Carmustine Zentiva

Package Leaflet: Information for the User

Carmustine Zentiva, 100 mg, powder and solvent for concentrate for solution for infusion

for infusion
carmustine

Read all of this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

• 1. What is Carmustine Zentiva and what is it used for
• 2. Important information before using Carmustine Zentiva
• 3. How to use Carmustine Zentiva
• 4. Possible side effects
• 5. How to store Carmustine Zentiva
• 6. Contents of the pack and other information

1. What is Carmustine Zentiva and what is it used for

Carmustine Zentiva, 100 mg, powder and solvent for concentrate for solution for infusion, contains carmustine. Carmustine belongs to a group of anti-cancer medicines, so-called nitrosourea derivatives, which act by slowing down the growth of cancer cells. Carmustine Zentiva is used in palliative treatment (relieving symptoms of the disease and preventing suffering in patients) as monotherapy or in established combination therapy with other approved anti-cancer medicines in certain types of cancer, such as:

• Brain tumors - glioma, medulloblastoma, astrocytoma, and brain metastases
• Multiple myeloma (malignant tumor originating in the bone marrow)
• Hodgkin's disease (lymphoma)
• Non-Hodgkin's lymphoma (lymphoma)
• Gastrointestinal or digestive tract tumors
• Malignant melanoma (skin cancer)

Carmustine is also used as conditioning treatment before autologous hematopoietic stem cell transplantation (autologous stem cell transplantation) in malignant hematological diseases of the lymphatic system (Hodgkin's lymphoma and non-Hodgkin's lymphoma).

2. Important information before using Carmustine Zentiva

When not to use Carmustine Zentiva:

(see section 6);

• Carmustine Zentiva must not be used in patients who have a reduced number of platelets, white blood cells, or red blood cells due to chemotherapy or other causes;
• in children and adolescents under 18 years of age;
• in breastfeeding women.

Warnings and precautions

Before starting treatment with Carmustine Zentiva, discuss it with your doctor, pharmacist, or nurse. The main side effect of this medicine is delayed bone marrow suppression, so your doctor will monitor your blood morphology every week for at least 6 weeks after administration of the dose. During treatment with the recommended doses, courses of Carmustine Zentiva will not be administered more frequently than every 6 weeks. Before administration, the doctor will monitor your blood morphology. You should immediately inform your doctor if you experience any of the following symptoms:

• Infection symptoms (fever, persistent sore throat)
• Increased tendency to bruise and/or bleeding
• Unusual fatigue
• Rapid and/or irregular heartbeat

Before starting treatment, liver, lung, and kidney function tests will be performed, which will be regularly repeated during treatment. During treatment, gastrointestinal symptoms may occur in the form of vomiting and nausea. Since the use of Carmustine Zentiva may lead to lung damage, a chest X-ray and lung function tests will be performed before starting treatment (see also "Possible side effects"). High-dose carmustine treatment (up to 600 mg/m2) is used only in combination with subsequent stem cell transplantation. High doses may increase the risk of toxic effects on the lungs, kidneys, liver, heart, and digestive system, as well as infections and electrolyte imbalance (low potassium, magnesium, and phosphorus levels in the blood). Abdominal pain (neutropenic enterocolitis) may occur as a side effect related to therapy, after chemotherapy. Patients who have multiple diseases and have a worse disease condition are more prone to side effects. This is especially important in elderly patients. The doctor will inform you about the possibility of lung damage and allergic reactions and their symptoms. If you experience such symptoms, you should contact your doctor immediately (see section 4). Women and men of childbearing age should use effective contraception during treatment and for at least 6 months after treatment (see "Pregnancy, breastfeeding, and fertility").

