Dacarbazine medak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DAKARBAZINE MEDAC (DACARBAZINE MEDAC)

Composition:

Active substance: dacarbazine;

1 vial contains dacarbazine citrate equivalent to dacarbazine 100 mg, or 200 mg, or 500 mg, or 1000 mg;

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

Pharmaceutical form. Powder for solution for injection or infusion.

Main physicochemical properties: white or light yellow powder or agglomerated mass.

Pharmacotherapeutic group. Antineoplastic agents. Alkylating agents.

ATC code: L01A X04.

Pharmacological Properties.

Pharmacodynamics.

Dacarbazine is an alkylating cytostatic agent with a triazene structure.

Its mechanism of action involves inhibition of cell growth (independent of the cell cycle) and inhibition of DNA synthesis. Dacarbazine also exerts an alkylating effect and may participate in other cytostatic mechanisms.

Dacarbazine itself is considered to lack antineoplastic activity; however, through microsomal N-demethylation, it is rapidly converted into 5-aminoimidazole-4-carboxamide and a methyl cation, which mediates the alkylating action of dacarbazine.

Pharmacokinetics.

Distribution.

After intravenous administration, dacarbazine rapidly penetrates tissues. Plasma protein binding is 5%. Plasma kinetics are biphasic, with an initial distribution half-life of 20 minutes and a terminal half-life of approximately 0.5–3.5 hours.

Biotransformation.

Dacarbazine is inactive until metabolized in the liver by cytochrome P450, resulting in the formation of active N-demethylated compounds HMMTIC and MTIC. This process is catalyzed by CYP1A1, CYP1A2, and CYP2E1 enzymes.

MTIC is further metabolized to 5-aminoimidazole-4-carboxamide (AIC).

Excretion.

Dacarbazine is primarily metabolized in the liver via both hydroxylation and demethylation. Approximately 20–50% of the drug is excreted unchanged by the kidneys through tubular secretion.

Preclinical safety data.

Dacarbazine demonstrates mutagenic, carcinogenic, and teratogenic effects, as observed in experimental test systems.

Clinical characteristics.

Indications.

Malignant metastatic melanoma.

In combination chemotherapy:

• Hodgkin's disease;
• progressive soft tissue sarcoma (excluding mesothelioma, Kaposi's sarcoma) in adults.

Contraindications.

• Hypersensitivity to dacarbazine or to any other component of the medicinal product;
• pregnancy or breastfeeding;
• leukopenia and/or thrombocytopenia;
• severe hepatic and/or renal impairment;
• in patients concurrently receiving yellow fever vaccination or concomitant use of fotemustine.

Special precautions. Standard precautions for handling cytotoxic medicinal products with teratogenic, mutagenic, and carcinogenic effects must be observed.

Dacarbazine is an antineoplastic agent. Before opening the vial, instructions for handling cytostatics must be reviewed.

Dacarbazine should be handled only by experienced medical personnel. As with all cases involving handling of cytostatic agents, exposure of personnel to the drug must be avoided. During pregnancy, any contact with cytostatic agents should be avoided. Solution preparation should be performed in a designated area, working over a washable tray or over absorbent paper placed on a plastic-backed absorbent pad.

Appropriate protective eyewear, gloves, face mask, and gown must be worn. Syringes and administration devices should be carefully assembled to ensure their integrity and prevent leakage of the drug solution.

If the solution comes into contact with any surface, the surface must be immediately and thoroughly cleaned; hands and face must also be washed thoroughly.

In case of spillage, the liquid should be cleaned up using absorbent material. All contaminated materials must be disposed of properly (by incineration).

Interaction with other medicinal products and other forms of interaction.

If prior or concomitant treatment with agents that adversely affect bone marrow (cytostatics, radiation therapy) is administered, enhanced myelotoxicity of dacarbazine may occur.

Metabolism studies have not been conducted, but it is known that hydroxylation of the parent compound contributes to enhancement of its antitumor activity. Dacarbazine is metabolized in the liver via P450 enzymes (CYP1A1, CYP1A2, and CYP2E1). This should be taken into account when administering concomitantly medicinal products that are metabolized by the same enzymes.

Dacarbazine may enhance the photosensitizing effect of methoxsalen.

Administration of live vaccines to patients whose immune system is compromised due to chemotherapy agents such as dacarbazine may result in serious and potentially fatal infections. Therefore, live vaccines should be avoided during dacarbazine therapy. Generally, live viral vaccines should be used with caution only after discontinuation of chemotherapy, taking into account the patient's immune status depending on the disease and other treatment modalities. Live vaccines should not be administered earlier than 3 months after completion of chemotherapy. Inactivated vaccines may be used if necessary.

