Active ingredients: Dacarbazine
Dacarbazine Lipomed 100 mg powder for solution for injection or solution for infusion
Dacarbazine package inserts are available for pack sizes:- Dacarbazine Lipomed 100 mg powder for solution for injection or solution for infusion
- Dacarbazine Lipomed 200 mg powder for solution for injection or solution for infusion
Why is Dacarbazine used? What is it for?
The full name of the medicine is Dacarbazine Lipomed. The abbreviated name Dacarbazine is used in this leaflet. The medicine belongs to a group of medicines called 'cytotoxic drugs' or chemotherapy. Treatment with Dacarbazine should only be done by doctors who specialize in the treatment of cancer (oncologists) or blood disorders (haematologists).
Dacarbazine is used to treat a type of skin cancer called 'metastatic malignant melanoma'. It is a type of skin cancer that has spread to other parts of the body. Dacarbazine is also used with other medicines to:
- advanced cancer of the portion of the immune system called the "lymphatic system"; this type of cancer is called "Hodgkin's lymphoma".
- advanced soft tissue sarcomas in adults (with the exception of mesothelioma and Kaposi's sarcoma). Soft tissue sarcomas are malignant tumors that originate in the soft tissues of the body; these tumors can be found in various locations, such as around nerves, muscles or blood vessels.
Dacarbazine helps stop the growth and multiplication of cancer cells.
Contraindications When Dacarbazine should not be used
Dacarbazine should not be given to you if:
- you are allergic (hypersensitive) to dacarbazine or any of the other ingredients of this medicine
- are pregnant or breastfeeding
- have a low white blood cell count (leukopenia) or a low platelet count (thrombocytopenia)
- have severe liver or kidney problems
- in combination with yellow fever vaccine
Dacarbazine should not be given to you if you are in any of the conditions described. If you are not sure, consult your doctor, nurse or pharmacist before using Dacarbazine.
Precautions for use What you need to know before taking Dacarbazine
Your doctor will need to ensure that dacarbazine is administered properly to avoid tissue damage and pain. Extravasation (injection of the solution into the tissues surrounding the vein) can cause tissue damage and severe pain.
Exams
During the treatment the following tests will be carried out:
- liver volume and liver function (via blood test), to check that the veins in the liver are not blocked. If the liver is compromised, treatment will be stopped.
- number of red blood cells, white blood cells and platelets in the blood (via blood test), to check that the bone marrow is producing blood cells adequately. If the bone marrow is compromised, treatment can be stopped temporarily or permanently.
Men treated with dacarbazine should use contraceptive methods during therapy and for 6 months after the end of therapy.
Interactions Which drugs or foods can modify the effect of Dacarbazine
Tell your doctor or nurse if you are taking or have recently taken any other medicines, including those obtained without a prescription and herbal preparations. This is because Dacarbazine can affect the way some other medicines work. Other medicines can also affect the way they work. mode of action of Dacarbazine.
In particular, this medicine should not be given to you and you should tell your doctor, nurse or pharmacist if you are using any of the following medicines:
- phenytoin - against seizures (convulsions).
- other medicines that can damage the liver.
Do not use Dacarbazine if you are using any of these medicines. If you are unsure, consult your doctor, nurse or pharmacist before you are given Dacarbazine. Tell your nurse or pharmacist if you are taking any of the following treatments:
- radiotherapy or other medicines that reduce the growth of tumors (chemotherapy) The use of these medicines with Dacarbazine may increase the damage to the bone marrow.
- other medicines metabolised by the liver enzyme system called cytochrome P450.
- methoxypsoralen against certain skin problems, such as psoriasis and eczema Administration of Dacarbazine with methoxypsoralen can increase sensitivity to sunlight (photosensitization).
- fotemustine - you should not use dacarbazine earlier than one week after administration of fotemustine, to avoid lung damage.
- cyclosporine or tacrolimus: these medicines can reduce the function of the immune system.
If you are using any of these medicines or if you are not sure consult your doctor, nurse or pharmacist before being given Dacarbazine.
Your doctor will decide whether to give you medicines that improve blood flow and will check your blood clotting.