Carmustine Zentiva and other medicines

Tell your doctor or pharmacist about all medicines you are taking or have recently taken, as well as any medicines you plan to take, including those available without a prescription, such as:

• Phenytoin used in epilepsy
• Cimetidine used in case of stomach problems, such as indigestion
• Digoxin used in case of irregular heartbeat
• Melphalan - an anti-cancer medicine
• Dexamethasone used as an anti-inflammatory and immunosuppressive medicine
• Methotrexate, cyclophosphamide, procarbazine, chloroethyl nitrosourea (nitrogen mustard), fluorouracil, vinblastine, actinomycin (dactinomycin), bleomycin, doxorubicin (adriamycin) used in the treatment of various types of cancer.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, ask your doctor or pharmacist for advice before using this medicine. Pregnancy and fertility This medicine must not be used during pregnancy because it may harm the unborn child. Therefore, it is usually not given to pregnant women. If used during pregnancy, the patient must be aware of the potential risks to the unborn child. Women of childbearing age should avoid becoming pregnant during treatment with this medicine. Women who are able to become pregnant should be informed of the need to use effective contraception to prevent pregnancy during treatment with this medicine and for at least 6 months after treatment. Men should use appropriate contraceptive measures during treatment with Carmustine Zentiva and for at least 6 months after treatment to prevent pregnancy in their partners. Carmustine Zentiva may impair fertility in men. Patients should be advised to seek counseling on fertility/planning before starting treatment with Carmustine Zentiva. Breastfeeding You must not breastfeed while using this medicine and for 7 days after treatment. A risk to newborns/infants cannot be excluded.

Driving and using machines

The effect of the medicine on the ability to drive and use machines is unknown. You should consult your doctor before driving or operating any tools or machines, as dizziness is a side effect reported during treatment with this medicine, which may affect your ability to drive or operate machines.

Carmustine Zentiva contains propylene glycol

Propylene glycol in this medicine may have the same effects as drinking alcohol and increase the likelihood of side effects. Do not use this medicine in children under 5 years of age. Use this medicine only if your doctor has prescribed it. Your doctor may perform additional tests while you are taking this medicine.

3. How to use Carmustine Zentiva

Carmustine Zentiva will always be administered by medical personnel experienced in the use of anti-cancer medicines.

Adults

Dosing depends on the patient's health, body surface area, and response to treatment. The medicine is usually administered no more frequently than every 6 weeks. The recommended dose of Carmustine Zentiva used as monotherapy in previously untreated patients is 150 to 200 mg/m2 body surface area (BSA) intravenously every 6 weeks. The medicine can be administered in a single dose or divided into daily infusions of 75 to 100 mg/m2 BSA over two consecutive days. Dosing is also dependent on whether Carmustine Zentiva is administered with other anti-cancer medicines. Doses will be increased according to the patient's response to treatment. The recommended dose of carmustine administered intravenously in combination with other chemotherapeutic agents before hematopoietic stem cell transplantation is 300-600 mg/m2. To avoid toxic effects on the bone marrow, blood morphology will be frequently monitored, and the dose will be adjusted if necessary.

Method of administration

After reconstitution and dilution, Carmustine Zentiva is administered intravenously by infusion over a period of one to two hours. The duration of the infusion should not be less than one hour; otherwise, burning and pain may occur at the injection site. The injection site will be monitored during the infusion. The duration of treatment will be determined by your doctor and may vary from patient to patient.

Use in children and adolescents (under 18 years of age)

Carmustine Zentiva must not be used in children and adolescents due to the high risk of pulmonary toxicity.

Use in the elderly

Carmustine Zentiva may be used in elderly patients with caution. Kidney function will be monitored.

Overdose of Carmustine Zentiva

Since the medicine will be administered by a doctor or nurse, the use of an incorrect dose is unlikely. You should inform your doctor or nurse if you have any doubts about the amount of medicine you received. If you have any further questions about using this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You should immediately inform your doctor or nurse if you experience any of the following symptoms:

Wheezing, breathing difficulties, swelling of the eyelids, face, or lips, rash, or itching (especially if it affects the whole body), as well as a feeling of impending fainting. These may be symptoms of a severe allergic reaction.

Carmustine Zentiva may cause the following side effects:

Very common(may affect more than 1 in 10 people)

• Delayed myelosuppression (reduced number of blood cells produced by the bone marrow);
• Ataxia (lack of voluntary coordination of muscle movements);
• Dizziness;
• Headache;
• Transient eye redness, blurred vision, retinal hemorrhage, uveitis, and optic neuritis;
• Hypotension (decreased blood pressure) in case of high-dose treatment;
• Phlebitis associated with pain, swelling, redness, and tenderness;
• Respiratory disorders (disorders affecting the lungs) associated with difficulty breathing. This medicine may cause severe (potentially life-threatening) lung damage. Lung damage may occur after many years of treatment. You should immediately inform your doctor if you experience any of the following symptoms: shortness of breath, persistent cough, chest pain, persistent weakness/fatigue;
• Severe nausea and vomiting; occurring within 2-4 hours after administration and lasting 4-6 hours;
• In case of contact with the skin: skin inflammation;
• Accidental contact with the skin may cause transient discoloration (darkening of the skin or nail area).

