CARMUSTINE ACCORD 100 mg POWDER AND SOLVENT FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the Patient

Carmustine Accord 100 mg powder and solvent for concentrate for solution for infusion EFG

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

Keep this leaflet, you may need to read it again.

• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor or nurse, even if it is not listed in this leaflet. See section 4.

Contents of the pack

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

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

Carmustine is a medicine that contains carmustine. Carmustine belongs to a group of anticancer medicines, known as nitrosoureas, which work by slowing down the growth of cancer cells.

Carmustine is indicated in adults for the following malignant neoplasms as monotherapy or in combination with other antineoplastic agents and/or other therapeutic measures (radiotherapy, surgery):

• Brain tumors (glioblastoma, brainstem gliomas, medulloblastoma, ependymoma, astrocytoma), brain metastases
• Second-line treatment in Hodgkin's disease and non-Hodgkin's lymphoma
• Tumors of the gastrointestinal tract or digestive tract
• Malignant melanoma (skin cancer)
• As conditioning treatment prior to autologous hematopoietic progenitor cell transplantation (AHPCT) in malignant hematological disorders (Hodgkin's disease / non-Hodgkin's lymphoma).

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

Do not use Carmustine Accord

• if you are allergic to carmustine or any of the other ingredients of this medicine (listed in section 6);
• if you have bone marrow suppression, resulting in a reduced number of platelets, white blood cells (leukocytes), or red blood cells (erythrocytes), either as a result of chemotherapy or for other reasons;
• if you have severe kidney impairment;
• in children and adolescents;
• if you are breastfeeding.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting treatment with Carmustine.

The main side effect of this medicine is delayed bone marrow suppression, which can cause fatigue, bleeding from the skin and mucous membranes, infections, and fever as a result of changes in the blood. Therefore, your doctor will monitor your blood counts every week for at least 6 weeks after each dose. Following the recommended dosage, carmustine cycles will not be administered more frequently than every 6 weeks. The dosage will be confirmed with the blood count.

Before treatment, liver, lung, and kidney function will be evaluated and monitored periodically during treatment.

Since the use of carmustine can cause lung damage, a chest X-ray and lung function tests will be performed before starting treatment (see also the section "Possible side effects").

High-dose treatment with Carmustine Accord (up to 600 mg/m2) is only performed in combination with subsequent stem cell transplantation. Such a high dose may increase the frequency or severity of pulmonary, renal, hepatic, cardiac, and gastrointestinal toxicities, as well as infections and electrolyte imbalances (low levels of potassium, magnesium, and phosphate in the blood).

Abdominal pain (neutropenic enterocolitis) may occur as an adverse event related to therapy after treatment with chemotherapeutic agents.

Your doctor will inform you about the possibility of lung damage and allergic reactions and their symptoms. If these symptoms occur, you should contact your doctor immediately (see section 4).

Children and adolescents

Carmustine should not be used in children and adolescents under 18 years of age.

Other medicines and Carmustine Accord

Tell your doctor if you are taking, have recently taken, or might take any other medicines, including those obtained 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 if you have an abnormal heart rhythm.
• Melphalan, an anticancer medicine.

Using Carmustine Accord with alcohol

The amount of alcohol present in this medicine may alter the effects of other medicines.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy and fertility

Carmustine should not be used during pregnancy because it may harm the fetus.

Therefore, this medicine should not be administered to pregnant women. If it is used during pregnancy, the patient should be aware of the possible risk to the fetus. Women of childbearing age are advised to use effective contraceptive methods to avoid becoming pregnant during treatment with this medicine and for at least 6 months after the end of treatment.

Male patients should use adequate contraceptive methods during treatment with carmustine and for at least 6 months after the end of treatment to avoid getting their partners pregnant.

Breastfeeding

Do not breastfeed while taking this medicine and for 7 days after treatment. The risk to newborns/infants cannot be excluded.

Driving and using machines

Carmustine has no or negligible influence on the ability to drive and use machines. You should talk to your doctor before driving or using tools or machines, as the amount of alcohol in this medicine may affect your ability to drive or use machines.

Carmustine Accord contains ethanol (alcohol)

This medicine contains 2.37 g of ethanol (alcohol) per vial, which is equivalent to 33.86 mg/kg. The amount in the maximum dose of this medicine (600 mg/m2) 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 use machinery. This is because it may affect your judgment and reaction speed.

