Carmustine Accordpharma

Package Leaflet: Information for the User

Carmustine Accordpharma, 50 mg, powder and solvent for concentrate for solution for infusion

for infusion

Carmustine Accordpharma, 300 mg, powder and solvent for concentrate for solution for infusion

Carmustinum

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

• You should 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 Accordpharma and what is it 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 is Carmustine Accordpharma and what is it used for

Carmustine Accordpharma is a medicine that contains carmustine. Carmustine belongs to a group of anti-cancer medicines called nitrosoureas, which work by slowing down the growth of cancer cells.

Carmustine Accordpharma is effective in treating the following types of cancer:

• Brain tumors (glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, and ependymoma) and metastases to the brain
• Second-line therapy for non-Hodgkin's lymphoma and Hodgkin's disease
• Gastrointestinal tumors
• Malignant melanoma (skin cancer)
• As a conditioning treatment before autologous hematopoietic stem cell transplantation in malignant hematological diseases (Hodgkin's disease/non-Hodgkin's lymphoma).

2. What you need to know before you use Carmustine Accordpharma

When not to use Carmustine Accordpharma:

• If you are allergic to carmustine or any of the other ingredients of this medicine;
• If you have bone marrow depression, which is characterized by a reduced number of platelets, white blood cells (leukocytes), or red blood cells (erythrocytes) due to chemotherapy or other causes;
• If you have severe kidney problems;
• In children and adolescents under 18 years of age;
• In breastfeeding women.

Warnings and precautions

Before starting treatment with Carmustine Accordpharma, discuss it with your doctor, pharmacist, or nurse.

The main side effect of this medicine is delayed bone marrow suppression, which can cause fatigue, bleeding from the skin and mucous membranes, and infections and fever due to changes in the blood. Therefore, your doctor will check your blood count every week for at least 6 weeks after administration of the dose. During treatment with the recommended doses, courses of Carmustine Accordpharma will not be given more frequently than every 6 weeks. Before administration of the medicine, your doctor will check your blood count.

Before starting treatment, liver, lung, and kidney function tests will be performed, which will be regularly repeated during treatment.

Since the use of Carmustine Accordpharma can lead to lung damage, a chest X-ray and lung function tests will be performed before starting treatment.

Treatment with high doses of Carmustine Accordpharma (up to 600 mg/m2) is used only in combination with subsequent autologous hematopoietic stem cell transplantation. High doses may increase the risk of toxic effects on the lungs, kidneys, liver, heart, and gastrointestinal tract, as well as infections and electrolyte disturbances (low levels of potassium, magnesium, and phosphorus in the blood).

Abdominal pain (neutropenic enterocolitis) may occur as a side effect related to chemotherapy.

Your doctor will inform you about the possibility of lung damage and the possibility of allergic reactions and their symptoms. If you experience such symptoms, you should contact your doctor immediately.

Children and adolescents

Carmustine Accordpharma should 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 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
• Dexamethasone used as an anti-inflammatory and immunosuppressant
• Cimetidine used for stomach problems, such as indigestion
• Digoxin used for irregular heart rhythm
• Melphalan - an anti-cancer medicine

Using Carmustine Accordpharma with alcohol

The amount of alcohol in this medicinal product may change the effect of other medicines.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

Pregnancy and fertility

Carmustine Accordpharma should not be used during pregnancy, as 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 possible risks to the unborn child. Women of childbearing potential should be informed about the need for effective contraception to prevent pregnancy during treatment with this medicine and for at least 6 months after the end 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 on fertility and/or family planning before starting treatment with Carmustine Accordpharma.

Breastfeeding

You should not breastfeed while taking this medicine and for 7 days after treatment. It is not possible to exclude the risk to newborns and infants.

Driving and using machines

Carmustine Accordpharma has no or negligible influence on the ability to drive and use machines.

Before driving or operating any tools or machines, consult your doctor, as the amount of alcohol in this medicine may impair your ability to drive or operate machines.

