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Composition:


active ingredient: dacarbazine;


1 bottle contains dacarbazine citrate in terms of dacarbazine 100 mg or 200 mg, or


500 mg or 1000 mg;


excipients: citric acid anhydrous, mannitol (E 421). 


Dosage form. Powder for preparing a solution for injection or infusion.


Basic physical and chemical properties: white or light yellow powder or sintered mass.


Pharmacotherapeutic group. Antineoplastic agents. Alkylating compounds.


ATX code L01A X04.


Pharmacological properties.


Pharmacodynamics.


Dacarbazine is an alkylating cytostatic agent of triazene structure.


The mechanism of action consists in inhibiting cell growth (which is not related to the cell cycle) and inhibiting DNA synthesis. Dacarbazine also has an alkylating effect and may be involved in other cytostatic mechanisms.


It is believed that dacarbazine itself does not have an antineoplastic effect, but as a result of microsomal n-demethylation, it is rapidly converted to 5-amino-imidazole-4-carboxamide and a methyl cation, which cause the alkylating effect of dacarbazine. 


Pharmacokinetics.


Distribution.


After intravenous administration, dacarbazine quickly penetrates the tissues. Binding to plasma proteins is 5 %. The kinetics in blood plasma is biphasic, with an initial Half – Life of 20 minutes and a terminal Half-Life of approximately 0.5-3.5 hours.


Biotransformation.


Dacarbazine is inactive until it is metabolized in the liver by cytochrome P450, which leads to the formation of active n-demethylated compounds NMTIS and MTIs. This process is catalyzed by the enzymes CYP1A1, CYP1A2, and CYP2E1.


MTIs is further metabolized to 5-amino-imidazole-4-carboxamide (AIS).


Output.


Dacarbazine is subject to both hydroxylation and demethylation in the liver. Approximately 20-50% of the drug is excreted unchanged by the kidneys due to tubular secretion.


Preclinical safety data


Dacarbazine exhibits mutagenic, carcinogenic and teratogenic effects that have been identified in experimental studies. 


Clinical characteristics.


Indications.


Malignant metastatic melanoma.


As part of combined chemotherapy:


- Hodgkin's disease;


- progressive sarcoma of soft tissues (except mesothelioma, Kaposi's sarcoma) in adults. 


Contraindications.


- Hypersensitivity to dacarbazine or to any other component of the drug;


- the period of pregnancy or lactation;


- leukopenia and / or thrombocytopenia;


- severe hepatic and / or renal failure


- in patients with concomitant yellow fever vaccination or concomitant use of photemustine.


Special security measures. Standard precautions should be taken when working with cytotoxic drugs that have teratogenic, mutagenic and carcinogenic effects.


Dacarbazine is an antitumor agent. Before opening the bottle, you should familiarize yourself with the rules for working with cytostatics.


Dacarbazine can only be opened by experienced medical professionals.  Just as in all cases of working with cytostatics, the effect of the drug on personnel should be avoided. During pregnancy, any contact with cytostatics should be avoided. Preparation of the solution should be carried out in a special place, working on a tray that can be washed, or on adsorbing paper, under which to lay a plastic litter.


Wear appropriate safety glasses, gloves, a face mask, and an apron. Syringes and injection devices should be carefully assembled to ensure their tightness and avoid leakage of the drug solution.


If the solution gets on any surface, it should be immediately thoroughly washed, as well as wash your hands and face.


If the solution leaks out, remove the liquid with an adsorbent material. All contaminated material must be disposed of (incinerated). 


Interactions with other drugs and other types of interactions.


In the case of previous or concomitant treatment with drugs that have an adverse effect on the bone marrow (cytostatics, radiation therapy), it is possible to increase the myelotoxicity of dacarbazine.


The study of metabolism has not been carried out, but it is known that hydroxylation of the initial substance enhances its antitumor effect. Dacarbazine is metabolized in the liver by P 450 (CYP1A1, CYP1A2, and CYP2E1). This should be taken into account when prescribing drugs that are metabolized by the same enzymes at the same time.


Dacarbazine may enhance the photosensitizing effect of methoxypsoralene.


Administration of live vaccines to patients whose immunity is compromised as a result of treatment with chemotherapeutic agents such as dacarbazine can cause serious and potentially fatal infections. Therefore, live vaccine immunization should be avoided during dacarbazine therapy. It is generally recommended to use live viral vaccines with caution only after discontinuation of chemotherapy and taking into account the patient's immune status, depending on the disease and other treatments. Vaccination with live vaccines should be carried out no earlier than 3 months after the end of chemotherapy. Inactivated vaccines can be used if necessary.


