Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: medac, Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany
It is recommended that dacarbazine should only be administered under the supervision of a physician specialised in oncology who has the facilities for regular monitoring of clinical, biochemical and haematological effects, during and after therapy.
If symptoms of a liver or kidney functional disorder or symptoms of a hypersensitivity reaction are observed immediate cessation of therapy is required. If veno-occlusive disease of the liver occurs, further therapy with dacarbazine is contraindicated.
Note: The responsible physician should be aware of a rarely observed severe complication during therapy resulting from liver necrosis due to occlusion of intrahepatic veins. Therefore frequent monitoring of liver size, function and blood counts (especially eosinophils) is required. In single cases of suspected veno-occlusive disease early therapy with high-dose corticosteroids (for example hydrocortisone 300 mg/day) with or without fibrinolytic agents like heparin or tissue plasminogen activator was successful (see section 4.8).
Long-term therapy can cause cumulative bone marrow toxicity. The possible bone marrow depression requires careful monitoring of white blood cells, red blood cells and platelet levels. Haemopoietic toxicity may warrant temporary suspension or cessation of therapy.
Extravasation of the medicinal product during i.v. administration may result in tissue damage and severe pain.
Concomitant use with phenytoin should be avoided because reduced absorption of phenytoin from the gastrointestinal tract may predispose the patient to convulsions (see section 4.5).
Dacarbazine is a moderate immunosuppressive agent. Administration of live vaccines to patients who are immunocompromised as a result of treatment with chemotherapeutics such as dacarbazine can cause serious and potentially fatal infections. Immunisation with live vaccines should therefore be avoided during dacarbazine therapy. It is generally advised to use live virus vaccines with caution after stopping chemotherapy and to take the patient’s immune status into account, depending also on the disease and other therapies. Vaccination with live vaccines should be administrated no sooner than 3 months after the completion of chemotherapy. Inactivated vaccines can be used if available.
Concomitant use of fotemustine can cause acute pulmonary toxicity (adult respiratory distress syndrome), which may lead to a fatal outcome. Fotemustine and dacarbazine should not be used concomitantly.
Hepatotoxic medicinal products and alcohol should be avoided during chemotherapy.
Men are advised to take contraceptive measures during and for 6 months after cessation of therapy.
Dacarbazine is not recommended for use in the paediatric age group until further data become available.
For precaution on handling, please see section 6.6.
In case of previous or concomitant treatment having adverse effects on the bone marrow (particularly cytostatic agents, irradiation) myelotoxic interactions are possible.
Studies to investigate the presence of phenotypic metabolism have not been undertaken but hydroxylation of the parent compound to metabolites with anti-tumour activity has been identified.
Dacarbazine is metabolised by cytochrome P450 (CYP1A1, CYP1A2, and CYP2E1). This has to be taken into account if other medicinal products are co-administered which are metabolised by the same hepatic enzymes.
Dacarbazine can enhance the effects of methoxypsoralen because of photosensitization.
Immunisation with live vaccines should be avoided during therapy with dacarbazine due to the risk of serious and potentially fatal infections. It is advised to use live virus vaccines with caution after stopping chemotherapy and vaccinate not sooner than 3 months after the last dose of chemotherapy. It is recommended to use an inactivated vaccine if available (see also section 4.4).
Risk of thrombosis is increased in malignant diseases; therefore, use of concomitant anticoagulation is common. If the patient is to receive oral anticoagulants, the frequency of INR monitoring must be increased due to large interindividual variability in coagulation and due to possible interaction between anticoagulants and cytostatics.
Concomitant use with phenytoin may cause reduced absorption of phenytoin from the gastrointestinal tract and may predispose the patient to convulsions (see section 4.4).
Concomitant use of cyclosporine (and in some cases tacrolimus) must be considered carefully because these agents may cause excessive immunosuppression and lymphoproliferation.
Concomitant use of fotemustine can cause acute pulmonary toxicity (adult respiratory distress syndrome). Fotemustine and dacarbazine should not be used concomitantly.
Dacarbazine has been shown to be mutagenic, teratogenic and carcinogenic in animals. It must be assumed that an increased risk for teratogenic effects exists in humans. Therefore Dacarbazine medac is contraindicated during pregnancy (see section 4.3 and 4.4).
Women of child-bearing potential have to use effective contraception during treatment.
Dacarbazine medac is contraindicated during breast-feeding (see section 4.3).
Dacarbazine may influence the ability to drive or operate machines because of its central nervous side effects or because of nausea and vomiting.
Frequencies:
Very common (> 1/10)
Common (> 1/100 to < 1/10)
Uncommon (> 1/1000 to < 1/100)
Rare (> 1/10000 to < 1/1000)
Very rare (< 1/10000)
Not known (cannot be estimated from the available data)
The most commonly reported ADRs are gastrointestinal disorders (anorexia, nausea and vomiting) and blood and lymphatic system disorders such as anaemia, leukopenia and thrombocytopenia. The latter are dose-dependent and delayed, with the nadirs often only occurring after 3 to 4 weeks.
Uncommon: Infections
Common: Anaemia, leukopenia, thrombocytopenia
Rare: Pancytopenia, agranulocytosis
Rare: Anaphylactic reactions
Rare: Headaches, impaired vision, confusion, lethargy, convulsions, facial paraesthesia
Rare: Facial flushing
Common: Anorexia, nausea, vomiting
Rare: Diarrhoea
Rare: Hepatic necrosis due to veno-occlusive disease (VOD) of the liver, Budd-Chiari syndrome (with potentially fatal outcome)
Rare: Impaired renal function
Uncommon: Alopecia, hyperpigmentation, photosensitivity
Rare: Erythema, maculopapular exanthema, urticaria
Uncommon: Flu-like symptoms
Rare: Application site irritation
Rare: Hepatic enzymes increased (e.g. alkaline phosphatase, ASAT, ALAT), blood lactate dehydrogenase (LDH) increased, blood creatinine increased, blood urea increased
Changes in blood counts often observed (anaemia, leukopenia, thrombocytopenia) are dose-dependent and delayed, with the nadirs often only occurring after 3 to 4 weeks.
Flu-like symptoms with exhaustion, chills, fever and muscular pain are occasionally observed during or often only days after dacarbazine administration. These disturbances may recur with the next infusion.
Rarely liver necrosis due to occlusion of intrahepatic veins (veno-occlusive disease of the liver) has been observed after administration of dacarbazine in monotherapy or in combined treatment modalities. In general the syndrome occurred during the second cycle of therapy. Symptoms included fever, eosinophilia, abdominal pain, enlarged liver, jaundice and shock which worsened rapidly over a few hours or days. As fatal outcome has been described special care has to be taken (see sections 4.2 and 4.4).
Application site irritations and some of the systemic adverse reactions are thought to result from formation of photodegradation products.
Facial paraesthesia and flushing may occur shortly after injection.
Allergic reactions of the skin in the form of erythema, maculopapular exanthema or urticaria are observed rarely.
Inadvertent paravenous injection is expected to cause local pain and necrosis.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Dacarbazine solution is chemically incompatible with heparin, hydrocortisone, L-cysteine and sodium hydrogen carbonate.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