Carmustine Accordpharma contains ethanol (alcohol)

This medicine contains 2.374 g of ethanol (alcohol) per vial for the 50 mg strength and 7.11 g of ethanol (alcohol) per vial for the 300 mg strength, which is equivalent to 25.596 g per maximum dose (600 mg/m2 in patients with a body weight of 70 kg). The amount of alcohol in this medicine is equivalent to 640 ml of beer or 256 ml of wine.

The amount of alcohol in this medicine may affect your ability to drive or operate machines, as it may affect your judgment and reaction time.

Patients with epilepsy or liver disease should consult their doctor or pharmacist before taking this medicine.

The amount of alcohol in this medicine may change 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 patients should consult their doctor or pharmacist before taking this medicine.

Since this medicine is usually administered slowly over 1-2 hours, the effect 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 anti-cancer medicines.

Recommended dosage for adults

The dosage 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 Accordpharma used as monotherapy in previously untreated patients is 150-200 mg/m2 intravenously every 6 weeks. The medicine can be administered as a single dose or divided into daily infusions of 75-100 mg/m2 over two consecutive days.

Dosage is also dependent on whether Carmustine Accordpharma is administered with other anti-cancer medicines.

Doses will be increased according to the patient's response to treatment.

Recommended dose of Carmustine Accordpharma administered intravenously in combination with other chemotherapeutic agents before autologous hematopoietic stem 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.

Method of administration

After reconstitution and dilution, Carmustine Accordpharma is administered intravenously in an infusion over a period of 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 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.

Overdose of Carmustine Accordpharma

Since the medicine will be administered by a doctor or nurse, incorrect dosing is unlikely. If you have any concerns about the amount of medicine you have received, inform your doctor or nurse.

If you have any further questions about the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, Carmustine Accordpharma 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:

Sudden wheezing, breathing problems, 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 Accordpharma 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), which may increase the risk of infections in case of reduced white blood cell count;
• Ataxia (lack of spontaneous coordination of muscle movements);
• Dizziness;
• Headache;
• Transient eye redness, blurred vision due to retinal hemorrhage;
• Hypotension (decreased blood pressure);
• Phlebitis associated with pain, swelling, redness, and tenderness;
• Respiratory disorders (respiratory problems) associated with difficulty breathing. This medicine may cause severe (potentially life-threatening) lung damage. Lung damage may occur many years after 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;
• 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 and bone marrow dysplasias (abnormal development of bone marrow). Possible symptoms include: gum bleeding, bone pain, fever, frequent infections, frequent nosebleeds or heavy bleeding, tumors caused by swollen lymph nodes in the neck or armpits, abdomen, or groin, paleness, shortness of breath, weakness, fatigue, or general loss of energy;
• Anemia (reduced number of red blood cells in the blood);
• Encephalopathy (brain disease). Possible symptoms include: muscle weakness in one area, inability to make decisions or poor concentration, involuntary muscle twitching, tremors, difficulty speaking or swallowing, seizures;
• Anorexia;
• Constipation;
• Diarrhea;
• Oral and lip inflammation;
• Reversible liver toxicity in case of high-dose treatment. This condition may lead to increased liver enzyme activity and bilirubin levels (these are parameters measured in blood tests);
• Alopecia (excessive hair loss);
• 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 veins in the liver) characterized by fluid accumulation in the abdomen, enlarged spleen, severe bleeding from the esophagus, yellowing of the skin and whites of the eyes;
• Breathing problems due to interstitial fibrosis (when using smaller doses);
• Kidney problems;
• Gynecomastia (breast enlargement in men).

Unknown(frequency cannot be estimated from the available data):

• Muscle pain;
• Seizures (including status epilepticus),
• Tissue damage due to leakage at the injection site;
• Infertility;
• It has been shown that carmustine has an adverse effect on the development of unborn children.
• Electrolyte disturbances [and electrolyte imbalance (low levels of potassium, magnesium, and phosphorus in the blood)].