Malignant tumors increase the risk of thrombosis, so it is common practice to prescribe anticoagulants at the same time. If a patient is receiving oral anticoagulants, the international normalization index (INR) should be monitored more frequently due to different individual sensitivity and possible interactions between anticoagulants and cytostatics.


Concomitant use with phenytoin should be avoided, as a decrease in the absorption of phenytoin in the gastrointestinal tract may increase the tendency to seizures.


Concomitant use of photemustine can cause acute pulmonary toxicity (acute respiratory distress syndrome in adults), which can lead to death. Photemustine and dacarbazine should not be used simultaneously.


Concomitant use of cyclosporine (and in some cases tacrolim) requires careful monitoring, as it may increase immunosuppression and lymphoproliferation.

Application features.


Therapy should be performed by an experienced oncologist-hematologist in medical institutions where it is possible to check clinical, biochemical and hematological parameters during and after therapy.


If hypersensitivity reactions or functional renal or hepatic insufficiency occur, dacarbazine treatment should be discontinued immediately. If occlusive diseases of the hepatic veins are observed, further treatment with this drug is contraindicated.


Note. The doctor should be aware of a serious complication of therapy (which rarely occurs and is a consequence of liver necrosis) caused by blockage of intrahepatic veins. Therefore, it is necessary to periodically monitor the size of the liver, its function and blood tests (especially the level of eosinophils). In some cases, if venous obstruction is suspected, early therapy with high doses of corticosteroids (for example, hydrocortisone 300 mg per day) with or without Heparin or tissue plasminogen activators is effective.


Long-term therapy can cause cumulative toxic effects on the bone marrow.


Given the possible suppression of bone marrow function, it is necessary to periodically check the level of white blood cells, red blood cells and platelets in the blood. Inhibition of hematopoiesis may be a reason for temporary or final discontinuation of therapy with this drug. Extravasation of the drug during intravenous administration leads to tissue damage and severe pain.


During dacarbazine therapy, it is necessary to refrain from taking alcohol and hepatotoxic drugs.


Men are advised to use reliable contraceptives during treatment and for 6 months after the end of treatment. 


Use during pregnancy or lactation.


In animal experiments, dacarbazine has shown mutagenic, teratogenic and carcinogenic effects. Humans also have a risk of teratogenic effects.


Dacarbazine is contraindicated during pregnancy or lactation.


Women of reproductive age should use effective methods of contraception during treatment with dacarbazine. 


Ability to influence the reaction rate when driving vehicles or other mechanisms.


 Dacarbazine can affect the ability to drive a car or work with complex mechanisms through adverse reactions from the central nervous system, nausea and vomiting. 


Dosage and administration.


Apply intravenously. Therapy should be performed by a doctor who has experience in oncology and hematology.


Dacarbazine is sensitive to sunlight. All dacarbazine solutions must be protected from light, as well as during administration (light-resistant infusion set).


Administration should be carried out very carefully, avoiding getting dacarbazine solution into the tissues, because this can cause tissue damage and pain at the injection site. If extravasation has occurred, the administration should be stopped immediately and the remaining dose should be injected into another vein.


Malignant melanoma.


With monotherapy, dacarbazine is usually prescribed at a dose of 200-250 mg/m2 of body surface area in the form of an intravenous injection 1 time a day for 5 days, repeated courses – every 3 weeks.


As an alternative to intravenous bolus injection, dacarbazine solution can be administered by short-term infusion (within 15-30 minutes).


It is also possible to prescribe dacarbazine as an intravenous infusion at a dose of 850 mg/m2 1 time a day and then 1 time every 3 weeks.


Hodgkin's Disease.


Dacarbazine is prescribed at a dose of 375 mg/m2 of body surface area per day (intravenously) every 15 days. In this case, dacarbazine should be used in combination with doxorubicin, bleomycin and vinblastine (ABVD dosage regimen).


Soft tissue sarcoma in adults.


For the treatment of soft tissue sarcoma in adults, dacarbazine should be administered intravenously at a dose of 250 mg/m2 per day (1-5 days) in combination with doxorubicin every 3 weeks (ADIC).