Use of vaccines
Different indications apply to the different types of vaccines:
- yellow fever - yellow fever vaccine should not be given to you if you are being treated with Dacarbazine.
- live vaccines - "live" vaccines should not be given to you if you are being treated with Dacarbazine. This is because Dacarbazine can weaken the immune system and thus make serious infections more likely.
- killed vaccines - "killed" or inactivated vaccines can be given to you if you are treated with Dacarbazine.
Administration of Dacarbazine with food and drink
- Avoid eating just before taking Dacarbazine. This way, you may have less nausea or vomiting.
- Avoid alcoholic beverages during treatment.
Warnings It is important to know that:
Pregnancy and breastfeeding
- Dacarbazine is not given to you if you are pregnant or planning to become pregnant. This is because the medicine can harm the baby.
- During the treatment, both men. both women must use an effective method of birth control. Tell your doctor immediately if you become pregnant.
- Men treated with Dacarbazine must use an effective method of birth control even for 6 months after the end of therapy.
- Do not breastfeed during treatment with Dacarbazine.
Driving and using machines
You may feel sleepy, confused or have problems with your vision while taking Dacarbazine. He may also feel nauseous or vomit. In these cases, do not drive or use any tools or machinery.
Dosage and method of use How to use Dacarbazine: Dosage
The doctor will determine the duration of the treatment. The duration of the treatment depends on:
- the type of cancer and how advanced it is
- the type of treatment you receive and how well you respond to the treatment
- the presence of any undesirable effect
Dose that will be given to you
The dose you will receive is calculated based on your body size (m2 of body surface area).
Skin cancer that has spread (metastatic malignant melanoma)
- The usual dose is 200-250 mg per m2 of body surface area, once a day.
- The dose will be given to you for 5 subsequent days, every 3 weeks. So there will be a break.
- The medicine will be given to you as a quick injection into a vein or as a slow infusion over 15-30 minutes into a vein.
- Alternatively, you may be given a higher dose of 850 mg per m2 of body surface area every 3 weeks. This dose will be given to you as a slow infusion into a vein.
Cancer of the lymphatic system (Hodgkin's lymphoma)
- The usual dose is 375 mg per m2 of body surface area, every 15 days.
- You will also receive the medicines doxorubicin, bleomycin and vinblastine (this combination is called the ABVD regimen).
- Generally, this combination of medicines is given 6 times.
- The combination will be given to you as a slow infusion into a vein.
Cancer of the tissues that connect the various parts of the body (soft tissue sarcoma)
- The usual dose is 250 mg per m2 of body surface area, once a day.
- You will also receive the medicine doxorubicin (this combination is called the ADIC regimen).
- This combination will be given to you for 5 subsequent days, every 3 weeks. So there will be a break.
- The combination of medicines will be given to you as a slow 15-30 minute infusion into a vein.
Patients with kidney or liver problems
If you have mild or moderate kidney or liver problems, your dose of the medicine usually does not need to be reduced. If you have both kidney and liver problems, your body uses and eliminates the medicine more slowly. Your doctor may then give you a lower dose.
Senior citizens
There are no special instructions for the use of Dacarbazine in the elderly.
Children
No specific recommendations for the use of Dacarbazine in children can be made until further data are available.
Administration of the injection / infusion preparation
After reconstitution (preparation of the solution) with water for injections and without further dilution with 5% isotonic sodium chloride or glucose solution, Dacarbazine Lipomed preparations are hypo-osmolar (approximately 100 mOsmol / kg), i.e. the solutions contain a concentration of dissolved substances lower than the blood and should therefore be administered as a slow intravenous injection, e.g. in 1 minute, and not as an IV injection as a bolus (rapid injection) in seconds.
Dacarbazine is sensitive to light. The reconstituted solutions must therefore be protected from light even during infusion (infusion sets that do not allow light to pass through).
The solution should be administered with caution to avoid extravasation (injection of the solution into the tissues around the vein), which would cause local pain and tissue damage.
In case of extravasation, the injection should be stopped immediately and the remaining dose given into another vein.