If you have epilepsy or liver problems, talk to your doctor or pharmacist before taking this medicine.

The amount of alcohol in this medicine may alter the effects of other medicines. Talk to your doctor or pharmacist if you are taking other medicines.

If you are pregnant or breastfeeding, talk to your doctor or pharmacist before taking this medicine.

If you have a history of alcoholism, talk to your 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 Accord

Carmustine will always be administered by a healthcare professional with experience in the use of anticancer medicines.

Adults

The dosage depends on the disease, body size, and response to treatment. It is usually administered at least every 6 weeks. The recommended dose of carmustine as monotherapy in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. This amount can be administered in a single dose or divided into daily infusions of 75 to 100 mg/m2 over two consecutive days. The dosage will also depend on whether carmustine is administered with other anticancer medicines.

The doses will be adjusted according to your response to treatment.

The recommended dose of carmustine administered in combination with other anticancer substances before autologous stem cell transplantation is 300 to 600 mg/m2 intravenously.

Blood counts will be monitored frequently to avoid bone marrow toxicity and the dose will be adjusted if necessary.

Method of administration

After reconstitution and dilution, carmustine is administered intravenously through a drip (intravenously) over a period of one to two hours, protected from light. The infusion duration should not be less than one hour to avoid burning and pain at the injection site. The injection site will be monitored during administration.

The duration of treatment will be determined by your doctor and may vary for each patient.

If you use more Carmustine Accord than you should

Since it will be your doctor or nurse who administers this medicine to you, it is unlikely that you will receive an incorrect dose. Tell your doctor or nurse if you have any doubts about the amount of medicine you have received.

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

4. Possible side effects

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

Tell your doctor or nurse immediately if you experience any of the following side effects:

Sudden wheezing, difficulty breathing, swelling of the eyelids, face, or lips, rash, or itching (especially if it affects the whole body) and feeling faint. These may be signs of a severe allergic reaction.

Carmustine may cause the following side effects:

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

• Late bone marrow suppression (decrease in blood cells in the bone marrow) which can increase the risk of infections if white blood cells are reduced
• Ataxia (lack of voluntary muscle coordination)
• Dizziness
• Headaches
• Transient eye redness, blurred vision due to retinal hemorrhage
• Hypotension (low blood pressure)
• Phlebitis (inflammation of the veins) associated with pain, swelling, redness, sensitivity
• Respiratory disorders (related to the lungs) with breathing difficulties;
• This medicine may cause severe lung damage (potentially life-threatening). Lung damage can occur years after treatment. Tell your doctor immediately if you experience any of the following symptoms: difficulty breathing, persistent cough, chest pain, persistent weakness/tiredness

• Severe nausea and vomiting
• When used on the skin, skin inflammation (dermatitis)
• Accidental contact with the skin can cause transient hyperpigmentation (darkening of a skin or nail area)

Common(may affect up to 1 in 10 people)

• Acute leukemias and bone marrow dysplasias (abnormal development of the bone marrow). Some of the symptoms are gum bleeding, bone pain, fever, frequent infections, frequent or severe nosebleeds, swelling of lymph nodes in the neck, armpits, abdomen, or groin, pallor, difficulty breathing, weakness, fatigue, or general decrease in energy.

• Anemia (reduced number of red blood cells in the blood)
• Encephalopathy (brain disorder). This can include symptoms of muscle weakness in one area, decreased ability to make decisions or concentrate, involuntary contractions, tremors, difficulty speaking or swallowing, seizures;
• Anorexia
• Constipation
• Diarrhea
• Inflammation of the mouth and lips
• Reversible liver toxicity with high-dose treatment. This can cause an increase in liver enzymes and bilirubin (detected by blood tests)
• Alopecia (hair loss)
• Skin redness
• Injection site reactions

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

• Venous occlusive disease (progressive blockage of small veins) in the liver, which can include symptoms of fluid accumulation in the abdomen, liver enlargement, severe bleeding from the esophagus, yellowing of the skin and the whites of the eyes.
• Respiratory problems caused by interstitial fibrosis (at lower doses)
• Kidney problems
• Gynecomastia (breast growth in males)

Frequency not known(cannot be estimated from the available data)

• Muscle pain
• Seizures (including status epilepticus)
• Tissue damage due to leakage at the injection site
• Any sign of infection
• Infertility
• Carmustine has been shown to have a negative effect on fetal development.
• Electrolyte imbalances (and alterations in electrolyte balance (low levels of potassium, magnesium, and phosphate in the blood))

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if it is not listed in this leaflet. You can also report side effects directly through the Spanish Medicines Monitoring System for Human Use: https://www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Carmustine Accord

This medicine will be stored by your doctor or healthcare professional.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after "EXP". The expiry date refers to the last day of the month stated.