During therapy with dacarbazine, it is necessary to periodically check blood parameters, the functional state of the kidneys and liver. Since reactions from the gastrointestinal tract are often observed, it is recommended to conduct maintenance therapy and use antiemetics.


Since gastrointestinal and hematological disorders may occur, a thorough risk-benefit analysis is necessary before each course of dacarbazine therapy.


Duration of treatment.


The doctor determines the duration of treatment individually for each case, taking into account many factors (type and stage of the disease, combination therapy, side effects and therapeutic effect caused by dacarbazine, etc.). In the case of Hodgkin's disease, 6 cycles of ABVD combination therapy are usually recommended. In the case of soft tissue sarcoma and malignant melanoma, the duration of treatment is determined by the effectiveness of dacarbazine and the patient's tolerance to it.


Patients with renal and hepatic insufficiency.


If the patient has only minor renal or hepatic impairment, dose adjustment is optional. In patients with combined renal and hepatic insufficiency, the elimination time of dacarbazine increases. However, there are still no approved recommendations for dose reduction for such patients.


Elderly people.


There are no recommendations for the use of dacarbazine in the elderly, as there is no sufficient experience in using this drug in this category of patients.


Input speed.


Doses of less than 200 mg/m2 can be administered slowly by intravenous injection. Large doses of dacarbazine (200 to 850 mg/m2) should be administered intravenously for 15-30 minutes.


It is recommended to first check the patency of the vessel by injecting 5-10 ml of 0.9% sodium chloride solution for infusions or 5% glucose solution. The same solutions are used to wash the bottle after injections from residual amounts of the drug.


When dissolved in water without further dilution with 0.9% sodium chloride solution for injection or 5% glucose solution, the resulting solution of the drug (100 or 200 mg of dacarbazine) is hypoosmolar (100 mosmol/kg), so it should be administered slowly, more than 1 minute, instead of rapid bolus intravenous administration in a few seconds.


Preparation of a solution for intravenous administration.


Prepare the solution immediately before Administration, use immediately.


Dacarbazine is sensitive to sunlight, so all means for preparing and injecting the solution must be protected from light, such as polyvinyl chloride infusion systems that are resistant to light.


When using conventional infusion systems, they should be wrapped in UV-resistant foil.


a) preparation of dacarbazine solution (dosage 100 mg).


Aseptically inject 10 ml of water for injection into the bottle with the drug and shake until completely dissolved. A freshly prepared solution containing 10 mg/mL of dacarbazine (osmolarity of the solution r = 1.007 g/ml) should be administered slowly intravenously.


For intravenous infusion, the resulting freshly prepared solution is diluted in 200-300 ml of 0.9% sodium chloride solution for injection or 5% glucose solution. This solution should be administered as a short-term intravenous infusion for 15-30 minutes.


B) preparation of dacarbazine solution (dosage 200 mg).


Aseptically inject 20 ml of water for injection into the bottle with the drug and shake until completely dissolved. A freshly prepared solution containing 10 mg/mL of dacarbazine (osmolarity of the solution r = 1.007 g/ml) should be administered slowly intravenously.


For intravenous infusion, the resulting solution is diluted in 200-300 ml of 0.9% sodium chloride solution for injection or 5% glucose solution. This solution should be administered as a short-term intravenous infusion for 15-30 minutes.


C) preparation of dacarbazine solution (dosage 500 mg).


Aseptically inject 50 ml of water for injection into the bottle with the drug and shake until completely dissolved. A freshly prepared solution containing 10 mg/mL of dacarbazine (osmolarity of the solution r = 1.007 g/ml) should be dissolved in 200-300 ml of 0.9% sodium chloride solution for injection or 5% glucose solution. The resulting infusion solution containing 1.4-2.0 mg/mL of dacarbazine should be administered intravenously for 20-30 minutes.

d) preparation of dacarbazine solution (dosage 1000 mg).


Aseptically inject 50 ml of water for injection into the bottle with the drug and shake until completely dissolved. A freshly prepared solution containing 20 mg/mL of dacarbazine (osmolarity of the solution r = 1.015 g/ml) should be dissolved in 200-300 ml of 0.9% sodium chloride solution for injection or 5% glucose solution. The resulting infusion solution containing 2.8-4.0 mg/mL of dacarbazine should be administered intravenously for 20-30 minutes.


Dacarbazine Medac is used only once. Before Administration, visually check the solution, use only a transparent solution that is practically free of undissolved particles. Do not use a solution with mechanical inclusions.


