CARMUSTINE MEDAC

Package leaflet: Information for the user

Carmustine medac 100 mg powder and solvent for concentrate for solution for infusion
carmustine
Please read 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 questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, including those not listed in this leaflet, please contact your doctor or nurse. See section 4.

Contents of this leaflet

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

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

Carmustine medac is a medicine containing carmustine. Carmustine belongs to a group of anticancer drugs known as nitrosoureas, which work by slowing the growth of cancer cells.
Carmustine is indicated in adults for the following malignant neoplasms as a single agent or in combination with other antineoplastic agents and/or other therapeutic measures (radiotherapy, surgery):

• Brain tumours (glioblastoma, brainstem gliomas, medulloblastoma, astrocytoma, and ependymoma), brain metastases;
• Secondary therapy in non-Hodgkin lymphoma and Hodgkin's disease;
• Tumours of the gastrointestinal tract or digestive system;
• Malignant melanoma (skin cancer);
• Conditioning treatment prior to autologous haematopoietic progenitor cell transplantation (HPTC) in malignant haematological diseases (Hodgkin's disease / non-Hodgkin lymphoma).

2. What you need to know before using Carmustine medac

Do not use Carmustine medac:

• if you are allergic to carmustine or to any of the other ingredients of this medicine (listed in section 6);
• if you have bone marrow suppression resulting in reduced numbers of platelets, white blood cells (leukocytes), or red blood cells (erythrocytes), due to chemotherapy or other causes;
• if you have severe kidney dysfunction;
• in children and adolescents;
• if you are breastfeeding.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Carmustine medac.
The main side effect of this medicine is delayed myelosuppression, which may manifest as fatigue, bleeding of the skin and mucous membranes, and infections and fever due to changes in blood counts. Therefore, after each dose, your doctor will monitor your blood counts weekly for at least 6 weeks. At the recommended doses, administrations of Carmustine medac should not occur more frequently than every 6 weeks. The dosage will be confirmed based on blood counts.
Liver, lung, and kidney function will be assessed before treatment and monitored regularly during treatment.
Since the use of Carmustine medac may cause lung damage, a chest X-ray and lung function tests will be performed before starting treatment (see also section “Possible side effects”).
High-dose treatment with Carmustine medac (up to 600 mg/m²) is only administered in combination with subsequent stem cell transplantation. Such high doses may increase the frequency or severity of toxicity affecting the lungs, kidneys, liver, heart, and gastrointestinal tract, as well as increase the risk of infections and electrolyte imbalances (low levels of potassium, magnesium, and phosphate in the blood).
Abdominal pain (neutropenic enterocolitis) may occur as an adverse reaction related to therapy following treatment with chemotherapeutic agents.
Your doctor will inform you about the possibility of lung damage and allergic reactions, as well as the related symptoms. If such symptoms occur, contact your doctor immediately (see section 4).
Children and adolescents
Carmustine medac must not be used in children and adolescents under 18 years of age.
Other medicines and Carmustine medac
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those not requiring a prescription, such as:

• phenytoin, used in epilepsy;
• dexamethasone, used as an immunosuppressive and anti-inflammatory agent;
• cimetidine, used for stomach problems such as indigestion;
• digoxin, used in the treatment of arrhythmia;
• melphalan, an antineoplastic drug.