Notes on safe handling
Dacarbazine is an antineoplastic agent (it reduces the growth of cancer cells). Prior to preparation of the solution consult the local cytotoxic guidelines relating to the handling of cytotoxic (cell-damaging) agents. Vials of dacarbazine should only be opened by trained personnel. As with all cytotoxic agents, precautions should be taken to avoid exposure of personnel. Handling of cytostatic drugs should generally be avoided during pregnancy. Preparation of the solution for administration should be carried out in a specially designated area for administration. handling, placing the material on a washable support or on disposable plasticized absorbent paper on the back. It is recommended to wear suitable eye protection, disposable gloves, mask and disposable gown. Syringes and infusion sets must be assembled carefully to avoid leakage (use of Luer lock fittings is recommended). Upon completion, all exposed surfaces should be thoroughly cleaned and the operator washed hands and face. In case of splashes, the operator must wear gloves, mask, eye protection and disposable gown and remove the splashes with the absorbent material placed for the purpose in the work area. The area must then be clean and all contaminated material transferred to a cytotoxic bag or vessel or sealed for incineration.
Preparation of the solution for intravenous use (administration into a vein)
Dacarbazine Lipomed solutions should be prepared immediately before use. Dacarbazine is sensitive to light. During treatment, the container and infusion set should be protected from light, for example by using a non-leaking PVC infusion set. other infusion sets may, for example, be wrapped with aluminum foil that does not let light through.
Preparation and administration of the solution for injection / infusion
Dacarbazine Lipomed 100 mg powder for solution for injection or solution for infusion must be reconstituted with 9.9 ml of water for injections to completely dissolve the powder. The solution thus obtained contains 10 mg / ml of dacarbazine. The solution will be given by slow injection, that is, it will be slowly injected into a vein. At higher doses, the reconstituted solution should be diluted with 200 ml of 5% glucose or 0.9% sodium chloride solution and infused intravenously over 15-30 minutes (slow injection into a vein).
Dacarbazine Lipomed is for single use only.
The dacarbazine solution is chemically incompatible with the medicinal products heparin, hydrocortisone, L-cysteine and sodium hydrogen carbonate; this means that the dacarbazine solution must not be mixed with medicines containing these substances. This medicinal product must not be mixed with other medicinal products except those mentioned above.
Shelf life of the reconstituted solution
Chemical and physical in-use stability has been demonstrated for 1 hour at 25 ° C and for 24 hours at 4 ° C protected from light. From a microbiological point of view, the reconstituted solution should be used immediately. If the reconstituted solution is not used immediately, the storage duration and conditions are the responsibility of the user. The reconstituted solution should not be stored for more than 24 hours in a refrigerator (2-8 ° C) protected from light, unless that the reconstitution has not been carried out under controlled and validated aseptic conditions.
Shelf life of the diluted solution for infusion
Chemical and physical in-use stability has been demonstrated for 30 minutes at 25 ° C and for 8 hours at 4 ° C protected from light.
From a microbiological point of view, the diluted solution should be used immediately. If the diluted solution for infusion is not used immediately, the storage duration and conditions are the responsibility of the user. The diluted solution for infusion should not be stored for more than 8 hours in a refrigerator (2-8 ° C) protected from light, unless reconstitution has taken place under controlled and validated aseptic conditions.
Overdose What to do if you have taken too much Dacarbazine
If you think you have received too much Dacarbazine, tell your doctor or nurse immediately.
- If overdose is suspected, blood cell numbers will be checked and supportive measures, such as transfusions, may be needed.
- An overdose causes severe damage to the bone marrow (marrow toxicity). This can result in a complete loss of bone marrow function (medullary aplasia). This effect can appear even after 2 weeks.
If you have any further questions on the use of Dacarbazine, ask your doctor, nurse or pharmacist.
Side Effects What are the side effects of Dacarbazine
Like all medicines, Dacarbazine can cause side effects, although not everybody gets them. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.
Common (affects 1 to 10 users in 100)
- Loss of appetite (anorexia), nausea or vomiting. If someone helps her get rid of the vomit, she should wear gloves. This is because some of the medicine can pass through the skin.
