Carmustine accordpharma

Package leaflet: Information for the user

Carmustine Accordpharma, 50 mg, powder and solvent for solution for concentrate for infusion
Carmustine Accordpharma, 300 mg, powder and solvent for solution for concentrate for infusion
Carmustinum
Please read all of this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet as 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 or nurse. This includes any side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

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

Carmustine Accordpharma is a medicine containing carmustine. Carmustine belongs to a group of anticancer medicines called nitrosourea derivatives, which work by slowing the growth of cancer cells.
Carmustine Accordpharma is indicated in adults for the treatment of the following malignant diseases as monotherapy or in combination with other anticancer medicines or other therapeutic modalities (radiotherapy, surgery):

• Brain tumours (glioblastoma multiforme, brainstem gliomas, medulloblastoma, astrocytoma, and ependymoma) and brain metastases
• Second-line treatment of non-Hodgkin's lymphoma and Hodgkin's disease
• Gastrointestinal tumours
• Malignant melanoma (skin cancer)
• As conditioning treatment prior to autologous haematopoietic stem cell transplantation in malignant haematological diseases (Hodgkin's disease/non-Hodgkin's lymphoma).

2. Important information before using Carmustine Accordpharma

When not to use Carmustine Accordpharma:

• if the patient is allergic to carmustine or any of the other ingredients of this medicine (listed in section 6);
• if the patient has bone marrow suppression disorders resulting in reduced numbers of platelets, white blood cells (leukocytes), or red blood cells (erythrocytes), due to prior chemotherapy or other causes;
• if the patient has severely impaired kidney function;
• in children and adolescents;
• in breastfeeding women.

Warnings and precautions
Before starting treatment with Carmustine Accordpharma, discuss this with your doctor, pharmacist,
or nurse.
The main adverse effect of this medicine is delayed bone marrow suppression,
which may manifest as fatigue, bleeding from the skin and mucous membranes, and infections with fever due to blood changes. Therefore, your doctor will monitor your blood counts weekly for at least 6 weeks after each dose. Treatment cycles with the recommended doses of Carmustine Accordpharma should not be administered more frequently than every 6 weeks. Your doctor will check your blood counts before each dose.
Before starting treatment, liver, lung, and kidney function tests will be performed and repeated regularly during treatment.
Because treatment with Carmustine Accordpharma may cause lung damage, a chest X-ray and pulmonary function tests will be performed before treatment begins (see also section "Possible side effects").
High-dose treatment with Carmustine Accordpharma (up to 600 mg/m² BSA) is used exclusively in combination with subsequent stem cell transplantation. High doses may increase the risk and severity of toxic effects on the lungs, kidneys, liver, heart, and gastrointestinal tract, as well as infections and electrolyte imbalances (low blood levels of potassium, magnesium, and phosphate).
Abdominal pain (neutropenic enterocolitis) may occur as an adverse reaction associated with therapy following administration of chemotherapeutic agents.
Your doctor will inform you about the possibility of lung damage and allergic reactions, including their symptoms. If such symptoms occur, contact your doctor immediately (see section 4).
Children and adolescents
Carmustine Accordpharma must not be used in children and adolescents under 18 years of age.
Carmustine Accordpharma and other medicines
Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, including medicines you plan to take, even those available without a prescription, such as:

• Phenytoin used for epilepsy
• Dexamethasone used as an anti-inflammatory and immunosuppressive agent
• Cimetidine used for stomach problems such as indigestion
• Digoxin used for irregular heartbeat
• Melphalan – an anticancer medicine