Common(may affect up to 1 in 10 people)

• Acute leukemias (blood cancer) dysplasias of the bone marrow (abnormal development of the bone marrow) due to long-term use. The following symptoms may occur: gum bleeding, bone pain, fever, frequent infections, frequent or severe nosebleeds, lumps caused by swelling of lymph nodes in the neck, forearm, abdomen, or groin, paleness of the skin, shortness of breath, weakness, fatigue, or general lack of energy;
• Anemia (reduced number of red blood cells in the blood);
• Encephalopathy (brain disease) in case of high-dose treatment; possible symptoms include: weakness of muscle strength in one area of the body, inability to make decisions or concentrate, involuntary muscle twitching, tremors, difficulty speaking or swallowing, seizures;
• Lack of appetite (anorexia);
• Constipation;
• Diarrhea;
• Mouth and lip inflammation;
• Reversible liver toxicity in case of high-dose treatment, delayed up to 60 days after administration. This disorder may lead to increased liver enzyme activity and bilirubin levels (these are parameters measured in blood tests);
• Hair loss (alopecia);
• Redness of the skin;
• Reactions at the injection site.

Rare(may affect up to 1 in 1,000 people)

• Veno-occlusive disease of the liver (progressive blockage of small liver veins) in case of high-dose treatment, in which very small veins in the liver become blocked. Possible symptoms include: fluid accumulation in the abdominal cavity, spleen enlargement, severe bleeding from the esophagus, yellowing of the skin and whites of the eyes;
• Difficulty breathing due to lung disease, in which lung tissue becomes scarred (pulmonary fibrosis) (in case of low-dose treatment); symptoms include: dry cough, shortness of breath, fatigue, weight loss;

Very rare(may affect up to 1 in 10,000 people)

• Phlebitis with thrombosis (thrombophlebitis).

Unknown frequency(cannot be estimated from the available data)

• Muscle pain;
• Secondary tumors (cancers caused by radiation or chemotherapy);
• Seizures (convulsions), including status epilepticus;
• Tissue damage due to leakage at the injection site;
• Infertility;
• Impaired fetal development and/or damage to the fetus in pregnant women;
• Any symptoms of infection;
• Rapid heartbeat, chest pain;
• Allergic reactions;
• Electrolyte imbalance (low potassium, magnesium, phosphorus levels in the blood);
• Abdominal pain (neutropenic enterocolitis);
• After high-dose cumulative treatment and long-term treatment with Carmustine Zentiva and other nitrosourea derivatives, kidney shrinkage, progressive accumulation of certain metabolic products in the blood (azotemia), and kidney failure have been observed. After lower total doses, kidney damage has also been observed.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse. Side effects can be reported to the national reporting system listed below. Reporting side effects will help to provide more information on the safety of this medicine. You can also report side effects directly via the contact details below. Department for Monitoring of Adverse Reactions to Medicinal Products, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, PL-02 222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl. Side effects can also be reported to the marketing authorization holder or its representative in Poland.

5. How to store Carmustine Zentiva

Keep this medicine out of the sight and reach of children. Store in a refrigerator (2°C-8°C). Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month. The medicine will be stored by your doctor or other medical personnel. After reconstitution according to the instructions, the carmustine injection is stable for 480 hours in the refrigerator (2°-8°C) and 24 hours at room temperature (25°C ±2°C) in a glass container. Before use, check the reconstituted vials for crystal formation. If crystals are observed, they can be redissolved by warming the vial to room temperature with mixing. From a microbiological point of view, the reconstituted solution should be used immediately. Store the vial in the outer packaging to protect from light. The prepared concentrate solution must then be further diluted to 500 ml with sodium chloride 0.9% solution for injection or 5% glucose solution for injection in glass or polypropylene containers and remains physically and chemically stable for 8 hours at 25°C±2°C, if protected from light. These solutions are also stable for 48 hours when stored in a refrigerator (2°C–8°C) and for an additional 6 hours at 25°C±2°C, if protected from light. The solution should be protected from light until the end of administration. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What Carmustine Zentiva contains