- Blood problems. They depend on the dose and are more likely after 3-4 weeks. You may feel tired, pale, bruise more than usual, or get more infections than usual. At blood tests you will find:
- anemia (reduced number of red blood cells)
- leukopenia (reduced number of white blood cells)
- thrombocytopenia (reduction in the number of platelets)
- bone marrow suppression (reduced formation of all blood cells in the bone marrow)
Uncommon (affects 1 to 10 users in 1000)
- Flu-like symptoms such as tiredness, chills, fever or muscle pain. These are most likely in the first few days of each treatment cycle
- Changes in kidney function or increases in liver enzymes (indicated by tests performed)
- Liver damage (hepatotoxicity)
- Blockage of a vein in the liver (also called Budd-Chiari syndrome)
- Liver damage (necrosis) due to blockage of a vein in the liver. The signs include fever, stomach pain, yellowing of the eyes and skin (jaundice). Your doctor may also notice an increase in liver volume and changes in the number of blood cells. This effect is more frequent in the second course of treatment.
- Dark spots on the skin (hyperpigmentation)
- Increased sensitivity of the skin to sunlight (photosensitivity)
- Hair loss (alopecia)
- Confusion
- Flushing of the face
- Transient rash
- Blurred vision
Rare (affects 1 to 10 users in 10,000)
- Reactions at the injection site, such as irritation of the vein
- Red skin (erythema), rash with spots and blisters (maculo-papular rash) or hives
- Skin reactions at the injection site
- Swelling of the face, lips, mouth and throat with difficulty in breathing (anaphylactic reaction)
- Somnolence, visual disturbances
- Headache
- Convulsions (seizures)
- Sensation of tingling in the face
- Diarrhea. If someone helps you to pass stool, you should wear gloves. This is because some of the medicine can pass through the skin.
- Blood problems. They depend on the dose and are more likely after 3-4 weeks. You may feel tired, pale, bruise more than usual, or get more infections than usual. At blood tests you will find:
- pancytopenia (reduction in the number of all blood cells)
- agranulocytosis (marked reduction in the number of a type of white blood cell, called "granulocytes")
If the medicine is accidentally injected into the tissues around the vein, it will painful and the tissues will be damaged.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.
Expiry and Retention
Keep Dacarbazine Lipomed out of the reach and sight of children.
Do not give Dacarbazine after the expiry date which is stated on the carton and bottle after EXP. The expiry date refers to the last day of the month.
Do not give Dacarbazine if the solution is cloudy or contains particles.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Do not store above 25 ° C. Store in the original package to protect the medicine from light.
Shelf life of the reconstituted solution
Chemical and physical in-use stability has been demonstrated for 1 hour at 25 ° C and for 24 hours at 4 ° C protected from light.
Shelf life of the diluted solution for infusion
Chemical and physical in-use stability has been demonstrated for 30 minutes at 25 ° C and for 8 hours at 4 ° C protected from light.
Other Information
What Dacarbazine contains
- The active substance is dacarbazine (100 mg per vial).
- The other ingredients are citric acid monohydrate and mannitol (E 421).
What Dacarbazine looks like and contents of the pack
Dacarbazine is a white powder that gives rise to a clear liquid for injection or infusion. It is packaged in boxes containing 10 vials each.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
DACARBAZINA LIPOMED 100 MG POWDER FOR SOLUTION FOR INJECTION OR FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial contains 100 mg of dacarbazine (10 mg / ml) (as dacarbazine citrate, formation in situ).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for solution for injection or solution for infusion.
White powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Dacarbazine Lipomed is indicated for the treatment of patients with metastatic malignant melanoma. Additional indications for the use of dacarbazine as a component of a combination chemotherapy are:
- advanced Hodgkin's lymphoma
- advanced soft tissue sarcomas in adults (except mesothelioma and Kaposi's sarcoma).
04.2 Posology and method of administration
Dacarbazine Lipomed therapy should be performed by physicians specialized in oncology or hematology, respectively.
Dacarbazine is sensitive to light exposure. All reconstituted solutions must be adequately protected from light even during administration (infusion sets that do not let light through).
