Carmustine (Carmustinum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Alkylating agents

Included in the formulation
  • BiKNU®
    lyophilizate in / in 
    Emkure Pharmaceuticals Co., Ltd.     India
    • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    VED

    АТХ:

    L.01.A.D.01   Carmustine

    Pharmacodynamics:Pharmacological action - antitumor, alkylating, cytostatic, immunosuppressive. In the body within the carmustine molecule, a ring is formed to form an ethylenimonium ion, which transfers the alkyl group to the components of the cell. Reacts with sulfhydryl, amide, hydroxyl, carboxyl and phosphate groups of cellular nucleotides. Oppresses the activity of enzymes of oxidative phosphorylation, the provision of synthetic energy processes and mitosis. Under the action of carmustine, discontinuities occur in the DNA molecule, intra- and intermolecular cross-linking of the chains is formed and DNA synthesis is disrupted. The effect of carmustine is not specific, there is no cross-resistance to other alkylating agents.
    Pharmacokinetics:After intravenous administration, it is rapidly metabolized in the liver with the formation of active metabolites. Metabolites can persist in the blood plasma for several days. It is slightly ionized at physiological pH values. Highly soluble in lipids; in this connection it penetrates the blood-brain barrier.At least 50% of the plasma concentration of carmustine is found in the cerebrospinal fluid. After intravenous administration is metabolized with the formation of active metabolites - isocyanates. Within 96 hours, 50-70% of the dose is excreted in the urine (less than 1% unchanged), about 10% with exhaled air, 1% with feces. The half-life (biological) period is 15-30 minutes, the chemical period is 5 minutes. Metabolites are determined in blood plasma for several days.
    Indications:Primary malignant brain tumors (glioblastoma, brain stem glioma, ependymoma, astrocytoma, medulloblastoma). Metastases in the brain of tumors of various locations. Stomach cancer. Colorectal cancer. Myeloma (treatment in combination with prednisolone). Malignant melanoma of the skin (common). Intravenous by 150 mg /m2 in combination with vincristine. Lymphogranulomatosis (as part of combination therapy of the second line in patients with relapse after primary therapy or in case of its ineffectiveness). Non-Hodgkin's lymphomas (as part of combination therapy of the second line in patients with relapse after primary therapy or with its ineffectiveness).
    ICD-10

    II.C43-C44.C43.9   Malignant melanoma of skin, unspecified

    II.C69-C72.C71   Malignant neoplasm of brain

    II.C69-C72.C71.6   Malignant neoplasm of the cerebellum

    II.C69-C72.C71.7   Malignant neoplasm of the brain stem

    II.C81-C96.C81   Hodgkin's disease [lymphogranulomatosis]

    II.C81-C96.C82   Follicular [nodular] non-Hodgkin's lymphoma

    II.C81-C96.C83   Diffuse non-Hodgkin's lymphoma

    II.C81-C96.C84   Peripheral and cutaneous T-cell lymphomas

    II.C81-C96.C85   Other and unspecified types of non-Hodgkin's lymphoma

    II.C81-C96.C90.0   Multiple myeloma

    Contraindications:Hypersensitivity to the drug; pregnancy and the period of breastfeeding.
    Carefully:Inhibition of bone marrow function (including on the background of concomitant radiation therapy, especially when irradiating the mediastinum area, or chemotherapy); acute infectious diseases of a viral, fungal or bacterial nature (including chicken pox, shingles); with hepatic insufficiency; severe renal dysfunction; respiratory insufficiency; in smokers (due to an increased risk of toxic effects on the lungs); in childhood (safety and efficacy have not been studied. Evaluate the benefit / risk ratio!).
    Pregnancy and lactation:Recommendations of the FDA category D. In view of the potential threat to the fetus for women of childbearing age, it is recommended that contraceptives be used during the treatment with carmustine. Controlled studies in humans have not been conducted. Possible development of fetal side effects observed in adults. Carmustine embryotoxic and carcinogenic when administered to rabbits and rats in doses appropriate for human use. It is recommended to avoid the use of antitumor, especially combined chemotherapy in pregnancy, especially in the first trimester. In the presence of indications, it is necessary to relate the risk and benefit and take into account the mutagenic, carcinogenic and teratogenic potential of these agents.