Malignant tumors increase the risk of thrombosis; therefore, concomitant administration of anticoagulants is common practice. If a patient is receiving oral anticoagulants, the international normalized ratio (INR) should be monitored more frequently due to variable individual sensitivity and possible interaction between anticoagulants and cytostatics.

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

Concomitant use of fotemustine may cause acute pulmonary toxicity (adult respiratory distress syndrome), which may lead to fatal outcome. Fotemustine and dacarbazine should not be administered simultaneously. Dacarbazine may be administered only one week after fotemustine administration.

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

Special precautions for use.

Treatment should be administered by an experienced oncologist-hematologist in medical facilities equipped to monitor clinical, biochemical, and hematological parameters during and after therapy.

If hypersensitivity reactions or functional renal or hepatic impairment occur, treatment with dacarbazine should be discontinued immediately. Dacarbazine is contraindicated in patients with hepatic veno-occlusive disease.

Note. Physicians should be aware of a severe, although rare, complication of therapy resulting from hepatic necrosis due to occlusion of intrahepatic veins. Therefore, periodic monitoring of liver size, liver function, and blood analysis (especially eosinophil levels) is necessary. In some cases, early treatment with high-dose corticosteroids (e.g., hydrocortisone 300 mg daily), with or without heparin or tissue plasminogen activators, may be effective when venous obstruction is suspected.

Prolonged therapy may result in cumulative toxic effects on the bone marrow.

Due to the potential for myelosuppression, periodic monitoring of leukocyte, erythrocyte, and platelet counts is required. Suppression of hematopoiesis may necessitate temporary or permanent discontinuation of therapy with this drug. Extravasation of the drug during intravenous administration may lead to tissue damage and severe pain.

Alcohol and hepatotoxic drugs should be avoided during dacarbazine therapy.

Women of childbearing potential/contraception in men and women

Due to the genotoxic potential of dacarbazine, women of childbearing potential must use effective contraception during treatment with Dacarbazine Medac and for 6 months after completion of therapy.

Men are advised to use effective contraception and to avoid fathering a child during treatment with Dacarbazine Medac and for 3 months after therapy ends.

Patients planning pregnancy should seek genetic counseling after the recommended contraception period (see section "Use during pregnancy or breastfeeding").

Use during pregnancy or breastfeeding

Pregnancy

Dacarbazine has been shown to have mutagenic, teratogenic, and carcinogenic effects in animals. A similar risk of teratogenic effects in humans should be assumed. Therefore, Dacarbazine Medac is contraindicated during pregnancy (see section "Contraindications").

Women of childbearing potential/contraception in men and women

Due to the genotoxic potential of dacarbazine, women of childbearing potential must use effective contraception during treatment with Dacarbazine Medac and for 6 months after completion of therapy.

Men are advised to use effective contraception and to avoid fathering a child during treatment with Dacarbazine Medac and for 3 months after therapy ends.

Breastfeeding

Dacarbazine Medac is contraindicated during breastfeeding (see section "Contraindications").

Fertility

Due to the genotoxic potential of dacarbazine, patients should be advised to consult on fertility preservation methods prior to initiating dacarbazine therapy. After treatment with dacarbazine, patients planning pregnancy are advised to seek genetic counseling.

Ability to affect reaction speed when driving or operating machinery.

Dacarbazine may impair the ability to drive or operate machinery due to adverse reactions affecting the central nervous system, nausea, and vomiting.

Method of Administration and Dosage

Administer intravenously. Therapy should be administered by a physician experienced in oncology and hematology.

Malignant melanoma

For monotherapy, dacarbazine is generally administered at a dose of 200–250 mg/m² body surface area as an intravenous injection once daily for 5 consecutive days, with repeated cycles every 3 weeks.

As an alternative to intravenous bolus injection, the dacarbazine solution may be administered by short-term infusion (over 15–30 minutes).

Dacarbazine may also be given as an intravenous infusion at a dose of 850 mg/m² once daily, followed by administration once every 3 weeks.

Hodgkin’s disease

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

Soft tissue sarcoma in adults

For treatment of soft tissue sarcoma in adults, dacarbazine is administered at a dose of 250 mg/m² daily intravenously (days 1–5) in combination with doxorubicin every 3 weeks (ADIC regimen).