Caution should be exercised when administering the solution for injection to avoid tissue extravasation, which causes local pain and tissue damage. In the event of extravasation, administration should be stopped immediately and any remaining dose should be given into another vein.
To reduce the intensity of nausea and vomiting, the patient should avoid eating foods prior to dacarbazine administration. Excretions and vomiting should be handled with caution.
The treatment regimens described below can be applied. For further details, please refer to the current scientific literature.
Malignant melanoma
Dacarbazine can be used as a single agent at doses between 200 and 250 mg / m2 body surface area / day as an IV injection. carried out for 5 days every 3 weeks. As an alternative to intravenous bolus injection, dacarbazine can be given as a short infusion (over 15-30 minutes).
850 mg / m2 body surface area may also be given on day 1 and once every 3 weeks thereafter as an intravenous infusion.
Hodgkin's lymphoma
Dacarbazine is administered intravenously. in a daily dose of 375 mg / m2 of body surface area every 15 days in combination with doxorubicin, bleomycin and vinblastine (ABVD regimen).
Soft tissue sarcoma
In soft tissue sarcomas in adults, dacarbazine is administered intravenously. in daily doses of 250 mg / m2 body surface area (days 1-5) in combination with doxorubicin every 3 weeks (ADIC regimen).
Frequent blood counts and liver and kidney function checks should be performed during treatment with dacarbazine. Since severe gastrointestinal reactions occur frequently, anti-emetic and supportive measures should be taken.
As severe gastrointestinal and haematological disturbances can occur, a very careful benefit-risk assessment should be made prior to each treatment with Dacarbazine Lipomed.
Duration of therapy
The treating physician must individually determine the duration of therapy, taking into account the type and stage of the disease, the combination therapy performed, the response to dacarbazine and the associated adverse effects.
In advanced Hodgkin's lymphoma, a usual recommendation is to administer 6 cycles of ABVD combination therapy.
In metastatic malignant melanoma and advanced soft tissue sarcoma, the duration of treatment depends on the efficacy and tolerability of the individual patient.
Rate of administration of the injection / infusion
Doses up to 200 mg / m2 can be administered as a slow intravenous injection over approximately 1 minute. Larger doses (between 200 and 850 mg / m2) should be administered as an intravenous infusion over 15-30 minutes.
It is recommended to first check the patency of the vein by injecting 5-10 ml of isotonic sodium chloride or 5% glucose solution for infusion. The same solutions should be used after the infusion to remove any remnants of the medicinal product from the infusion line.
After reconstitution with water for injections and without further dilution with isotonic sodium chloride or 5% glucose solution, Dacarbazine Lipomed 100 preparations are hypo-osmolar (approximately 100 mOsmol / kg) and should therefore be administered as a slow intravenous injection, e.g. ex. in 1 minute, and not as an IV injection bolus in seconds.
Special populations
Patients with renal / hepatic insufficiency: In the presence of only mild to moderate renal or hepatic insufficiency, it is generally not necessary to reduce the dose. In patients with combined renal and hepatic impairment, elimination of dacarbazine is prolonged. However, validated dose reduction recommendations cannot currently be made.
Elderly patients
As experience in elderly patients is limited, no specific instructions can be given for the elderly for the use of dacarbazine.
Children
No specific recommendations for the use of dacarbazine in the pediatric population can be made until further data are available.
For instructions on preparation and reconstitution, see section 6.6.
04.3 Contraindications
Dacarbazine Lipomed is contraindicated in the following cases:
- hypersensitivity to dacarbazine or to any of the excipients,
- pregnancy or breastfeeding,
- leukopenia and / or thrombocytopenia,
- severe liver or kidney disease,
- in combination with yellow fever vaccine (see section 4.5).
04.4 Special warnings and appropriate precautions for use
It is recommended that dacarbazine be administered only under the supervision of a physician specialized in oncology who has the necessary equipment available for regular monitoring of clinical, biochemical and haematological effects during and after therapy.
In the presence of symptoms of hepatic or renal dysfunction or a hypersensitivity reaction, therapy should be discontinued immediately.
In case of veno-occlusive liver disease, continued therapy with dacarbazine is contraindicated.