Use of Carmustine Accordpharma with alcohol
The amount of alcohol in this medicinal product may affect the action of other medicines.
Pregnancy, breastfeeding, and fertility
If you are pregnant, breastfeeding, think you may be pregnant, or are planning to become pregnant, you should consult your doctor or pharmacist before using this medicine.
Pregnancy and fertility
Carmustine Accordpharma must not be used during pregnancy, as it may harm the unborn child. Therefore, this medicine should generally not be given to pregnant women. If treatment during pregnancy is necessary, the patient must be aware of the potential risks to the unborn child. Women of childbearing potential must be advised to use effective contraception to prevent pregnancy during treatment with this medicine and for at least 6 months after completion of treatment.
Men should use appropriate contraceptive measures during treatment with Carmustine Accordpharma and for at least 6 months after treatment to prevent pregnancy in their partners. Treatment with Carmustine Accordpharma may impair fertility in men. Patients should be advised to seek counseling regarding fertility and (or) family planning before starting treatment with Carmustine Accordpharma.
Breastfeeding
Breastfeeding must be avoided during treatment with this medicine and for 7 days after treatment. A risk to newborns and infants cannot be excluded.
Driving and operating machinery
Carmustine Accordpharma has no or negligible influence on the ability to drive or operate machinery. However, before driving or operating any tools or machines, consult your doctor, because the alcohol content in this medicine may impair the ability to drive or operate machinery.
Carmustine Accordpharma contains ethanol (alcohol)
This medicine contains 2.374 g of alcohol (ethanol) per vial in the 50 mg strength and 7.11 g of alcohol (ethanol) per vial in the 300 mg strength, equivalent to 25.596 g per maximum dose (600 mg/m² BSA in patients weighing 70 kg). The alcohol content in the maximum dose is equivalent to 640 ml of beer or 256 ml of wine.
The amount of alcohol in this medicine may affect the ability to drive or operate machinery, as it may impair judgment and reaction speed.
Patients with epilepsy or liver disease should consult their doctor or pharmacist before taking this medicine.
The alcohol content in this medicine may alter the effect of other medicines. If you are taking other medicines, consult your doctor or pharmacist.
Pregnant or breastfeeding women should consult their doctor or pharmacist before taking this medicine.
Alcohol-dependent individuals should consult their doctor or pharmacist before taking this medicine.
Since this medicine is usually administered slowly over 1–2 hours, the effects of alcohol may be reduced.

3. How to use Carmustine Accordpharma

Carmustine Accordpharma will always be administered by medical personnel experienced in the use of anticancer medicines.
Recommended dosage for adults
The dosage depends on the patient's health status, body surface area, and response to treatment. The medicine is usually given no more frequently than every 6 weeks. The recommended dose of Carmustine Accordpharma used as monotherapy in previously untreated patients is 150 to 200 mg/m² intravenously every 6 weeks. The dose may be given as a single dose or may be divided into daily infusions of 75 to 100 mg/m² on two consecutive days. Dosing also depends on whether Carmustine Accordpharma is administered with other anticancer medicines.
Doses will be adjusted according to the patient's response to treatment.
The recommended dose of Carmustine Accordpharma administered intravenously in combination with other chemotherapeutic agents prior to hematopoietic progenitor cell transplantation is 300–600 mg/m².
To avoid toxic effects on the bone marrow, blood counts will be frequently monitored and the dose will be adjusted if necessary.
Route of administration
After reconstitution and dilution, Carmustine Accordpharma is administered intravenously by infusion (intravenous infusion) over one to two hours, protected from light. The duration of the infusion should not be less than one hour; otherwise, burning and pain at the injection site may occur. The infusion site will be monitored during administration.
The duration of treatment will be determined by the physician and may vary between individual patients.
Use of a higher than recommended dose of Carmustine Accordpharma
Since the medicine will be administered by a doctor or nurse, incorrect dosing is unlikely. Inform your doctor or nurse if you have any concerns regarding the amount of medicine received.
If you have any further 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 will experience them.
You should immediately inform your doctor or nurse if any of the following occurs:
Sudden wheezing, breathing problems, swelling of the eyelids, face or lips, rash or itching (especially if affecting the whole body), as well as a feeling of fainting. These may be symptoms of a severe allergic reaction.

