Carmustine Accordpharma

Leaflet accompanying the packaging: 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

You should carefully read the contents of the leaflet before using the medicine, as it contains important information for the patient.

• You should keep this leaflet, so that you can read it again if you need to.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Table of contents of the leaflet

• 1. What is Carmustine Accordpharma and what is it used for
• 2. Important information before using Carmustine Accordpharma
• 3. How to use Carmustine Accordpharma
• 4. Possible side effects
• 5. How to store Carmustine Accordpharma
• 6. Contents of the packaging 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 anticancer medicines called nitrosourea derivatives, which work by slowing down the growth of cancer cells.

Carmustine Accordpharma is effective in treating the following malignant tumors in monotherapy or in combination with other anticancer medicines or other therapeutic agents (radiotherapy, surgery):

• 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. Important information before using Carmustine Accordpharma

When not to use Carmustine Accordpharma:

• in children and adolescents;
• 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 suppression of bone marrow function, which may manifest as fatigue, bleeding from the skin and mucous membranes, and infections and fever due to changes in blood counts. Therefore, 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 Accordpharma therapy will not be administered more frequently than every 6 weeks. Before administration of the medicine, your doctor will monitor your blood morphology.

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 may lead to lung damage, a chest X-ray and lung function tests will be performed before starting treatment (see also "Possible side effects").

Treatment with high doses of Carmustine Accordpharma (up to 600 mg/m2) is used only in combination with subsequent 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 potassium, magnesium, and phosphorus levels 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 any such symptoms, you should contact your doctor immediately (see section 4).

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 immunosuppressive agent
• Cimetidine used in case of stomach problems, such as indigestion
• Digoxin used in case of irregular heart rhythm
• Melphalan - an anticancer 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, ask your doctor or pharmacist for advice 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 administered to pregnant women. If used during pregnancy, the patient must be aware of the potential 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 advice 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 cannot be excluded that there is a 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 alcohol (ethanol) per vial for the 50 mg strength and 7.11 g of alcohol (ethanol) 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 anticancer medicines.

Recommended dosing in adults

The dose 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 in 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.

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

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 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.

Using a higher dose of Carmustine Accordpharma than recommended

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 concerns about the amount of medicine you have received.

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, 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:

Any sudden wheezing, difficulty breathing, 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 (decreased number of blood cells produced by the bone marrow), which may increase the risk of infections in case of decreased 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, pale skin, shortness of breath, weakness, fatigue, or general energy decline;
• Anemia (decreased 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 disorder may lead to increased liver enzyme activity and bilirubin levels (these are parameters measured in blood tests);
• Alopecia (excessive 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 small veins) in the liver, which may manifest as fluid accumulation in the abdomen, enlarged spleen, severe bleeding from the esophagus, and 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 (convulsions), 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 potassium, magnesium, and phosphorus levels in the blood)].

Reporting side effects

If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. Side effects can be reported directly to the Department of Adverse Reaction Monitoring of Medicinal Products, Medical Devices, and Biocides of the Office for Registration of Medicinal Products, Medical Devices, and Biocides

Jerozolimskie Avenue 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 your doctor or other medical personnel.

Store 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 month stated.

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

Store the vials in the outer packaging 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 injection solution or 5% glucose injection solution at a final concentration of 0.2 mg/ml has been demonstrated if stored in a glass or polypropylene container 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 the product is not used immediately, the in-use storage times and conditions are the responsibility of the user.

**24-hour storage time of the diluted solution is the total time during which carmustine remains in solution, including the time of 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 packaging 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 the 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.

Taśmowa Street 7

02-677 Warsaw

tel: +48 22 577 28 00

Manufacturer/Importer

Accord Healthcare Polska Sp. z o.o.

Lutomierska Street 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:

Below is a brief description of the method of preparation and/or use, incompatibilities, dosing, 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.

By following the recommended storage conditions, decomposition of the substances contained in the 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 lyophilizate may have the appearance of a fine powder, but handling may cause it to have a heavier and more granular appearance than a powder lyophilizate due to the mechanical instability of the lyophilizate granules. The presence of an oily layer may indicate that the product has melted. Such products are not suitable for use due to the risk that they have been exposed to temperatures above 30°C. Such a product should not be used further.

In case of doubt as to whether the product has been stored in the correct 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

Dissolve the carmustine (powder) in the required amount of supplied sterile, cooled 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 mixed thoroughly.

One milliliter of the solution contains 3.3 mg of carmustine.

After reconstitution and dilution, the solution should be clear, colorless to yellowish, and practically free of visible particles, and should then be diluted immediately to the required amount of sodium chloride injection solution or 5% glucose injection solution. The diluted solution (i.e., the solution ready for use) should be mixed for at least 10 seconds before administration. The solution prepared according to the instructions should be administered within 1-2 hours.

pH and osmolality of the diluted solutions for infusion are:

pH: 3.2 to 7.0 [in the case of dilution in sodium chloride injection solution at a concentration of 9 mg/ml (0.9%) or in 5% glucose injection solution].

Osmolality: 340 to 400 mOsmol/l [in the case of dilution in 5% glucose injection solution or sodium chloride injection solution at a concentration of 9 mg/ml (0.9%)].

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. The infusion should be performed using an infusion set made of polyethylene not containing PCV; otherwise, glass containers should be used.

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

During administration of the medicine, the injection site should be monitored.

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

Guidelines for safe handling of anticancer medicines and their disposal should be followed.

Dosing and laboratory tests

Initial doses

The recommended dose of Carmustine Accordpharma used in 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 hematologic profile, as presented below.

Monitoring and subsequent doses

A subsequent course of Carmustine Accordpharma therapy can be administered only when the blood morphology 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 morphology should be monitored frequently, and a subsequent course of treatment should not be administered before six weeks have elapsed 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 leukocytes and platelets (e.g., leukocyte 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).

There are no restrictions on 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 to patients with malignant hematological diseases before 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 carefully, 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 disorders; also, concomitant diseases and treatment with other medicines should 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 renal impairment, the dose of carmustine should be reduced in case of decreased glomerular filtration rate.

Compatibility/incompatibility with containers

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 not containing PCV; otherwise, glass containers should be used.