Active substanceDacarbazineDacarbazine
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  • Dakarbazin Lahema
    lyophilizate in / in 
    Pliva-Lahema, AO     Czech Republic
  • Dakarbazin medak
    lyophilizate in / in 
    medac GmbH     Germany
  • Dakarbazin-Lens®
    lyophilizate in / in 
    VEROPHARM SA     Russia
  • Dosage form: & nbsplyophilizate for the preparation of a solution for intravenous administration
    Composition:

    Active substance:

    Dacarbazine 100 mg 200 mg 500 mg 1000 mg

    Excipients:

    Citric acid anhydrous

    100 mg

    200 mg

    500 mg

    1000 mg

    Mannitol

    50 mg

    75 mg

    187.5 mg

    375 mg

    Description:White or slightly yellowish powder or porous mass.
    Pharmacotherapeutic group:An antitumour agent, an alkylating compound
    ATX: & nbsp

    L.01.A.X   Other alkylating preparations

    L.01.A.X.04   Dacarbazine

    Pharmacodynamics:Dacarbazine is a cytostatic agent. The antitumor effect is realized due to inhibition of cell growth and DNA synthesis, regardless of the cell cycle. Dacarbazine has an alkylating action, and also exhibits other cytostatic effects. It is believed that the antitumor effect of dacarbazine, which does not show its own activity, is not direct, but is realized due to microsomal N-detylation in the liver, leading to the formation of active metabolites: 5-amino-imidazole-4-carboxamide and methyl-cation, which determine the alkylating effect of the drug.
    Pharmacokinetics:

    After intravenous administration dacarbazine quickly distributed in tissues. Binding to plasma proteins is about 5%. The kinetics of the drug in the blood plasma is biphasic in nature: in the first phase (distribution), half-life (T1 / 2) is about 20 minutes, the final half-life is 0.5-3.5 hours. Dacarbazine as a result of metabolism in the liver with the participation of cytochrome P450 forms the active compounds of 5- [3- (hydroxy-methyl-1,3-methyl-triazen-1-yl) imidazole-5-carboxamide (GMMAC) and 3-monomethyl- (triazene-1- yl) -imidazole-4-carboxamide (MTIC), further catalyzed to 5-aminoimidazole-4-carboxamide.

    Metabolized mainly in the liver through hydroxylation and demethylation; about 20-50% of dacarbazine is excreted unchanged by kidneys due to tubular secretion.
    Indications:

    - metastasizing malignant melanoma;

    in combination therapy:

    - common lymphogranulomatosis (Hodgkin's disease);

    - a common soft tissue sarcoma in adults (except for mesothelioma, Kaposi's sarcoma).

    There are reports of the effectiveness of dacarbazine in combination with other cytostatics in the treatment of osteogenic sarcoma, sarcoma of the uterus,mesothelioma of the pleura and peritoneum, small cell lung cancer, thyroid cancer, carcinoid, pheochromocytoma, insulinoma, neuroblastoma and gliomas.
    Contraindications:

    - increased hypersensitivity to dacarbazine or any other component that is part of the drug,

    - pregnancy and the period of breastfeeding,

    - severe leukopenia and / or thrombocytopenia,

    marked hepatic or renal insufficiency

    Carefully:Acute infectious diseases of the viral (including chicken pox, shingles), fungal or bacterial nature (risk of serious complications and generalization of the process), concomitant radiation therapy.

    Pregnancy and lactation:

    In preclinical studies it was shown that dacarbazine has a mutagenic, teratogenic and carcinogenic effect to the beingthe risk of teratogenic effects of the drug on the fetus. The drug should not be administered during pregnancy and lactation. Women of childbearing age should use reliable means of contraception during treatment with the drug. In case of pregnancy, women should immediately inform their doctor about this.

    In view of the possible negative impact on the health of infants who are breastfeeding, breastfeeding should be discontinued for the duration of treatment with dacarbazine.
    Dosing and Administration:

    The drug is used intravenously. The drug must be administered with caution in order to prevent its exavation, which can cause local pain and soft tissue damage. When there are signs of extravasation, the injection should be stopped immediately, and the remaining dose of the drug should be injected into another vein. The following are the commonly used therapy regimens.

    When selecting individual treatment should use the data of special medical literature.

    Malignant melanoma

    Dakarbazine can be used in monotherapy intravenously in a dose of 200-250 mg / m2 body surface per day for 5 days every 3 weeks.

    The drug is administered bolus or as a short (15 - 30 min) infusion. It is also possible to administer the drug intravenously in-fusion at a dose of 850 mg / m2 body surface on the first day of therapy and then once every 3 weeks.

    Hodgkin's disease

    Dakarbazine is used in a daily dose of 375 mg / m2 body surface intravenously every 15 days in combination with doxorubicin, bleomycin and vinblastine (scheme ABVD).

    Soft tissue sarcoma

    With soft tissue sarcoma, the drug is used in adults intravenously at a daily dose of 250 mg / m2 body surface on days 1-5 every 3 weeks in combination with doxorubicin (regimen ADIC).