Store and transport refrigerated (between 2°C and 8°C).

Store in the original packaging to protect from light.

After reconstitution (reconstituted mother solution)

The physical and chemical stability of the reconstituted mother solution has been demonstrated for 24 hours at 2-8 °C.

After dilution (solution for infusion after dilution)

The chemical and physical stability of the solution after dilution for infusion in 500 ml of sodium chloride injection solution or 5% glucose injection solution and stored in a glass or polypropylene container for 4 hours at a temperature of 20 to 25 °C, protected from light, has been demonstrated. These solutions will also remain stable for 24 hours** in the refrigerator (2 to 8 °C) and for another 3 hours at 20 to 25 °C, protected from light.

From a microbiological point of view, unless the method of opening, reconstitution, and dilution precludes the risk of microbiological 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 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. This will help protect the environment.

**The in-use storage time of 24 hours for the final diluted solution is the total time that carmustine is in solution, including the time it takes to reconstitute using 3 ml of ethanol and 27 ml of water for injection preparations.

6. Container contents and additional information

Composition of Carmustina Accord

The active ingredient is carmustine.

Each 30 ml vial of powder for concentrate for solution for infusion contains 100 mg of carmustine.

Each vial of solvent contains 3 ml of anhydrous ethanol.

After reconstitution with the solvent and dilution in 27 ml of water for injectable preparations, one ml of solution contains 3.3 mg of carmustine.

The other ingredients are:

• Powder: Does not contain excipients
• Solvent: Anhydrous ethanol

Appearance of Carmustina Accord and container contents

Carmustina Accord is a powder and solvent for concentrate for solution for infusion. The pale yellow or solidified dry mass lyophilized flakes are supplied in a 30 ml amber glass vial closed with a gray bromobutyl rubber stopper and sealed with an aluminum cap with a polypropylene top.

The solvent is a clear, colorless liquid supplied in a 5 ml clear glass vial closed with a fluorotec-coated butyl rubber stopper and sealed with an aluminum cap with a polypropylene top.

Package sizes: The package contains 1 vial with 100 mg of powder and 1 vial with 3 ml of solvent.

The package contains 10 vials with 100 mg of powder and 10 vials with 3 ml of solvent.

Only some package sizes may be marketed.

Marketing authorization holder and manufacturer

Marketing authorization holder

Accord Healthcare S.L.U.

World Trade Center. Moll de Barcelona, s/n,

Edifici Est, 6ª planta. 08039, Barcelona.

Spain

Manufacturer:

Accord Healthcare Polska Sp.z o.o.

ul. Lutomierska 50,

95-200 Pabianice, Poland

Or

Laboratori Fundació Dau

C/ C, 12-14 Pol. Ind.

Zona Franca, Barcelona, 08040, Spain

Or

Accord Healthcare B.V.

Winthontlaan 200, 3526KV Utrecht

Netherlands

This medicinal product has been authorized in the Member States of the European Economic Areawith the following names

Date of last revision of this leaflet:September 2024

Detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS)http://www.aemps.gob.es

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This information is intended only for healthcare professionals

This information is a brief description of the preparation and/or handling, incompatibilities, dosage of the medicinal product, overdose or monitoring measures and laboratory tests based on the current technical data sheet.

Carmustina Accord is a powder and solvent for concentrate for solution for infusion that does not contain preservatives and is not designed as a multiple-dose vial. It should be handled with care and skin contact with the medicinal product should be avoided. Reconstitution and subsequent dilutions should be performed under aseptic conditions.

Following the recommended storage conditions, it is possible to avoid the degradation of the unopened vial until the expiration date indicated on the packaging.