Carmustine medac and alcohol
The amount of alcohol contained in this medicine may alter the effect of other medicines.
Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy, breastfeeding and fertility
Carmustine medac must not be used during pregnancy because it may cause harm to the fetus. This medicine should therefore normally not be given to pregnant women. If used during pregnancy, the patient must be aware of the potential risks to the fetus. Women of childbearing potential are advised to use effective contraceptive methods to avoid becoming pregnant during treatment and for at least 6 months after completion of treatment with this medicine.
Male patients must use adequate contraception during treatment with Carmustine medac and for at least 6 months after the end of treatment to prevent their partner from becoming pregnant.
Breastfeeding
Do not breastfeed during treatment with this medicine and for 7 days after treatment. Risk to newborns/infants cannot be excluded.
Driving and using machines
Carmustine medac does not affect or has negligible influence on the ability to drive or use machines. However, consult your doctor before driving or operating tools or machinery, as the alcohol content in this medicine may impair your ability to drive or operate machinery, since judgment and reaction speed may be affected.
Carmustine medac contains ethanol (ethyl alcohol)
This medicine contains 2.4 g of alcohol (ethanol) per vial, equivalent to 25.92 g per maximum dose (10% vol.). The amount of alcohol in the maximum dose (600 mg/m² in a 70 kg patient) of this medicine is equivalent to 648 ml of beer or 259 ml of wine.
The amount of alcohol contained in this medicine may impair the ability to drive or use machinery, as judgment and reaction speed may be impaired.
If you have epilepsy or liver problems, consult your doctor or pharmacist before taking this medicine.
The amount of alcohol contained in this medicine may alter the effects of other medicines. Consult your doctor or pharmacist if you are taking other medicines.
If you are pregnant, consult your doctor or pharmacist before taking this medicine.
If you suffer from alcoholism, consult your doctor or pharmacist before taking this medicine.

3. How to use Carmustine medac

Carmustine medac will always be administered by a healthcare professional experienced in the use of anticancer medicines.
Adults
The dose depends on the medical condition, body size, and response to treatment. It is generally administered at intervals of at least 6 weeks. The recommended dose of Carmustine medac as a single agent in previously untreated patients is 150 to 200 mg/m² given intravenously every 6 weeks. It may be administered as a single dose or divided into daily infusions of 75–100 mg/m² on two consecutive days. The dosage may also vary depending on whether Carmustine medac is used in combination with other antineoplastic agents.
Doses are adjusted according to the response to treatment.
The recommended dose of Carmustine medac when administered in combination with other chemotherapeutic agents prior to hematopoietic progenitor cell transplantation is 300–600 mg/m² intravenously.
Blood counts are monitored frequently to avoid bone marrow toxicity, and the dose is adjusted as necessary.
Route of administration
After reconstitution and dilution, Carmustine medac is administered intravenously by infusion over a period of 1–2 hours, protected from light. The infusion duration must not be less than one hour to avoid burning and pain at the injection site. The injection site is checked during administration.
The duration of treatment is determined by the physician and may vary for each patient.
If you use more Carmustine medac than you should
Since this medicine will be administered by a doctor or nurse, it is unlikely that you will receive an incorrect dose. Inform your doctor or nurse if you have any doubts regarding the amount of medicine administered.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Immediately inform your doctor or nurse if you notice the following:
sudden wheezing, difficulty breathing, swelling of the eyelids, face or lips, skin rash or itching (especially over the whole body), or feeling faint. These may be signs of a severe allergic reaction.

Carmustine medac may cause the following side effects:

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

• delayed myelosuppression (reduction in blood cells in the bone marrow), which may increase the likelihood of developing infections if white blood cells are reduced;
• ataxia (lack of voluntary coordination of muscle movements);
• dizziness;
• headache;
• temporary redness of the eyes, blurred vision due to retinal bleeding;
• hypotension (low blood pressure);
• phlebitis (inflammation of the veins) associated with pain, swelling, redness, and tenderness;
• respiratory disorders (lung problems) with breathing difficulties. This medicine may cause severe (even fatal) lung damage, which may appear years after treatment. Contact your doctor immediately if you experience any of the following symptoms: shortness of breath, persistent cough, chest pain, ongoing weakness/tiredness;
• severe nausea and vomiting;
• skin inflammation (dermatitis) when used on the skin;
• accidental skin contact may cause transient hyperpigmentation (darkening of an area of skin or nails);

Common (may affect up to 1 in 10 people)

• acute leukaemia and myelodysplasia (abnormal development of the bone marrow). Symptoms may include bleeding gums, bone pain, fever, frequent infections, frequent or severe nosebleeds, lumps caused by swelling of lymph nodes in the neck and surrounding areas, armpits, abdomen or groin, pale skin, shortness of breath, weakness, tiredness or general loss of energy;
• anaemia (reduction in the amount of red blood cells in the blood);
• encephalopathy (brain disorder). Symptoms may include muscle weakness in a specific area, poor decision-making or concentration, involuntary muscle contractions, tremors, difficulty speaking or swallowing, seizures;
• anorexia;
• constipation;
• diarrhoea;
• inflammation of the mouth and lips;
• reversible liver toxicity at high doses, which may cause increased liver enzymes and bilirubin (detected by blood tests);
• alopecia (hair loss);
• skin redness;
• reactions at the injection site;