Note: During therapy, the responsible physician should be aware of the possibility of a rare and serious complication of hepatic necrosis following occlusion of intrahepatic veins. Regular monitoring of volume, liver function and blood count (in particular of eosinophils) is of particular importance. In individual suspected cases of veno-occlusive disease, early treatment with high doses of corticosteroids (eg hydrocortisone 300 mg / day), with or without fibrinolytic substances such as "heparin or tissue plasminogen activator" has been effective (see also section 4.8 ).
Long-term therapy can cause cumulative bone marrow toxicity. Possible bone marrow suppression requires careful monitoring of erythrocytes, leukocytes and platelets. Hematopoietic toxicity may justify temporary or permanent discontinuation of therapy.
Extravasation can cause tissue damage and severe pain.
Concomitant use of phenytoin should be avoided because there is a risk of exacerbation of seizures due to reduced absorption of phenytoin in the digestive system (see section 4.5).
Immunosuppressive effects / increased susceptibility to infections
Dacarbazine is a moderate immunosuppressive agent. Administration of live (live attenuated) vaccines to patients immunocompromised due to treatment with chemotherapeutic agents, including dacarbazine, can cause serious or fatal infections. Vaccination with live vaccines should be avoided in patients treated with dacarbazine. Inactivated vaccines can be used if available.
Hepatotoxic drugs and alcohol are contraindicated during chemotherapy.
Contraceptive measures
Men should be informed about the adoption of contraceptive measures during therapy and for 6 months following the end of therapy.
Administration of dacarbazine to children
No specific recommendations can be made for the use of dacarbazine in the pediatric population until further data are available.
Manipulation of dacarbazine
Dacarbazine should be handled in accordance with standard procedures for cytostatics with mutagenic, carcinogenic and teratogenic effects.
04.5 Interactions with other medicinal products and other forms of interaction
Concomitant use of yellow fever vaccine is contraindicated due to the risk of fatal systemic disease (see section 4.3).
Since the thrombotic risk is increased in the presence of tumors, anticoagulant treatment is frequent. The high intra-individual variability of coagulability during disease and the possible interactions between oral anticoagulants and antineoplastic chemotherapy make more frequent monitoring of INR necessary if the patient is to be treated with oral anticoagulants.
Concomitant use of phenytoin should be avoided because there is a risk of exacerbation of seizures due to reduced absorption of phenytoin in the digestive system (see section 4.4).
The concomitant use of live attenuated vaccines should be avoided, because there is a risk of a systemic, possibly fatal disease. This risk is increased in those already immunosuppressed due to the aforementioned disease. It is recommended to use an inactivated vaccine, if available (poliomyelitis ) (see also section 4.4).
The concomitant use of cyclosporine (and, by extrapolation, of tacrolimus) must be carefully considered, because the use of these agents induces excessive immunosuppression, with the risk of lymphoproliferation.
Concomitant use of fotemustine may cause acute pulmonary toxicity (adult respiratory distress syndrome). Fotemustine and dacarbazine should not be used simultaneously. Dacarbazine should be administered more than one week after photemustine administration.
In case of previous or concomitant treatment with adverse effects on the bone marrow (in particular cytostatic agents, irradiation), myelotoxic interactions are possible.
No studies have been performed to evaluate possible phenotypic metabolism. The hydroxylation of the parent compound to metabolites with antitumor activity has been identified.
Dacarbazine is metabolised by cytochrome P450 (CYP1A1, CYP1A2 and CYP2E1). This should be taken into consideration when dacarbazine is co-administered with other medicinal products metabolised by the same hepatic enzymes.
Dacarbazine may potentiate the effects of methoxypsoralen due to photosensitization.
04.6 Pregnancy and breastfeeding
Dacarbazine possesses mutagenic, teratogenic and carcinogenic effects in animals. An increased risk of teratogenic effects in humans should therefore be assumed. Therefore, dacarbazine should not be used during pregnancy and lactation (see also sections 4.3 and 4.4). It is not known whether dacarbazine crosses the placenta or passes into breast milk.
Women of childbearing age
Women of childbearing age must use effective contraceptive methods.