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Drug Safety, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products

Al. Jerozolimskie 181C

02-222 Warsaw

tel.: +48 22 49 21 301

fax: +48 22 49 21 309

Website: https://smz.ezdrowie.gov.pl

By reporting side effects, you can help provide more information on the safety of this medicine.

Side effects can also be reported to the marketing authorization holder.

5. How to store Carmustine Accordpharma

The medicine will be stored by a doctor or other medical personnel.

Store in a place inaccessible to 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 month stated.

Store and transport at a refrigerated temperature (2°C-8°C).

Store the vials in the outer carton to protect from light.

After reconstitution (reconstituted solution)

Chemical and physical stability of the reconstituted solution has been demonstrated for 24 hours at a temperature of 2°C to 8°C.

After dilution (diluted solution for infusion)

Chemical and physical stability of the diluted solution for infusion in sodium chloride 9 mg/ml (0.9%) injection or 5% glucose injection has been demonstrated for 4 hours at a temperature of 20°C to 25°C and protected from light. These solutions will also remain stable for 24 hours** in the refrigerator (2°C to 8°C) and for a further 3 hours at 20°C to 25°C, protected from light.

From a microbiological point of view, unless the method of opening, reconstitution, and dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the in-use storage times and conditions are the responsibility of the user.

**The 24-hour storage time for the diluted solution is the total time the carmustine is in solution, including the time for reconstitution with ethanol and water for injection.

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 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 anhydrous 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 anhydrous ethanol.

After reconstitution with the supplied solvent and further dilution with water for injection, 1 ml of solution contains 3.3 mg of carmustine.

Excipients:

• Powder: No excipients.
• Solvent: Anhydrous 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 in the form of pale yellow dry flakes or dry powder in a vial made of orange glass (type I) with a bromobutyl rubber stopper and an aluminum seal and a PP cap.

The solvent is a clear, colorless liquid in a vial made of clear glass (type I) with a FluroTec-coated rubber stopper and an aluminum seal and a PP cap.

Pack sizes:

The pack contains 1 vial containing 50 mg of powder and 1 vial containing 3 ml of solvent.

The pack contains 10 vials containing 50 mg of powder and 10 vials containing 3 ml of solvent.

The pack contains 1 vial containing 300 mg of powder and 1 vial containing 9 ml of solvent.

The pack contains 10 vials containing 300 mg of powder and 10 vials containing 9 ml of solvent.

Not all pack sizes may be marketed.

Marketing authorization holder

Accord Healthcare Polska Sp. z o.o.

ul. Taśmowa 7

02-677 Warsaw

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

Accord Healthcare B.V.

Winthontlaan 200

3526KV Utrecht

Netherlands

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

Date of last revision of the leaflet: May 2023

Information intended for healthcare professionals only:

The following is a brief description of the method of preparation and/or use, incompatibilities, dosage, overdose, or actions required for monitoring, as well as laboratory tests, based on the current Summary of Product Characteristics.

Carmustine powder for concentrate for solution for infusion does not contain preservatives and is not intended for use in multidose vials. Reconstitution and further dilution should be carried out under aseptic conditions.

Provided the storage conditions are observed, degradation of the contents of an unopened vial can be avoided until the expiry date stated on the packaging.

The lyophilized product does not contain any preservatives and is intended for single use only. The lyophilized powder may appear as a fine powder, but handling can cause it to appear more dense and lumpy than a powder due to the mechanical instability of the powder cake. The presence of an oily film may indicate that the product has melted. Such products should not be used due to the risk of having exceeded 30°C. If there is any doubt about whether the product has been stored at the correct temperature, the entire 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

Dissolve the carmustine (powder) in the required amount of supplied sterile, chilled solvent (ethanol) in the primary packaging (vial of brown glass). The carmustine should be completely dissolved in ethanol before adding sterile water for injection. Then, aseptically add the required amount of sterile water for injection to the ethanol solution. The resulting solution should be thoroughly mixed.