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

• veno-occlusive disease (progressive blockage of veins), in which very small veins in the liver (microscopic in size) become blocked. Symptoms may include: fluid accumulation in the abdomen, enlarged spleen, severe bleeding from the oesophagus, yellowing of the skin and whites of the eyes;

• breathing problems caused by interstitial fibrosis (at lower doses);

• kidney problems;

• gynaecomastia (development of breasts in men);

Not known (frequency cannot be estimated from the available data)

• muscle pain;
• seizures (fits), including status epilepticus;
• tissue damage due to leakage at the injection site;
• any signs of infection;
• infertility;
• confirmed impairment of fetal development;
• electrolyte abnormalities (and electrolyte imbalances (low levels of potassium, magnesium and phosphate in the blood)).

Reporting of side effects
If you get any side effects, including ones not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly through the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Carmustine medac

This medicine will be stored by the doctor or healthcare personnel.
Keep the medicine out of the sight and reach of children.
Do not use the medicine after the expiry date stated on the vial and the carton after "EXP.". The expiry date refers to the last day of that month.
Store and transport in a refrigerator (2°C - 8°C).
Keep the vial in the outer packaging to protect the medicine from light.

After reconstitution and dilution
After reconstitution, Carmustine medac remains stable for 3 hours when stored in a glass container protected from light.
The solution must be administered within 3 hours after reconstitution and dilution of the product. The solution must be kept protected from light until administration is completed.

Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use: this will help protect the environment.

6. Package contents and other information

What Carmustine medac contains

• The active substance is carmustine. Each vial of powder for concentrate for solution for infusion contains 100 mg of carmustine. After reconstitution and dilution, 1 ml of solution contains 3.3 mg of carmustine.
• Excipients:
• powder: no excipients;
• solvent: anhydrous ethanol.