Men treated with dacarbazine
Men should be informed about the adoption of contraceptive measures during therapy and for 6 months following the end of therapy.
04.7 Effects on ability to drive and use machines
Dacarbazine may affect the ability to drive or use machines due to its central nervous system side effects and due to nausea and vomiting.
04.8 Undesirable effects
Frequencies:
Very common (≥1 / 10) Common (≥1 / 100 to
Uncommon (≥1 / 1000,
Rare (≥1 / 10,000,
Not known (frequency cannot be estimated from the available data)
Disorders of the digestive system such as anorexia, nausea and vomiting are common and severe. In rare cases, diarrhea has been observed.
The changes in blood counts often observed (anemia, leukopenia, thrombocytopenia) are dose-dependent and delayed, nadirs often occur only after 3-4 weeks. In rare cases, pancytopenia and agranulocytosis have been described.
Flu-like symptoms with exhaustion, chills, fever and muscle pain are occasionally observed during or frequently a few days after dacarbazine administration. These disturbances may recur with the next infusion.
An increase in liver enzymes (e.g. transaminases (AST, ALT), alkaline phosphatase, lactate dehydrogenase (LDH)) has been observed uncommonly.
Hepatic necrosis due to intrahepatic vein occlusion (veno-occlusive disease) has been observed uncommonly after administration of dacarbazine alone or in combination chemotherapy. The syndrome usually occurred during the second course of therapy. Symptoms included fever, eosinophilia. , abdominal pain, hepatomegaly, jaundice and shock, with rapid worsening within hours or days. Since lethal outcomes have been described, frequent monitoring of liver volume and function and blood count (particularly eosinophils) is of particular importance. during treatment. In individual suspected cases of veno-occlusive disease, early treatment with high doses of corticosteroids (eg hydrocortisone 300 mg / day), with or without fibrinolytic agents such as "heparin or tissue plasminogen activator" has been effective (see also sections 4.2 and 4.4).
Local disturbances at the administration site, such as venous irritation, and some of the systemic adverse reactions are considered to be due to the formation of photodegradation products. Local pain and necrosis are expected following accidental extravasation.
Impaired renal function, with increased blood levels of substances to be excreted in the urine, is uncommon.
Central nervous system disorders such as headache, visual disturbances, confusion, lethargy and convulsions may occur rarely. Facial paraesthesia and flushing of the face may occur shortly after injection.
Skin allergic reactions in the form of erythema, maculo-papular rash or urticaria are rarely observed. Alopecia, hyperpigmentation and photosensitivity of the skin may occur uncommonly. In rare cases, anaphylactic reactions have been reported.
04.9 Overdose
Severe bone marrow toxicity and even bone marrow aplasia can be expected following an overdose; Onset may be delayed for up to 2 weeks. Time to onset of leukocyte and thrombocyte nadirs can be as high as 4 weeks. Even in cases of only suspected overdose, careful long-term haematological monitoring is essential.
There are no known antidotes available and therefore particular caution should be used with each administration to avoid overdose.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other alkylating agents.
ATC code: L01AX04.
Dacarbazine is a cytostatic agent. The antineoplastic effect is due to the inhibition of cell growth independent of the cell cycle and due to the inhibition of DNA synthesis. An alkylating effect has also been demonstrated and other cytostatic mechanisms may also be influenced by dacarbazine.
Dacarbazine does not possess an antineoplastic effect per se. However, through microsomal N-demethylation, it is rapidly converted into 5-amino-imidazole-4-carboxamide and a methyl cation, which is responsible for the alkylating effect.
05.2 Pharmacokinetic properties
After intravenous administration, dacarbazine is rapidly distributed from the intravascular space to the tissues. The plasma protein binding is 5%. The kinetics of dacarbazine in plasma are biphasic; the initial (distribution) half-life is only 20 minutes, the terminal half-life is between 0.5 and 3.5 hours.
Dacarbazine crosses the blood brain barrier to a limited extent; concentrations in cerebrospinal fluid correspond to approximately 14% of plasma concentrations.