Carmustine Accordpharma may cause the following side effects:

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

• Delayed myelosuppression (reduced production of blood cells by the bone marrow), which may increase the risk of infections due to low white blood cell count;
• Ataxia (lack of voluntary muscle coordination);
• Dizziness;
• Headache;
• Transient eye redness, blurred vision due to retinal haemorrhage;
• Hypotension (low blood pressure);
• Phlebitis (inflammation of veins) associated with pain, swelling, redness, and tenderness on pressure;
• Respiratory disorders (lung-related problems) involving difficulty in breathing. This medicine may cause severe (potentially fatal) lung damage. Lung damage may occur several years after treatment. You should inform your doctor immediately if you experience any of the following symptoms: shortness of breath, persistent cough, chest pain, or persistent fatigue/weakness.
• Severe nausea and vomiting;
• Skin inflammation in case of contact with the medicine;
• Accidental skin contact may cause transient skin or nail discoloration (darkening of the skin area or nails)

Common (may affect up to 1 in 10 people):

• Acute leukaemias and myelodysplastic syndromes (abnormal bone marrow development). Possible symptoms include: bleeding gums, bone pain, fever, frequent infections, frequent or severe nosebleeds, lumps caused by swollen lymph nodes in the neck or surrounding areas, under the arms, in the abdomen or groin, pale skin, shortness of breath, weakness, fatigue or general lack of energy;
• Anaemia (reduced number of red blood cells in the blood);
• Encephalopathy (brain disorder). Possible symptoms include: muscle weakness in one area, inability to make decisions or poor concentration, involuntary muscle twitching, tremors, difficulty speaking or swallowing, seizures;
• Loss of appetite;
• Constipation;
• Diarrhoea;
• Inflammation of the mouth and lips;
• Reversible liver toxicity when treated with high doses. This disorder may lead to increased liver enzyme activity and bilirubin levels (parameters measured in blood tests);
• Hair loss (alopecia);
• Skin redness;
• Reactions at the injection site.

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

• Veno-occlusive disease (progressive blockage of veins), characterized by blockage of very small (microscopic) veins in the liver. Possible symptoms 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 (when lower doses are used);
• Kidney problems;
• Gynaecomastia (enlargement of breasts in males).

Unknown frequency (cannot be estimated from available data):

• Muscle pain;
• Seizures, including status epilepticus;
• Tissue damage due to leakage at the site of administration;
• Any signs of infection;
• Infertility;
• Carmustine has been shown to have harmful effects on the development of unborn children.
• Electrolyte disturbances [and electrolyte imbalance (low levels of potassium, magnesium and phosphate in the blood)].

Reporting of side effects
If you experience any side effects, including any not listed in this leaflet, tell your doctor or pharmacist. Side effects can be reported directly to the Department of Monitoring Adverse Drug Reactions at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Reporting side effects helps provide more information on the safety of this medicine.
Side effects can also be reported to the responsible entity.

5. How to store Carmustine Accordpharma

The medicine will be stored by a doctor or other healthcare professional.
Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after EXP.
The expiry date refers to the last day of the stated month.
Store and transport in a refrigerated condition (2°C–8°C).
Store vials in their outer packaging to protect from light.

After reconstitution (reconstituted stock solution):
Chemical and physical stability of the reconstituted stock solution has been demonstrated for 24 hours
at a temperature of 2°C to 8°C.

After dilution (diluted infusion solution):
Chemical and physical stability of the diluted infusion solution has been demonstrated for 4 hours
at 20°C to 25°C when stored in a glass or polypropylene container and protected from light,
in sodium chloride solution for injection or 5% glucose solution for injection at a final concentration of 0.2 mg/ml.
These solutions remain stable for 24 hours** when stored refrigerated (2°C to 8°C) and for an additional 3 hours
at 20°C to 25°C, protected from light.

From a microbiological point of view, if the method of opening, reconstitution, and dilution does not exclude
the risk of microbiological contamination, the product should be used immediately.
If the product is not used immediately, the user is responsible for the storage duration and conditions during use.

**The 24-hour storage period for the ready-to-use diluted solution is the total time during which carmustine
remains in solution, including the time of reconstitution using ethanol and water for injection.

The solution must be protected from light until administration is completed.