The active substance is carmustine. One vial of powder for concentrate for solution for infusion contains 100 mg of carmustine. One vial of solvent contains 3 mL of propylene glycol. After reconstitution using the provided solvent, one mL of solution contains 33.3 mg of carmustine. The other ingredients are:

• Powder: no excipients.
• Solvent: propylene glycol.

What Carmustine Zentiva looks like and contents of the pack

Carmustine Zentiva is a powder and solvent for concentrate for solution for infusion. The powder is pale yellow and is supplied in a vial made of orange glass type I (30 mL) with a dark gray rubber stopper and a polypropylene cap. The solvent is a clear, colorless, viscous liquid and is supplied in a vial made of clear glass type I (5 mL) with a gray rubber stopper and a polypropylene cap. One pack contains one vial of 100 mg powder and one vial of 3 mL solvent.

Marketing authorization holder and manufacturer

Marketing authorization holder Zentiva k.s., U Kabelovny 130, Dolni Měcholupy, 102 37 Prague 10, Czech Republic. Importer: MIAS Pharma Limited, Suite 2, Stafford House, Strand Road, Portmarnock, Co. Dublin, Ireland. Tillomed Malta Limited, Malta Life Sciences Park, LS2.01.06 Industrial Estate, San Gwann, SGN 3000, Malta

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Belgium: Carmustine Tillomed 100 mg powder and solvent for concentrate for solution for infusion, Czech Republic: Carmustine Zentiva, Denmark: Carmustin Macure, Finland: Carmustine Macure 100 mg powder and solvent for concentrate for solution for infusion, Greece: Carmustine/Tillomed 100 mg powder and solvent for concentrate for solution for infusion, Hungary: Carmustine Zentiva 100 mg powder and solvent for concentrate for solution for infusion, Ireland: Carmustine 100 mg powder and solvent for concentrate for solution for infusion, Italy: BICNU, Lithuania: Carmustine Zentiva 100 mg powder and solvent for concentrate for solution for infusion, Netherlands: Carmustine Glenmark 100 mg powder and solvent for concentrate for solution for infusion, Norway: Carmustine Macure, Poland: Carmustine Zentiva, Portugal: Carmustine Tillomed 100 mg powder and solvent for concentrate for solution for infusion, Slovakia: Carmustine Zentiva, Slovenia: Karmustin Tillomed 100 mg powder and solvent for concentrate for solution for infusion, Sweden: Carmustine Macure, Date of last revision of the package leaflet:March 2025 ---------------------------------------------------------------------------------------------------------------------
Information intended for healthcare professionals only:
The following is a brief description of the method of preparation and/or administration, incompatibilities, dosing, overdose, or actions required for monitoring, as well as laboratory tests, based on the current summary of product characteristics.
The lyophilized powder for concentrate for solution for infusion does not contain preservatives and is not intended for use in multidose vials. The medicinal product is intended for single use only. Caution should be exercised when handling the medicinal product, and contact with the skin should be avoided. Reconstitution and further dilution should be carried out under aseptic conditions. By following the recommended storage conditions, degradation of the substances contained in the unopened vial can be avoided until the expiry date stated on the packaging. Storage of carmustine at a temperature of 27°C or higher may lead to melting of the substance, as carmustine has a low melting point (approximately 30.5°C to 32.0°C). The presence of an oily layer at the bottom of the vial may indicate degradation of the product. Such a medicinal product should not be used. If there is any doubt as to whether the product has been stored under appropriate cooling conditions, all vials in the carton should be checked immediately. For verification, the vial should be placed in bright light. Reconstitution and dilution of the powder for concentrate for solution for infusion should be carried out as follows.

Step 1: Remove both vials from the packaging and wait until they reach room temperature. (Min. 10 minutes).

Step 2: Aseptically withdraw 3 mL of sterile solventfrom the solvent vial using a sterile syringe. Make sure that the entire amount (3 mL) of sterile solvent has been withdrawn into the syringe.