Storage of carmustine at 28 °C or higher may cause the liquefaction of the substance, as the melting point of carmustine is low (around 28.0 to 29.0 °C). When inspected with bright light, the oily film seen at the bottom of the vial is a sign of deterioration. Deteriorated medicinal product should not be used. Flakes with sharp edges and a solid mass may be seen in unopened vials without carmustine having decomposed.

Reconstitution and dilution of the powder for concentrate for solution for infusion

Dissolve carmustine (100 mg of powder) with 3 ml of the anhydrous ethanol refrigerated sterile solvent supplied in the primary packaging (amber glass vial). Carmustine should be completely dissolved in ethanol before adding sterile water for injectable preparations. The dilution of the powder may take 3 minutes. Then, add 27 ml of sterile water for injectable preparations aseptically to the alcohol solution. The 30 ml parent solution should be mixed well.

One ml of reconstituted parent solution contains 3.3 mg of carmustine in 10% ethanol and has a pH of 4.0 to 6.8.

Reconstitution, following the recommendations, results in a practically particle-free, yellowish solution.

The 30 ml of parent solution must be immediately diluted by adding the 30 ml of parent solution to either 500 ml of sodium chloride 9 mg/ml (0.9%) injectable solution or 500 ml of 5% glucose injectable solution.

Mode of administration:

Carmustina Accord is used intravenously after reconstitution and subsequent dilution.

When reconstituting the powder with the sterile solvent (3 ml vial) provided, a solution should be prepared by adding 27 ml of additional sterile water for injectable preparations, resulting in a yellowish parent solution. The parent solution should be further diluted with 500 ml of sodium chloride 9 mg/ml (0.9%) injectable solution or 500 ml of 5% glucose injectable solution.

The resulting ready-to-use infusion solution should be administered immediately by intravenous drip over a period of one to two hours, protected from light. The infusion duration should not be less than one hour to avoid burning and pain at the injection site. The injected area should be monitored during administration.

Pregnant personnel should not handle this medicinal product.

Guidelines for the correct handling and disposal of antineoplastics should be followed.

Dosage and laboratory tests

Initial doses

The recommended dose of Carmustina Accord as monotherapy in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. This amount can be administered in a single dose or divided into daily infusions of 75 to 100 mg/m2 over two consecutive days.

When Carmustina Accord is used in combination with other myelosuppressive medicinal products or in patients in whom the bone marrow reserve is depleted, the doses should be adjusted according to the patient's hematological profile, as shown below.

Monitoring and subsequent doses

A new cycle of Carmustina Accord should not be administered until the circulating blood elements have recovered to acceptable levels (platelets above 100,000/mm3, white blood cells above 4,000/mm3), and this usually occurs in six weeks. Blood counts should be monitored frequently, and repeat cycles should not be administered before six weeks due to delayed hematologic toxicity.

Subsequent doses to the initial dose should be adjusted according to the patient's hematological response to the previous dose, both as monotherapy and in combination with other myelosuppressive medicinal products. The following scheme is suggested as a guide for dose adjustment:

Table

In cases where the nadir of white blood cells and platelets after the initial dose is not in the same row (e.g., white blood cells > 4,000 and platelets <25,000), the value corresponding to the lowest percentage of the previous dose should be used (e.g., if the platelet value is <25,000, a maximum of 50% of the previous dose should be administered).

Pre-TCHP conditioning treatment

Carmustine is administered in combination with other chemotherapeutic agents in patients with malignant hematological diseases before TCHP at a dose of 300 mg/m2 to 600 mg/m2 intravenously.

Special populations

Pediatric population

Carmustine should not be used in children and adolescents under 18 years of age for safety reasons.

Elderly patients

In general, the dose for an elderly patient should be selected with caution, usually starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medicinal product treatment. Since elderly patients are more likely to have decreased renal function, dose selection should be cautious, and glomerular filtration should be monitored, and the dose reduced according to this.

Renal impairment

In patients with renal impairment, the dose of Carmustina Accord should be reduced if glomerular filtration is decreased.

Compatibility/Incompatibility with containers

The intravenous solution is unstable in polyvinyl chloride containers. All plastics that come into contact with the carmustine infusion solution (e.g., infusion equipment, etc.) should be PVC-free polyethylene; otherwise, glass containers should be used.