Medicines must 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 Accordpharma contains
The active substance is carmustine.
Carmustine Accord, 50 mg
One 20 ml vial of powder for concentrate for solution for infusion contains 50 mg of carmustine.
One 5 ml vial of solvent contains 3 ml of absolute ethanol.
Carmustine Accord, 300 mg
One 100 ml vial of powder for concentrate for solution for infusion contains 300 mg of carmustine.
One 10 ml vial of solvent contains 9 ml of absolute ethanol.
After reconstitution with the supplied solvent and further dilution with water for injections, 1 ml of
solution will contain 3.3 mg of carmustine.
Excipients:

• Powder: No excipients.
• Solvent: Absolute ethanol.

What Carmustine Accordpharma looks like and contents of the pack
Carmustine Accordpharma is a powder and solvent for concentrate for solution for infusion.
The powder is a pale yellow, dry flake or dry powder in an amber glass vial (type I) with a bromobutyl rubber stopper, aluminium seal, and a polypropylene cap.
The solvent is a clear, colourless liquid in a colourless glass vial (type I) with a polymer-coated (FluroTec) rubber stopper, aluminium seal, and a polypropylene cap.
Pack sizes:
The pack contains 1 vial with 50 mg of powder and 1 vial with 3 ml of solvent.
The pack contains 10 vials each with 50 mg of powder and 10 vials each with 3 ml of solvent.
The pack contains 1 vial with 300 mg of powder and 1 vial with 9 ml of solvent.
The pack contains 10 vials each with 300 mg of powder and 10 vials each with 9 ml of solvent.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Accord Healthcare Polska Sp. z o.o.
ul. Taśmowa 7
02-677 Warszawa
tel: +48 22 577 28 00
Manufacturer/Importer
Accord Healthcare Polska Sp. z o.o.
ul. Lutomierska 50
95-200 Pabianice
Laboratori Fundació Dau
C/ C, 12-14 Pol. Ind. Zona Franca
08040 Barcelona
Spain
This medicinal product is authorised in the Member States of the European Economic Area under the following names:

Information intended exclusively for healthcare professionals:
Below is a brief description of the method of preparation and (or) administration, pharmaceutical
incompatibilities, dosing of the medicinal product, overdose or required monitoring actions,
as well as laboratory tests, based on the current Summary of Product Characteristics.
Carmustine powder for solution for infusion concentrate does not contain preservatives and is not intended for use in multidose vials. Reconstitution and further dilution must be performed under aseptic conditions.
By adhering to the recommended storage conditions, degradation of the substance contained in the unopened vial can be avoided until the expiry date indicated on the packaging.
The lyophilized product contains no preservatives and is intended for single use only. The lyophilisate may appear as a fine powder; however, manipulation may cause it to have a heavier, more granular appearance than powder-like lyophilisate due to mechanical instability of the lyophilized cake. The presence of an oily layer may indicate melting of the medicinal product. Such products are not suitable for use due to the risk that the temperature has exceeded 30°C. Such medicinal products should not be used further. In case of doubt whether the product has been maintained under appropriate cooling conditions, all vials in the carton should be inspected immediately. For verification, place the vial under bright light.
Reconstitution and dilution of the powder for preparation of infusion concentrate solution
Dissolve carmustine (powder) in the required amount of supplied, sterile, cooled solvent (ethanol) in the primary container (brown glass vial). Carmustine must be completely dissolved in ethanol before adding sterile water for injections. Then, aseptically add the required amount of sterile water for injections to the alcoholic solution. The resulting stock solution should be thoroughly mixed.

Each millilitre of the concentrate contains 3.3 mg of carmustine in 10% ethanol.
After reconstitution according to the instructions, a clear, colourless to slightly yellow solution practically free from visible particles is obtained, which must then be immediately diluted to the required volume with sodium chloride injection solution 9 mg/ml (0.9%) or 5% glucose injection solution. The diluted solution (i.e. the ready-to-use solution) should be mixed for at least 10 seconds before administration. The solution prepared according to the instructions should be administered within 1–2 hours.