Step 3: Inject the sterile solvent into the vial containing 100 mg of carmustine and allow the product to soak for at least 10 minutes.

Step 4: Mix (by making circular movements) for at least 60 seconds without stoppingto obtain a clear solution.

Step 5: Hold the vial upside down for 5 minutes before withdrawing the reconstituted solution.

Step 6: Aseptically withdraw the reconstituted solution, upside down, and further dilute it to prepare the infusion solution.

Each milliliter of the reconstituted solution contains 33.3 mg of carmustine. The reconstituted solution is yellowish. The concentrate solution should be further diluted to 500 mL with sodium chloride 0.9% solution for injection or 5% glucose solution for injection in glass or polypropylene containers and remains physically and chemically stable for 8 hours at 25°C±2°C, if protected from light. These solutions are also stable for 48 hours when stored in a refrigerator (2°C–8°C) and for an additional 6 hours at 25°C±2°C, if protected from light. The solution should be protected from light until the end of administration. Before use, check the reconstituted vials for crystal formation. If crystals are observed, they can be redissolved by warming the vial to room temperature with mixing. Vials after reconstitution should be inspected for particulate matter and discoloration before administration. Method of administration: Carmustine is intended for intravenous administration after reconstitution and further dilution. The reconstituted solution should be administered immediately as an intravenous infusion over a period of 1-2 hours, protected from light. The duration of the infusion should not be less than 1 hour, as infusion in a shorter time may cause severe pain and burning at the injection site. The injection site should be monitored during administration. Administration of the product should be completed within 3 hours of its reconstitution/dilution. Infusion should be performed using an infusion set with PE that does not contain PCV. Precautions for handling anti-cancer medicines and their disposal should be observed. Dosing and laboratory tests Initial dosesThe recommended dose of Carmustine Zentiva used as monotherapy in previously untreated patients is 150 to 200 mg/m2 body surface area (BSA) intravenously every 6 weeks. The medicine can be administered in a single dose or divided into daily infusions of 75 to 100 mg/m2 BSA over two consecutive days. When Carmustine Zentiva is used in combination with other medicines that have a myelosuppressive effect or in patients with reduced bone marrow reserve, the dose should be adjusted according to the patient's hematologic profile, as presented below. Monitoring and subsequent dosesA subsequent course of Carmustine Zentiva can be administered only when the blood morphology parameters have returned to acceptable values (platelet count above 100,000/mm3, white blood cell count above 4,000/mm3), which usually occurs within six weeks. Blood morphology should be frequently monitored, and subsequent doses should not be administered before six weeks due to the possibility of delayed hematologic toxicity. After the initial dose, subsequent doses should be adjusted according to the patient's hematologic response to the previous dose, both in monotherapy and in combination therapy with other medicines that have a myelosuppressive effect. The following dose adjustment scheme is suggested: Table 1 In cases where the lowest value after the initial dose is not in the same row for white blood cells and platelets (e.g., white blood cell count >4,000 and platelet count <25,000), the value corresponding to the lowest percentage of the previous dose should be used (e.g., platelet count <25,000 - use a maximum of 50% of the previous dose). Conditioning treatment before hematopoietic stem cell transplantation Carmustine is administered intravenously in a dose of 300-600 mg/m2 in combination with other chemotherapeutic agents in patients with malignant hematological diseases before hematopoietic stem cell transplantation. Special patient populations Elderly patientsIn general, elderly patients should have their doses selected with caution, and in particular, the dose of the medicinal product should be started at the lower end of the dose range, due to the higher frequency of liver, kidney, or heart disorders; concomitant diseases and treatment with other medicinal products should also be taken into account. Since elderly patients are more likely to have kidney function disorders, caution should be exercised when selecting the dose, and kidney function should be monitored. Children and adolescentsCarmustine is contraindicated in children and adolescents under 18 years of age (see section 4.3) due to the high risk of pulmonary toxicity (see section 4.4). Compatibility/incompatibility with containers The infusion solution is unstable in polyvinyl chloride (PVC) containers. Carmustine solution should only be administered from glass or polypropylene containers. Do not mix the medicinal product with other medicinal products, except those mentioned in section 6.6.