depression (lethargy, abnormal drowsiness, confusion) and in some cases, there were seizures.
From the endocrine system: a small number of patients had transient and secondary hypothyroidism and reduced thyroxine-binding protein.
Dermatological reactions: A case of toxic epidermal necrolysis (Lyell's syndrome).

Contraindications
pancreatitis at the time of initiation of treatment or history;
Allergic reactions in the history of hosting asparaginase;
expressed in human liver;
marked impairment of renal function;
pregnancy;
Lactation (breastfeeding).

Pregnancy and lactation

The drug is contraindicated during pregnancy and lactation.

Use in hepatic dysfunction

Contraindicated in marked hepatic dysfunction.

Use in renal impairment

Contraindicated in marked renal impairment.

Cautions

In the case of allergic reactions, a drug should be stopped immediately. Must take appropriate measures: the introduction of antihistamines, corticosteroids and drugs that stabilize the hemodynamics.

With a significant reduction of clotting factors, particularly fibrinogen, in the case of clinical predisposition to bleeding, need replacement therapy of fresh frozen plasma. Recommended regular monitoring of blood glucose and urine indicators of blood coagulation.

During the period of drug treatment should avoid drinking alcohol.

Effects on ability to drive vehicles and management mechanisms Asparaginase can reduce psychomotor reaction and, consequently, the ability to drive vehicles and management mechanisms, especially while taking alcohol.

Overdose

Symptoms: anaphylaxis, hyperglycemia, blood clotting problems.

Treatment: the specific antidote is known. Spend simptomatichskuyu therapy. With the development of hyperglycemia spend insulin when blood clotting is possible to use fresh frozen plasma.

Drug Interactions

Vincristine and prednisone therapy immediately before or simultaneously with asparaginase increases the risk of toxicity of the latter (increased glucagon action of asparaginase, increased risk of neuropathies, impaired erythropoiesis).

Asparaginase in a dose-and time use has a synergistic or antagonistic effect on methotrexate and cytarabine.

Preliminary primenenenie methotrexate and cytarabine synergistically enhances the effect of asparaginase.