During dacarbazine therapy, periodic monitoring of blood counts and renal and liver function is required. Since gastrointestinal reactions are common, supportive therapy and antiemetic agents are recommended.

Due to the potential for gastrointestinal and hematological toxicities, a careful risk-benefit assessment is necessary before each treatment cycle.

Treatment duration

The duration of treatment is determined individually by the physician, taking into account multiple factors (type and stage of disease, combination therapy, adverse effects, and therapeutic response to dacarbazine, etc.). In Hodgkin’s disease, 6 cycles of ABVD combination therapy are generally recommended. For soft tissue sarcoma and malignant melanoma, treatment duration depends on the efficacy of dacarbazine and patient tolerance.

Renal and hepatic impairment

Dose adjustment is not required in patients with mild renal or hepatic dysfunction. In patients with combined renal and hepatic impairment, elimination of dacarbazine may be prolonged. However, there are currently no established recommendations for dose reduction in such patients.

Elderly patients

There are no specific recommendations for the use of dacarbazine in elderly patients due to insufficient experience with this drug in this patient population.

Method of Administration

Precautions to be taken before and during administration of the medicinal product

• Dacarbazine is light-sensitive. All dacarbazine solutions must be protected from light, including during administration (use a light-resistant infusion set).
• Administration should be performed very carefully to avoid leakage of the dacarbazine solution into surrounding tissues, which may cause tissue damage and local pain. If extravasation occurs, administration must be stopped immediately, and the remaining dose should be administered into another vein.

Refer to the instructions below for reconstitution prior to administration.

Rate of administration

Doses below 200 mg/m² may be administered slowly via intravenous bolus injection. Higher doses of dacarbazine (from 200 to 850 mg/m²) should be administered by intravenous infusion over 15–30 minutes.

It is recommended to first verify venous patency by administering 5–10 mL of 0.9% sodium chloride solution for infusion or 5% glucose solution. The same solutions should be used to flush the vial after injection to recover residual amounts of the drug.

When reconstituted in water without further dilution with 0.9% sodium chloride solution for injection or 5% glucose solution, the resulting solutions of 100 mg and 200 mg dacarbazine are hypo-osmolar (100 mOsmol/kg) and should therefore be administered slowly over more than 1 minute, rather than as a rapid intravenous bolus over a few seconds.

Preparation of solution for intravenous administration

The solution should be prepared immediately before administration and used promptly.

Dacarbazine is sensitive to sunlight; therefore, all materials used for preparation and administration of the solution must be protected from light, e.g., polyvinyl chloride infusion sets that are light-resistant.

When using standard infusion sets, they should be wrapped in UV-protective foil.

a) Preparation of Dacarbazine Medac, 100 mg solution

Aseptically add 10 mL of water for injections to the vial and shake until fully dissolved. The freshly prepared solution, containing 10 mg/mL dacarbazine (solution osmolarity ρ = 1.007 g/mL), should be administered slowly intravenously.

For intravenous infusion, dilute the freshly prepared solution in 200–300 mL of 0.9% sodium chloride solution for injection or 5% glucose solution. Administer this solution as a short-term intravenous infusion over 15–30 minutes.

b) Preparation of Dacarbazine Medac, 200 mg solution

Aseptically add 20 mL of water for injections to the vial and shake until fully dissolved. The freshly prepared solution, containing 10 mg/mL dacarbazine (solution osmolarity ρ = 1.007 g/mL), should be administered slowly intravenously.

For intravenous infusion, dilute the prepared solution in 200–300 mL of 0.9% sodium chloride solution for injection or 5% glucose solution. Administer this solution as a short-term intravenous infusion over 15–30 minutes.

c) Preparation of Dacarbazine Medac, 500 mg solution

Aseptically add 50 mL of water for injections to the vial and shake until fully dissolved. Dilute the freshly prepared solution, containing 10 mg/mL dacarbazine (solution osmolarity ρ = 1.007 g/mL), in 200–300 mL of 0.9% sodium chloride solution for injection or 5% glucose solution. Administer the resulting infusion solution, containing 1.4–2.0 mg/mL dacarbazine, by intravenous infusion over 20–30 minutes.

d) Preparation of Dacarbazine Medac, 1000 mg solution

Aseptically add 50 mL of water for injections to the vial and shake until fully dissolved. Dilute the freshly prepared solution, containing 20 mg/mL dacarbazine (solution osmolarity ρ = 1.015 g/mL), in 200–300 mL of 0.9% sodium chloride solution for injection or 5% glucose solution. Administer the resulting infusion solution, containing 2.8–4.0 mg/mL dacarbazine, by intravenous infusion over 20–30 minutes.