The pH and osmolality of the diluted ready-to-use infusion solutions are as follows:
pH: 3.2 to 7.0 [when diluted with sodium chloride injection solution 9 mg/ml (0.9%) or 5% glucose injection solution].
Osmolality: 340 to 400 mOsmol/l [when diluted with glucose injection solution 50 mg/ml (5%) or sodium chloride injection solution 9 mg/ml (0.9%)].

Method of administration
Intravenous administration after reconstitution and dilution.

The reconstituted and diluted solution (i.e. the ready-to-use solution) should be administered intravenously as an intravenous infusion over a period of one to two hours. The infusion should be administered using an infusion set made of PE not containing PCV. During administration of the medicinal product, an appropriate glass or polypropylene container should be used. Furthermore, the ready-to-use solution should be protected from light (e.g. by wrapping the container in aluminium foil); it is also advisable to store it at a temperature below 20–25°C, as carmustine decomposes more rapidly at higher temperatures.

Infusion of Carmustine Accordpharma over a period shorter than one hour may cause severe pain and burning at the injection site. The intravenous infusion site should be monitored during administration of the medicinal product.

Appropriate guidelines for safe handling and disposal of cytotoxic medicinal products should be followed.

Dosage and laboratory monitoring
Initial dosing
The recommended dose of Carmustine Accordpharma medicinal product used as monotherapy in previously untreated patients is 150 to 200 mg/m² administered intravenously every 6 weeks. The medicinal product may be given as a single dose or divided into daily infusions of 75 to 100 mg/m² on two consecutive days.

When Carmustine Accordpharma medicinal product is used in combination with other myelosuppressive medicinal products or in patients with reduced bone marrow reserve, doses should be adjusted according to the patient's haematological profile, as shown below.

Monitoring and subsequent doses
The next course of treatment with Carmustine Accordpharma medicinal product should only be administered once blood counts have returned to acceptable levels (platelet count above 100,000/mm³, white blood cell count above 4,000/mm³), which usually occurs within six weeks. Blood counts should be monitored frequently, and treatment should not be repeated before six weeks have elapsed due to the risk of delayed haematological toxicity.

After the initial dose, subsequent doses should be adjusted according to the patient's haematological response to the previous dose, both in monotherapy and in combination therapy with other myelosuppressive medicinal products. The following dose adjustment guidelines are recommended:

Table 1

In cases where the lowest value after administration of the initial dose does not fall within the same row for leukocytes and platelets (e.g., white blood cell count >4,000 and platelet count <25,000), the dose corresponding to the lower percentage of the previous dose should be used (e.g., platelet count <25,000 – maximum 50% of the previous dose should be administered).
There are no limitations regarding the duration of carmustine treatment. If the tumor remains refractory or severe or intolerable adverse reactions occur, carmustine treatment should be discontinued.
Conditioning treatment prior to hematopoietic stem cell transplantation
Carmustine Accordpharma is administered intravenously at a dose of 300–600 mg/m² BSA in combination with other chemotherapeutic agents to patients with malignant hematological disorders prior to hematopoietic stem cell transplantation.
Special patient groups
Children and adolescents
Carmustine should not be administered to children or adolescents under 18 years of age.
Elderly patients
Doses should generally be selected cautiously in elderly patients, particularly starting at the lower end of the dose range, due to the higher likelihood of impaired liver, kidney, or heart function. Concomitant diseases and concomitant medications should also be taken into account. Since elderly patients have a higher probability of impaired renal function, caution should be exercised when selecting the dose, glomerular filtration rate should be monitored, and the dose should be appropriately reduced.
Renal impairment
In patients with renal impairment, the dose of carmustine should be reduced if a decreased glomerular filtration rate is observed.
Compatibility/incompatibility with containers
The intravenous solution is unstable in containers made of polyvinyl chloride (PVC). All plastic materials coming into contact with the carmustine solution for infusion (e.g., infusion sets, etc.) should be made of polyethylene free of PVC; otherwise, glass containers should be used.