Description of the appearance of Carmustine medac and contents of the pack
Carmustine medac is a powder and solvent for concentrate for solution for infusion.
The powder is a nearly white to pale yellow powder, supplied in a brown glass vial.
The solvent is a clear, colourless liquid, supplied in a transparent glass ampoule.
One pack of Carmustine medac contains one 100 mg powder vial and one ampoule containing 3 ml of solvent.
Marketing Authorisation Holder and Manufacturer
medac
Gesellschaft für klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany
Tel.: +49 4103 8006-0
Fax: +49 4103 8006-100
E-mail: [email protected]
Other sources of information
Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/ema/.
The following information is intended for healthcare professionals only.
A brief description of preparation and/or handling, interactions, dosage, overdose, or monitoring and laboratory tests is provided, based on the current Summary of Product Characteristics.
Carmustine medac powder for concentrate for solution for infusion contains no preservatives and is not a multi-dose vial. Reconstitution and further dilutions must be carried out under aseptic conditions.
By following the storage instructions for the product, degradation of the intact vial can be avoided until the expiry date stated on the packaging.
The lyophilised product contains no preservatives and is for single use only. The lyophilised product may appear as a fine powder; however, due to mechanical instability of the lyophilised mass, it may appear denser and clumped after handling. The presence of an oily film may indicate product melting. In such cases, the product must not be used due to the risk of temperature excursions exceeding 30°C. The medicinal product must not be used. If there is any doubt about proper cooling of the product, each vial in the pack must be inspected. To perform this check, expose the vial to bright light.
Reconstitution and dilution of powder for concentrate for solution for infusion
Dissolve 100 mg of Carmustine powder for concentrate for solution for infusion with 3 ml of sterile refrigerated ethanol solvent provided in the primary pack (brown glass vial). Carmustine must be completely dissolved in ethanol before adding sterile water for injectable preparations. Subsequently, add 27 ml of sterile water for injection aseptically to the alcoholic solution. The resulting 30 ml stock solution must be mixed thoroughly. Reconstitution as described yields a clear, colourless to pale yellow stock solution.
The 30 ml stock solution must be diluted immediately by adding it either to 500 ml of glucose 50 mg/ml (5%) solution for injection or to 500 ml of sodium chloride 9 mg/ml (0.9%) solution for injection in glass containers. The diluted 530 ml solution (i.e. the ready-to-use solution) must be mixed for at least 10 seconds prior to administration.
pH and osmolarity of ready-to-use infusion solutions
pH from 4.0 to 5.0 and 385–397 mOsm/l [when diluted in glucose 50 mg/ml (5%) solution for injection] and
pH from 4.0 to 6.8 and 370–378 mOsm/l [when diluted in sodium chloride 9 mg/ml (0.9%) solution for injection].
Method of administration
The reconstituted and diluted solution (i.e. ready-to-use solution) must be administered intravenously via infusion over 1–2 hours. Administration must be completed within 3 hours of reconstitution/dilution of the medicinal product. A PVC-free polyethylene (PE) infusion set must be used for administration of the infusion.
During drug administration, use a suitable glass container. Furthermore, the ready-to-use solution must be protected from light (e.g. by wrapping the container with aluminium foil) and preferably maintained at temperatures below 20–22°C, as carmustine degrades more rapidly at higher temperatures.
A PVC-free polyethylene (PE) infusion set must be used for administration of the infusion.
Shorter infusion intervals of Carmustine medac may cause severe pain and burning at the injection site. The injection site must be monitored during administration.
Appropriate guidelines for handling and safe disposal of cytotoxic agents must be observed.
Dosage and laboratory monitoring
Initial doses
The recommended dose of Carmustine medac as a single agent in previously untreated patients is between 150 and 200 mg/m² administered intravenously every 6 weeks. This dose may be given as a single administration or divided into daily infusions of 75–100 mg/m² on two consecutive days.
When Carmustine medac is used in combination with other myelosuppressive medicinal products or in patients with depleted bone marrow reserve, doses must be adjusted according to the patient's haematological profile as indicated below.
Monitoring and subsequent doses
A new cycle of Carmustine medac must not be administered until circulating blood cells have returned to acceptable levels (platelets above 100,000/mm³, white blood cells above 4,000/mm³), which usually occurs within six weeks. Blood counts must be monitored frequently, and repeated cycles must not be administered at intervals shorter than six weeks due to delayed haematological toxicity.
Subsequent doses following the initial dose must be adjusted based on the patient's haematological response to the previous dose, whether used as monotherapy or in combination with other myelosuppressive medicinal products. The table below is provided as a guide for dose adjustment.

In cases where the nadir following the initial dose does not fall within the same row for leukocytes and platelets (e.g.,
leukocytes >4,000 and platelets <25,000), the value corresponding to the lower percentage of the previous dose should be used (e.g., with platelets <25,000, at most 50% of the previous dose should be administered).
There are no limitations regarding the duration of treatment with carmustine. If the tumor remains incurable or severe or intolerable adverse reactions occur, carmustine therapy must be discontinued.
Conditioning treatment prior to HPCT
Carmustine is administered intravenously in combination with other chemotherapeutic agents in patients with malignant hematological disorders prior to HPCT at a dosage of 300–600 mg/m².
Special populations
Paediatric population
For safety reasons, carmustine must not be used in individuals under 18 years of age.
Elderly
In general, dose selection for elderly patients should be cautious, usually starting at the lower end of the dosing range, considering the higher frequency of decreased hepatic, renal, or cardiac function, as well as concomitant diseases or therapies with other medicinal products. Since reduced renal function is more likely in elderly patients, careful attention must be paid when selecting the dosage, monitoring glomerular filtration rate, and reducing the dose accordingly.
Renal impairment
For patients with renal impairment, the dose of Carmustine medac must be reduced if there is a decrease in glomerular filtration rate.
Compatibility/Incompatibility with containers
The intravenous solution is unstable in polyvinyl chloride (PVC) containers. All plastic components coming into contact with the carmustine infusion solution (e.g., infusion sets, etc.) must be made of PVC-free polyethylene plastic; otherwise, glass must be used.