Any part of the contents of the bottle that remains after the solution is prepared should be destroyed, as well as solutions that have not passed visual inspection.


All materials used in the manufacture and administration of the solution must be disposed of (burned) in accordance with the current legislation. 


Children.


The safety and efficacy of dacarbazine in children/adolescents aged 15 years have not yet been studied.


There is insufficient information on the use of dacarbazine in Pediatrics.


Overdose.


The first expected complications of dacarbazine overdose are bone marrow suppression, eventually bone marrow aplasia, which occurs after 2 weeks. A decrease in the level of white blood cells and platelets can be observed at the 4th week. Even if an overdose is only suspected, long-term monitoring of the patient's blood parameters should be carried out.


Do not overdose with dacarbazine. The specific antidote is unknown. 


Adverse reactions.


Adverse reactions are classified by frequency of occurrence: very common (> 1/10), common (> 1/100, 1/10), non-common (> 1/1000, 1/100), rarely common (> 1/10000, 1/1000), very rarely common ( 1/10000), unknown (cannot be determined from available data).


Infections and infestations: rarely common – infections.


From the circulatory and lymphatic systems: common – anemia, leukopenia, thrombocytopenia; rarely common – pancytopenia, agranulocytosis.


Immune system disorders: rarely common – anaphylactic reactions.


From the nervous system: rarely common – headache, blurred vision, confusion, convulsions, paresthesia of the face.


From the side of blood vessels: rarely common – hot flashes.


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


From the hepatobiliary system: rarely common – obstruction of the hepatic vein – to liver necrosis, Budd – Chiari Syndrome ( with a potentially fatal outcome).


From the urinary system: rarely common – renal failure.


From the skin and skin appendages: rare – alopecia, hyperpigmentation, photosensitization; rarely common – erythema, maculopapular exanthema, urticaria.


General and local disorders: non – common – flu-like syndrome; rarely common-inflammation at the injection site.


Laboratory parameters: rarely common-increased levels of liver enzymes (for example, alkyl phosphatase, AST, ALT), increased levels of lactate dehydrogenase (LDH), creatinine and urea.


Often there were changes in the blood test (anemia, leukopenia, thrombocytopenia), which were dose-dependent and delayed, with the lowest frequency after 3-4 weeks of treatment.


After dacarbazine administration, a flu-like syndrome with fatigue, chills, fever, and muscle pain was observed. These symptoms may recur after subsequent injections.


During dacarbazine monotherapy or in combination therapy, liver necrosis was rarely observed due to blockage of intrahepatic veins (veno-obliterating liver disease), which occurred during the second treatment cycle. Symptoms included fever, eosinophilia, abdominal pain, enlarged liver, jaundice, and shock, which progressed rapidly over several hours or days. Since a fatal outcome has been described, increased attention should be paid to the appearance of such symptoms.


Irritation at the injection site and some systemic adverse reactions are considered to result from the formation of photodegradation products.


After the injection, paresthesia and redness of the face may be observed.


Very rarely, allergic skin reactions such as erythema, maculopapular erythema, or urticaria may occur.


A paravenous injection can lead to local pain and necrosis. 


Reports of adverse drug reactions.


Reports of adverse drug reactions after drug registration are very important. They allow you to continue monitoring the benefit/risk balance of the drug. In case of any drug reactions, you should inform your doctor.


Expiration date. 3 years.


Shelf life of the reconstituted solution of dacarbazine Medac 100 mg (200 mg):


Chemical and physical stability was maintained for 24 hours at a temperature of 20 °C in a place protected from light.


From a microbiological point of view, the solution should be used immediately. If the solution was not used immediately, the user is responsible for the duration and storage conditions, which should not exceed 24 hours at a temperature of 2-8 °C, unless dilution was carried out under controlled and validated aseptic conditions.


Shelf life of the reconstituted and further diluted solution of dacarbazine Medak 100 mg (200 mg):


The reconstituted and diluted solution should be used immediately. 


Shelf life of the reconstituted and further diluted solution of dacarbazine Medak 500 mg (1000 mg):


The reconstituted and diluted solution should be used immediately. 


Storage conditions.


Store at a temperature not exceeding 25 °C OUT of the reach of children in the original packaging to protect from light. 


Incompatibility.


Dacarbazine is chemically incompatible with heparin, hydrocortisone, L-cysteine, and sodium bicarbonate.

Tags: Dacarbazine