One milliliter of the solution contains 3.3 mg of carmustine.

After reconstitution as directed, a clear, colorless to yellowish solution without visible particles is obtained, which should then be immediately diluted to the required volume with sodium chloride 9 mg/ml (0.9%) injection or 5% glucose injection.

The diluted solution (i.e., the solution ready for use) should be mixed for at least 10 seconds before administration. The solution prepared as directed should be administered within 1-2 hours.

pH and osmolality of the diluted solutions for infusion are:

pH: 3.2 to 7.0 [when diluted in sodium chloride 9 mg/ml (0.9%) injection or 5% glucose injection].

Osmolality: 340 to 400 mOsmol/l [when diluted in 5% glucose injection or sodium chloride 9 mg/ml (0.9%) injection].

Method of administration

Intravenous administration after reconstitution and dilution.

The solution after reconstitution and dilution (i.e., the solution ready for use) should be administered intravenously, in an intravenous drip infusion, over a period of one to two hours, protected from light. Infusion should be performed using a polyethylene infusion set that does not contain PVC; otherwise, glass containers should be used.

In addition, the solution ready for use should be protected from light (e.g., by wrapping the container with aluminum foil); it is also recommended to store it at a temperature below 20-25°C, as carmustine degrades faster at higher temperatures.

Administration of Carmustine Accordpharma in less than one hour may cause severe pain and burning at the injection site. The injection site should be monitored during administration.

Guidelines for the safe handling and disposal of cytotoxic medicines should be followed.

Dosage and laboratory tests

Initial doses

The recommended dose of Carmustine Accordpharma used as monotherapy in previously untreated patients is 150-200 mg/m2 intravenously every 6 weeks. The medicine can be administered as a single dose or divided into daily infusions of 75-100 mg/m2 over two consecutive days.

When Carmustine Accordpharma 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 hematological profile, as described below.

Monitoring and subsequent doses

A subsequent course of Carmustine Accordpharma can be given only when the blood count parameters have returned to an acceptable level (platelet count above 100,000/mm3, leukocytes above 4,000/mm3), which usually occurs within six weeks. Blood counts should be frequently monitored, and the next course of treatment should not be given 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 with other medicines that have a myelosuppressive effect. The following dosage adjustment scheme is suggested:

Table 1

In cases where the lowest value after the initial dose is not in the same row for leukocytes and platelets (e.g., leukocytes >4,000 and platelets <25,000), the value corresponding to the lowest percentage of the previous dose should be used (e.g., platelets <25,000 - use a maximum of 50% of the previous dose).

There is no limit to the duration of treatment with carmustine. If the tumor remains incurable or severe or intolerable side effects occur, treatment with carmustine should be discontinued.

Conditioning treatment before hematopoietic stem cell transplantation

Carmustine Accordpharma is administered intravenously at a dose of 300-600 mg/m2 in combination with other chemotherapeutic agents in patients with malignant hematological diseases before autologous hematopoietic stem cell transplantation.

Special populations

Children and adolescents

Carmustine should not be administered to children and adolescents under 18 years of age.

Elderly

Generally, in elderly patients, doses should be selected cautiously, and in particular, the dose should be started at the lower end of the dose range, due to the higher frequency of liver, kidney, or heart problems; concomitant diseases and other medicines should also be taken into account. Since elderly patients are more likely to have impaired renal function, caution should be exercised when selecting the dose, and the glomerular filtration rate should be monitored, as well as the dose reduced as appropriate.

Renal impairment

In patients with impaired renal function, the dose of carmustine should be reduced in case of decreased glomerular filtration rate.

Compatibility

The intravenous solution is unstable in polyvinyl chloride containers. All plastics that come into contact with the carmustine solution intended for infusion (e.g., infusion set, etc.) should be made of polyethylene that does not contain PVC; otherwise, glass containers should be used.