    In the process of treatment with dacarbazine, regular monitoring of blood elements and indicators of liver and kidney function is necessary. Since dacarbazine therapy often causes severe adverse reactions from the gastrointestinal tract, it is recommended to prescribe antiemetic therapy and supportive measures.

    In view of the possible serious violations of the functions of the gastrointestinal tract and the hematopoietic system, the ratio of benefit / risk to the patient should be weighed before the beginning of each cycle of dacarbazine therapy. The duration of therapy is determined by the attending physician in each case individually, taking into account the disease, the stage of the disease, the therapy, the response to therapy, side effects.

    With widespread lymphogranulomatosis, it is usually recommended to assign 6 cycles of therapy according to the scheme ABVD. With metastatic malignant melanoma and common soft tissue sarcoma, the duration of therapy is determined by its effectiveness and tolerability in each specific case.

    Method of administration
    Doses up to 200 mg / m are intravenously injected slowly. Large doses (from 200 to 850 mgLg) should be administered intravenously infusion for 15-30 minutes. Before the introduction of the drug, it is recommended to check the permeability of the vein by means of a jet injection of 0.9% sodium chloride solution or 5% dextrose solution. The same solutions can be used to remove the remaining drug from a syringe or dropper after the end of the injection.

    A solution of a dosage preparation of 100 and 200 mg reconstituted with water for injection (concentration 10 mg / ml) and ready for use without further dilution is hypoosmotic (about 100 mOsmol / kg) and therefore should be administered by slow intravenous injections duration more than 1 min; this method is preferable to rapid intravenous bolus administration lasting several seconds.

    Peculiarities of application in separate groups of patients

    Patients with renal / hepatic insufficiency
    In the presence of mild or moderate degree of failure of the kidney or liver, correction of the dose of dacarbazine is usually not required. In patients with combined failure of renal and hepatic function, excretion of dacarbazine is slowed. However, at present there are no specific recommendations to reduce the dose of the drug in such patients.

    Elderly patients
    Due to the limited experience of dacarbazine in elderly people, there are no specific recommendations for the use of the drug in this category of patients.

    Preparation of solution and use preparation
    Handling and disposal of the drug must be carried out in compliance with the rules for handling cytotoxic drugs.

    Preparation of the drug solution should be carried out in a specially designated place with the use of special consumables, goggles, masks, gloves, apron. It is necessary to comply with the norms of asepsis.

    Preparation of the drug solution is carried out immediately before its use.

    Dacarbazine is a photosensitive drug. The solution must be prepared and stored under conditions that exclude the effects of UV light, even during administration.During administration, the drug solution must be protected from exposure to light, for example by using a special light-shielded infusion set of PVC. A typical infusion set should be wrapped in a UV-impermeable foil or film.

    Preparation of the drug solution
    A) Bottles 100 mg, 200 mg
    The preparation is dissolved before use with 10 ml (100 mg bottle) or 20 ml (200 mg bottle) of water for injection (to reach a concentration of 10 mg / ml). The solution is slowly injected.

    If the intravenous drip is advisable, the resulting solution is then diluted with 200-300 ml of a 0.9% solution of sodium chloride or 5% glucose solution, after which the drug is administered in the form of a short infusion of 15-30 min.

    E) Bottles 500 mg, 1000 mg
    The drug is dissolved in 50 ml of water for injection. Further for the preparation of a solution for infusions, the resulting the solution is diluted in 200-300 ml of a 0.9% solution of sodium chloride or 5% solution of dextrose. The concentration of the solution for infusion is 1.4 - 2.0 mg / ml (500 mg bottle) or 2.8 - 4.0 mg / ml (1000 mg bottle). The solution is administered by short infusions for 20-30 minutes.

    The prepared solution of the preparation should be transparent and should not contain undissolved particles. Otherwise, the solution can not be used.

    The drug is intended for single use only. Unused solution of the drug should be destroyed. The materials used to prepare the solution and its administration must be disposed of in accordance with the rules for the use and disposal of cytotoxic drugs.
    Side effects:

    The most common side effects when using dacarbazine are disorders of the gastrointestinal tract (anorexia, nausea and vomiting), as well as hematopoiesis (anemia, leukopenia, thrombocytopenia), the latter are dose-dependent and delayed, often reaching minimum values ​​only 3-4 weeks after the chemotherapy.

    The incidence of adverse reactions listed below is described in accordance with the following gradation: very often (> 1/10), often (> 1/100, 1/10); infrequently (> 1/1000, 1/100); rarely (> 1/10000, 1/1000); rarely ( 1/10000, including individual messages).

    On the part of the hematopoiesis system: often anemia, leukopenia, thrombocytopenia; rare-pancreatic, agranulocytosis. From the immune system: rarely anaphylactic reactions.

    From the nervous system: rarely - headache, visual impairment, confusion, pronounced drowsiness, seizures, paresthesia of the facial skin.

    Vascular reactions: rarely - hyperemia of the face.