Dacarbazine Medac is for single use only. Before administration, visually inspect the solution; only clear, practically particle-free solutions should be used. Do not use solutions containing mechanical particles.

Solutions that fail visual inspection must be discarded.

All materials used during preparation and administration of the solution must be disposed of (incinerated) in accordance with applicable regulations.

Children

The safety and efficacy of dacarbazine in children/adolescents under 15 years of age have not been established. Specific recommendations for the use of dacarbazine in pediatric patients cannot be provided until additional data are available.

Overdose

The first expected complications of dacarbazine overdose are bone marrow suppression, eventually leading to bone marrow aplasia, which typically occurs 2 weeks after administration. Decreased leukocyte and platelet counts may be observed by the 4th week. Even suspected overdose requires prolonged monitoring of the patient's blood parameters.

Dacarbazine overdose must be avoided. There is no known specific antidote.

Adverse Reactions

Adverse reactions are classified by frequency of occurrence: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10,000, < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Infections and infestations: uncommon – infections.

Blood and lymphatic system disorders: common – anaemia, leucopenia, thrombocytopenia; rare – pancytopenia, agranulocytosis.

Immune system disorders: rare – anaphylactic reactions.

Nervous system disorders: rare – headache, visual disturbances, confusion, seizures, facial paraesthesia.

Vascular disorders: rare – flushes.

Gastrointestinal disorders: common – anorexia, nausea, vomiting; rare – diarrhoea.

Hepatobiliary disorders: rare – hepatic vein obstruction leading to liver necrosis, Budd-Chiari syndrome (with potentially fatal outcome).

Renal and urinary disorders: rare – renal failure.

Skin and subcutaneous tissue disorders: uncommon – alopecia, hyperpigmentation, photosensitization; rare – erythema, maculopapular exanthema, urticaria.

General and administration site conditions: uncommon – flu-like syndrome; rare – injection site inflammation.

Laboratory findings: rare – increased levels of liver enzymes (e.g. alkaline phosphatase, AST, ALT), increased lactate dehydrogenase (LDH), creatinine and urea levels.

Changes in blood counts (anaemia, leucopenia, thrombocytopenia) were frequently observed, being dose-dependent and delayed, with nadir occurring after the 3rd–4th week of treatment.

Following administration of dacarbazine, a flu-like syndrome with fatigue, chills, fever, and myalgia has been observed. These symptoms may recur after subsequent administrations.

During monotherapy with dacarbazine or in combination therapy, liver necrosis due to obstruction of intrahepatic veins (veno-occlusive liver disease) has been rarely observed, typically occurring during the second treatment cycle. Symptoms included fever, eosinophilia, abdominal pain, hepatomegaly, jaundice, and shock, progressing rapidly within hours or days. As fatal outcomes have been reported, careful attention should be paid to the emergence of such symptoms.

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

After injection, facial paraesthesia and flushing may occur.

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

Paravenous injection may lead to local pain and necrosis.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. In case of any adverse reactions, a healthcare professional should be informed.

Shelf life. 3 years.

Shelf life of reconstituted solution of Dacarbazine Medac 100 mg (200 mg, 500 mg, 1000 mg):

Chemical and physical stability was maintained for 48 hours at 2–8°C, protected from light.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the user is responsible for storage conditions and duration, which must not exceed 24 hours at 2–8°C, unless reconstitution was performed under controlled and validated aseptic conditions.

Shelf life of reconstituted and subsequently diluted solution of Dacarbazine Medac 100 mg (200 mg, 500 mg, 1000 mg):

Chemical and physical stability was maintained for 2 hours at 25°C in polyethylene containers, and for 24 hours at 2–8°C, protected from light, in polyethylene containers and glass vials.

From a microbiological standpoint, the reconstituted and diluted solution should be used immediately.

Storage conditions.

Store at temperatures not exceeding 25°C, protected from light, in the original packaging, in a place inaccessible to children.

Incompatibilities.

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

Packaging. 10 glass vials containing 100 mg or 200 mg of dacarbazine per cardboard package; 1 glass vial containing 500 mg or 1000 mg of dacarbazine per cardboard package.

Prescription category. Prescription only.

Manufacturer.

Medac Gesellschaft für klinische Spezialpräparate mbH.

Manufacturer's address and place of business.

Theaterstraße 6, 22880 Wedel, Germany.