    Lactation. There is no information on the penetration into breast milk. In view of the excretion of other antitumor drugs with milk and the potential risk of unwanted effects on the child (side effects, carcinogenicity, mutagenicity), breast-feeding should be discontinued.

    Dosing and Administration:Modes of treatment with carmustine (set individually):

    - intravenously in a dose of 150-200 mg /m2 in the form of a 1-2-hour infusion once every 6-8 weeks.

    - intravenously in a dose of 75-100 mg /m2 in the form of a 1-2-hour infusion in the 1 st and 2 nd days every 6 weeks.

    - intravenously in a dose of 40 mg /m2 in the form of a 1-2 hour infusion in the 1-5th days every 6 weeks.

    When combined with other antitumor drugs, the dose is reduced by 25-50%.

    Doses for subsequent administrations are selected according to the hematologic response to the previous treatment.

    If after the previous injection the smallest number of platelets was 100×109 / l and leukocytes more than 3×109 / l is administered 100% of the previous dose, with a platelet count of 25×109 / L-75×109 / l, white blood cells 2×109 / L-3×109 / l - 70%; when the platelet count is less than 25×109 / L and leukocytes less than 2×109 / l - 50% of the previous dose.

    Application in elderly patients

    Elderly age and related impaired renal function (probably a decrease in renal filtration) cause an increased cumulation of the drug. Differences in the tolerability of carmustine in elderly patients have not been documented, but dosage adjustment and dose reduction may be required.

    Use in children

    The drug is used with caution in the doses recommended for adults. In patients with childhood and early adolescence with intracranial tumors after treatment with cumulative doses of 770-1800 mg /m2 (in combination with irradiation of the skull) in remote periods (up to 15 years) describes distant pulmonary fibrosis. When chest radiographs are detected, lung hypoplasia with wrinkling of the upper sections is detected. At a scintigraphy with preparations of a gallium pathological changes are absent. With computer tomography, visualization of unusual fibrosis of the upper parts of the lungs. Often there is a delayed decrease in lung function. In rare cases, a progressive course of pulmonary fibrosis and a lethal outcome are possible.

    Side effects:Hematological: anemia, leukopenia, thrombocytopenia.

    From the digestive tract: nausea, vomiting, stomatitis, diarrhea, loss of appetite, difficulty swallowing.

    From the respiratory system: pneumonitis, pulmonary fibrosis. Most often occur with the appointment of high total doses (more than 1200-1400 mg /m2) or after several cycles of therapy (more than 5). Symptoms can be acute or worn out, damage to the lung tissue - reversible or irreversible. The dependence of pulmonary toxicity on dose is unclear. Important toxicity factors: previous mediastinal irradiation; concurrent use of cyclophosphamide or other pulmonary toxicity-detecting drugs; lung disease or smoking; decline vital capacity of the lungs up to 70% of the norm and less.

    From the nervous system: central neurotoxicity (dizziness, gait disturbance), encephalomyelopathy.

    From the side of the urinary tract: nephrotoxicity, renal failure, increased urea concentration in the blood (indicating nephrotoxicity).

    Dermatological: phlebitis, a discoloration of the skin over the vein into which the injection was made, alopecia, hyperpigmentation of the skin.

    Hypersensitivity: skin itching, rashes, edema of the conjunctiva, lowering of arterial pressure, tachycardia.

    On the part of the reproductive system: gonad suppression (azoospermia, amenorrhea), which can be irreversible; frequency and severity increase with combination with other alkylating agents.

    Carcinogenicity (mutagenicity): studies of carcinoma carcinogenicity have not been carried out, but secondary malignant tumors are a potential delayed side effect of many antitumor drugs.