    From the gastrointestinal tract: often - anorexia, nausea, vomiting; rarely diarrhea.

    From the liver and bile ducts: rarely - life-threatening necrosis of the liver due to occlusion of the intrahepatic veins. As a rule, this syndrome arose during the second course of therapy. Symptoms including fever, eosinophilia, abdominal pain, increased liver size and jaundice, shock, can quickly build up within a few hours or days.

    From the urinary system: rarely - a violation of kidney function. From the skin and skin: infrequently - alopecia, hyperpigmentation, skin photosensitization; rarely erythema, maculopapus-erosive rash, hives.

    Common disorders and reactions at the site of administration: infrequently - flu-like syndrome; rarely - tenderness at the injection site. When extravasation of the drug - severe pain at the injection site, necrosis of surrounding tissues.
    From the laboratory indicators: rarely - increased activity of liver enzymes.
    Overdose:

    The main expected complication of drug overdose is a severe suppression of bone marrow function, up to aplasia, which can occur delayed within 2 weeks after application of the drug. Leukopenia and thrombocytopenia can develop in 4 weeks. If you suspect an overdose long-term careful monitoring of hematologic parameters is necessary. The specific antidote is not known. Treatment is symptomatic.

    Interaction:

    Dacarbazine is chemically incompatible with heparin, hydroxy cortisone, Lcysteine ​​and sodium bicarbonate.

    When dacarbazine is applied simultaneously or after the end of treatment, which has an effect on hemopoiesis (including therapy with other cytostatic drugs, radiation therapy), it is possible to enhance myelotoxic effect.

    Dacarbazine is metabolized with the participation of cytochrome P450 iso-enzymes (CYP1A1, CYP1A2 and CYP2E1), which must be taken into account when it is co-administered with other drugs, the metabolism of which is carried out by the same enzymes of the liver.

    Dacarbazine can enhance the action of methoxypsoralen by photosensitization.
    Special instructions:

    Treatment with dacarbazine should be performed by a doctor who has experience in carrying out anti-tumor chemotherapy, in conditions that allow regular monitoring of clinical, biochemical and hematological parameters both during and after the course of treatment.

    When using dacarbazine, the same rules should be followed as with other cytostatics because of their mutagenic, carcinogenic and teratogenic properties. In case of signs of functional disorders of the liver or kidneys, or symptoms of the development of hypersensitivity reactions, the drug should be immediately discontinued. If there is occlusion of intrahepatic veins, further therapy with dacarbazine is contraindicated. The attending physician should remember about the possibility of manifesting rare severe complications during treatment associated with the development of necrosis of the hepatic tissue due to occlusion of the intrahepatic veins. Taking into account the existence of such a risk, it is often necessary to monitor the function and dimensions of the liver, as well as the analysis of the blood formula (in particular, eosinophils).In isolated cases, early therapy with high doses of glucocorticosteroids (for example, hydrocortisone 300 mg / day) in combination with or without fibrinolytic agents (in particular, heparin or tissue plasminogen activator) was effective in cases of suspected occlusion of intrahepatic veins.

    Long-term therapy can lead to a cumulative effect of toxic effects on bone marrow function.

    The ability to suppress bone marrow function requires careful monitoring of the level of leukocytes, red blood cells and platelets. Violations of hemopoiesis due to hematotoxicity may require temporary suspension or withdrawal of therapy. Extravasation during intravenous administration of the drug can lead to damage to surrounding tissues and severe pain. When the first signs of extravasation appear (burning or soreness at the injection site), the drug should be discontinued immediately. The remaining dose should be injected into another vein. Dacarbazine has a moderately pronounced immunosuppressive effect. During the course of chemotherapy, it is necessary to avoid the use of hepatotoxic drugs and alcohol.

    The use of dacarbazine in children is not recommended because of the lack of sufficient data on the use of the drug in patients in this group.

    Men and women should use reliable contraception during and for 6 months after completion of dacarbazine therapy.

    Effect on the ability to drive transp. cf. and fur:The use of dacarbazine increases the risk of nausea, vomiting and manifestations of neurologic symptoms affecting the reaction rate. It is necessary to avoid the management of vehicles and the employment of other potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.
    Form release / dosage:Lyophilizate for the preparation of a solution for intravenous administration.
    Packaging:100 mg or 200 mg or 500 mg or 1000 mg in a bottle of dark yellow hydrolytic glass of type I, capped with a butyl rubber stopper and crimped with an aluminum cap with a lid. 1 (bottles of 500 mg or 1000 mg) or 10 bottles (100 mg or 200 mg bottles), together with the instructions for use, are placed in a cardboard box.
    Storage conditions:

    In the dark place at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.
    Shelf life:

    3 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:П N016026 / 01
    Date of registration:25.11.2009 / 02.02.2016
    Expiration Date:Unlimited
    The owner of the registration certificate:medac GmbHmedac GmbH Germany
    Manufacturer: & nbsp
    Representation: & nbspTIRUFARM, LLCTIRUFARM, LLCRussia
    Information update date: & nbsp17.03.2017
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