CARMUSTINE MEDAC 100 mg POWDER AND SOLVENT FOR CONCENTRATE FOR PERFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Carmustine medac 100 mg powder and solvent for concentrate for solution for infusion

EFG

carmustine

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 they are not listed in this leaflet. See section 4.

Contents of the pack

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

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

Carmustine medac 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 for the following malignant neoplasias in monotherapy or in combination with other antineoplastic agents and/or other therapeutic measures (radiotherapy, surgery):

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

2. What you need to know before you take Carmustine medac

Do not use Carmustine medac:

• 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 and, as a result, have a reduced number of platelets, white blood cells (leukocytes), or red blood cells (erythrocytes), either due to chemotherapy or other causes;
• if you have severe kidney failure;
• in children and adolescents;
• if you are breastfeeding.

Warnings and precautions

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

The main side effect of this medicine is delayed bone marrow suppression, which can manifest as 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 medac 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 medac 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").

Treatment with high doses of Carmustine medac (up to 600 mg/m2) is only performed in combination with subsequent stem cell transplantation. These high doses can increase the frequency or severity of pulmonary, renal, hepatic, cardiac, and gastrointestinal toxicities, as well as infections and changes in electrolyte balance (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 appear, you should contact your doctor immediately (see section 4).

Children and adolescents

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

Other medicines and Carmustine medac

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription.

• 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.

Carmustine medac 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 taking this medicine.

Pregnancy and fertility

Carmustine medac 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 six months after the end of treatment.

Male patients should use adequate contraceptive methods during treatment with Carmustine medac 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

The influence of Carmustine medac on the ability to drive and use machines is negligible or non-existent. You should talk to your doctor before driving or using tools or machines, as the amount of alcohol contained in this medicine may affect your ability to drive or use machines.

Carmustine medac contains ethanol (alcohol)

This medicine contains 2.4 g of alcohol (ethanol) per vial, which is equivalent to 25.92 g per dose (10% v/v). The amount in the maximum dose (600 mg/m2 in a 70 kg patient) of this medicine is equivalent to 648 ml of beer or 259 ml of wine.

The amount of alcohol in this medicine may affect your ability to drive or use machinery, as 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, talk to your doctor or pharmacist before taking this medicine.

If you have an alcohol addiction, talk to your doctor or pharmacist before taking this medicine.

3. How to take Carmustine medac

Carmustine medac 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 medac as monotherapy in previously untreated patients is 150 to 200 mg/m2 by intravenous infusion every 6 weeks. This dose 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 medac is administered with other anticancer medicines.

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

The recommended dose of Carmustine medac administered in combination with other chemotherapeutic agents before hematopoietic progenitor cell transplantation is 300-600 mg/m2 by intravenous infusion.

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 medac is administered intravenously by infusion, protected from light, over a period of one to two hours. 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 medac than you should

Since it will be your doctor or nurse who administers this medicine, 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 of fainting. These may be signs of a severe allergic reaction.

Carmustine medac can cause the following side effects:

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

• Delayed bone marrow suppression (decrease in blood cells in the bone marrow) which can increase the risk of infections if white blood cells decrease
• Ataxia (lack of voluntary muscle coordination)
• Dizziness
• Headaches
• Transient eye redness, blurred vision due to retinal hemorrhage
• Hypotension (low blood pressure)
• Phlebitis (vein inflammation) associated with pain, swelling, redness, sensitivity
• Respiratory disorders (related to the lungs) with respiratory problems This medicine can cause severe (potentially fatal) lung damage. 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/fatigue
• 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 area or nails)

Common(may affect up to 1 in 10 people)

• Acute leukemias and bone marrow dysplasias (abnormal development of the bone marrow) after prolonged use. Some of the symptoms are gum bleeding, bone pain, fever, frequent infections, frequent or severe nosebleeds, swelling of lymph nodes in and around the neck, armpits, abdomen, or groin, paleness, difficulty breathing, weakness, fatigue, or general decrease in energy.
• Anemia (decrease in the 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
• Mouth and lip inflammation
• Reversible liver toxicity with high-dose treatment. This can cause an increase in liver enzymes and bilirubin (detected by blood tests)
• Alopecia (hair loss)
• Redness of the skin
• 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 can include symptoms of: fluid accumulation in the abdomen, enlargement of the spleen, severe bleeding from the esophagus, yellowing of the skin and the whites of the eyes.
• Respiratory problems caused by interstitial fibrosis (with 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 disturbances (and changes 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 they are not listed in this leaflet. You can also report side effects directly through the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Carmustine medac

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 is the last day of the month stated.