Dacarbazine is inactive until its metabolism in the liver by cytochrome P450, with the formation of the reactive N-demethylated species HMMTIC and MTIC. This reaction is catalyzed by CYP1A1, CYP1A2 and CYP2E1. MTIC is further metabolised to 5-aminoimidazole-4-carboxamide (AIC).
Dacarbazine is metabolised mainly in the liver via hydroxylation and demethylation, approximately 20% -50% is excreted unchanged by the kidneys via tubular secretion.
05.3 Preclinical safety data
Due to its pharmacodynamic properties, dacarbazine possesses mutagenic, carcinogenic and teratogenic effects, detectable in experimental analyzes.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Citric acid monohydrate
Mannitol (E 421)
06.2 Incompatibility
Note that the dacarbazine solution is chemically incompatible with heparin, hydrocortisone, L-cysteine and sodium hydrogen carbonate.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
06.3 Period of validity
3 years.
Shelf life of the reconstituted solution
The reconstituted solution is chemically and physically stable for 1 hour at 25 ° C and for 24 hours at 4 ° C and protected from light. From a microbiological point of view, the reconstituted solution should be used immediately.
If the reconstituted solution is not used immediately, the storage duration and conditions are the responsibility of the user. The reconstituted solution should not be stored for more than 24 hours in a refrigerator (2 - 8 ° C) protected from light, unless that the reconstitution has not been carried out under controlled and validated aseptic conditions.
Shelf life of the diluted solution for infusion
The diluted solution for infusion was chemically and physically stable for 30 minutes at 25 ° C and for 8 hours at 4 ° C protected from light. From a microbiological point of view, the diluted solution for infusion should be used immediately.
If the diluted solution for infusion is not used immediately, the storage duration and conditions are the responsibility of the user. The diluted solution for infusion should not be stored for more than 8 hours in a refrigerator (2 - 8 ° C) protected from light, unless reconstitution has taken place under controlled and validated aseptic conditions.
06.4 Special precautions for storage
Do not store above 25 ° C.
Store in the original package to protect the medicine from light.
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Single-dose brown vials (type I Ph.Eur.) Closed with bromobutyl rubber stoppers and packed in boxes of 10 vials.
06.6 Instructions for use and handling
Recommendations for safe handling
Dacarbazine is an antineoplastic agent. Local cytotoxic guidelines regarding handling of cytotoxic agents should be consulted prior to preparation of the solution.
Vials of dacarbazine should only be opened by trained personnel. As with all cytotoxic agents, precautions should be taken to avoid exposure of personnel. Handling of cytotoxic drugs should generally be avoided during pregnancy. Preparation of the solution for administration should be performed in a designated handling area. working on a washable support or on disposable absorbent paper plasticized on the back. It is recommended to wear suitable eye protection, disposable gloves, mask and disposable gown. Syringes and infusion sets must be assembled carefully to avoid leakage (use of Luer lock fittings is recommended).
When finished, all exposed surfaces must be thoroughly cleaned and the operator should wash his hands and face.
In case of splashes, the operator must wear gloves, mask, eye protection and disposable gown and remove the splashes with the absorbent material placed for the purpose in the work area. The area must then be cleaned and all contaminated material transferred to a cytotoxic bag or sealed for incineration.
Preparation and administration of the solution for injection or solution for infusion. Dacarbazine Lipomed 100 mg powder for solution for injection or solution for infusion must be reconstituted with 9.9 ml of water for injections. The resulting solution contains 10 mg / ml of dacarbazine and has a pH between 3.0 and 4.0.
For the preparation of the solutions for infusion, the reconstituted solution must be diluted with 200 ml of 5% glucose or 0.9% sodium chloride solution. The resulting solution contains 0.5 mg / ml.
The solution prepared by reconstitution or reconstitution and dilution should be clear and free of visible particles.
All prepared solutions must be protected from light; administration must also be carried out without exposure to daylight.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
For single use only.
07.0 MARKETING AUTHORIZATION HOLDER
Lipomed GmbH Hegenheimer Strasse 2
D-79576 Weil / Rhein
Germany
08.0 MARKETING AUTHORIZATION NUMBER
"100 mg powder for solution for injection or infusion" 10 Vials: AIC n. 041106016