    Other: hyperemia of the face, hepatotoxicity, increased activity of alkaline phosphatase, AST and bilirubin concentrations in the blood (indicating hepatotoxicity),the violation of visual functions up to irreversible loss of vision (with intra-arterial administration).

    Overdose:Increased severity of side effects. The specific antidote is unknown. Treatment is symptomatic: colony-stimulating factors, antibacterial drugs, blood transfusion and platelet transfusions; maintenance of vital functions.
    Interaction:Cimetidine - Increased leukopenia and thrombocytopenia are possible.

    Amphotericinum - it is possible to increase the accumulation of carmustine in cells.

    Sodium bicarbonate - when mixing, 27% of the carmustine is destroyed within 90 minutes.

    Hepatotoxic agents - with simultaneous use, the risk of toxic effects increases.

    Nephrotoxic drugs - increased nephrotoxicity, especially if the kidney function is impaired.

    Special instructions:When treating with carmustine, monitoring of the following parameters is necessary: ​​hematocrit and hemoglobin, the number of leukocytes, platelets (before and during the treatment, during and for 6 weeks after administration), hepatic transaminases, bilirubin, urea, creatinine and uric acid levels in the blood,as well as pulmonary function (before treatment and periodically during it, depending on the patient's condition).

    Distinctive characteristics

    A solution for intravenous infusions is prepared by adding 3 ml of sterile dehydrated ethanol for injection into the vial (supplied by the manufacturer), then the contents of the vial are dissolved in 27 ml of sterile water for injection (a clear, slightly yellowish solution, 1 ml of which contains 3.3 mg of carmustine in 10% ethanol, pH 5.6-6). The resulting preparation is diluted with 0.9% sodium chloride solution or 5% dextrose solution to a concentration not exceeding 0.5 mg / ml.

    The subsequent course of treatment with carmustine should be performed only after restoration of blood parameters to acceptable (the number of leukocytes is more than 4 × 109 / l, platelets - more than 100 × 109 / l).

    In view of the possibility of delayed and cumulative myelosuppression, administration of carmustine should be performed no more often than every 6 weeks.

    Cross-resistance to carmustine and lomustine is described.

    Due to the possibility of tissue necrosis carmustine can not be administered subcutaneously and intramuscularly.

    Carmustine penetrates through latex, polyvinyl chloride and rubber gloves.It is necessary to change the gloves regularly by the staff. If you accidentally get a solution of carmustine on the skin or mucous membranes (burning and hyperpigmentation of affected areas), immediately wash it off with soap and water.

    The solution of the contents of the vial in ethanol is stable for 8 hours at a temperature of 25 ° C or 24 hours at 4 ° C. Freezing does not change the properties of the drug.

    With the appointment of several courses (more than 5) or months of high cumulative doses (more than 1200-1400 mg /m2) and after 1-2 courses of use in low doses, development of lung hypoplasia with a decrease in volume of the upper lobe is observed.

    With prolonged use, it can induce mutations and the development of secondary malignant tumors (long-term effect), including acute leukemia and other bone marrow dysplasia.

    In experiments on rats and mice at doses close to clinical, exhibits carcinogenic properties. Causes irreversible degenerative changes in the sex glands, leading to amenorrhea or azoospermia, reduces the fertility of male rats. In doses equivalent to human doses, it is embryotoxic and teratogenic in experimental animals.

    The drug has delayed hematologic toxicity. This is due to a long period of complete excretion of metabolites from the blood (up to 10 days).

    With adjuvant therapy of malignant gliomas after surgery, intra-arterial administration of a combination of carmustine (200 mg /m2 every 8 weeks) and fluorouracil compared with intravenous administration does not improve the treatment results with an increase in the incidence of serious side effects (irreversible encephalopathy in 9.5% of patients, loss of vision in 15.5% of patients) and even worsens them in the treatment of anaplastic astrocytoma .

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