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

Store the vial and ampoule in the outer packaging to protect them from light.

After reconstitution and dilution

After reconstitution, Carmustine medac is stable for 3 hours when stored in a glass container and protected from light.

The solution should be administered within 3 hours of reconstitution and dilution of the product. The solution should remain 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.

6. Container Contents and Additional Information

Composition of Carmustina medac

• The active ingredient is carmustine.
• Each vial of powder for concentrate for solution for infusion contains 100 mg of carmustine.
• After reconstitution and dilution, one ml of solution contains 3.3 mg of carmustine.
• Excipients:
• Powder: does not contain excipients.
• Solvent: anhydrous ethanol.

Appearance of the Product and Container Contents

Carmustina medac is a powder and solvent for concentrate for solution for infusion.

The powder is a white to light yellow powder that is supplied in a brown glass vial.

The solvent is a clear, colorless liquid supplied in a transparent glass ampoule.

A container of Carmustina medac contains one vial with 100 mg of powder and one ampoule with 3 ml of solvent.

Marketing Authorization Holder and Manufacturer

medac

Gesellschaft für klinische Spezialpräparate mbH

Theaterstr. 6

22880 Wedel

Germany

Phone: +49 4103 8006-0

Fax: +49 4103 8006-100

e-mail: contact@medac.de

Date of Last Revision of this Leaflet: 08/2024

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/ema/.

--------------------------------------------------------------------------------------------------------------------

This information is intended solely 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 explorations based on the current summary of product characteristics.

The powder of Carmustina medac for concentrate for solution for infusion does not contain preservatives and is not designed as a multiple-dose vial. Reconstitution and subsequent dilutions should be performed under aseptic conditions.

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

The lyophilized product does not contain preservatives and is only suitable for single use. The lyophilized product may appear as a fine powder, but handling may make it appear as a heavier and more granular lyophilized product instead of a powdered lyophilized product due to the mechanical instability of the lyophilized powder for suspension. The presence of an oily film may be an indication of the melting of the medicinal product. These products are not valid for use due to the risk of temperature deviations above 30 °C. This medicinal product should no longer be used. When there are doubts about whether the product has been properly refrigerated, each vial in the box should be inspected immediately. For verification, hold the vial up to a strong light.

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

Dissolve the 100 mg of carmustine powder for concentrate for solution for infusion with 3 ml of the anhydrous ethanol solvent provided in the primary packaging (brown glass vial). The carmustine should be completely dissolved in ethanol before adding sterile water for injectable preparations. Then, add 27 ml of sterile water for injectable preparations to the alcohol solution in a sterile manner. The 30 ml parent solution should be mixed well. Reconstitution, following the recommendations, results in a clear, colorless, or light yellow parent solution.

The 30 ml parent solution should be diluted immediately by adding 30 ml of parent solution to 500 ml of glucose 50 mg/ml (5%) injectable solution or to 500 ml of sodium chloride 9 mg/ml (0.9%) injectable solution in glass containers. The 530 ml diluted solution (i.e., the solution ready for use) should be mixed for at least 10 seconds before administration.

The pH and osmolarity of the ready-to-use infusion solutions are:

pH 4.0 to 5.0 and 385-397 mOsm/l (if diluted in glucose 50 mg/ml [5%] injectable solution) and

pH 4.0 to 6.8 and 370-378 mOsm/l (if diluted in sodium chloride 9 mg/ml [0.9%] injectable solution).

Method of Administration

The reconstituted and diluted solution (i.e., the solution ready for use) should be administered intravenously by drip infusion over a period of one to two hours; administration should be completed within 3 hours following reconstitution/dilution of the medicinal product. The infusion should be administered with a PE infusion set without PVC. During administration of the medicinal product, the container should be made of suitable glass. Additionally, the ready-to-use solutions should be protected from light (e.g., by wrapping the container of the ready-to-use solution with aluminum foil) and stored preferably at temperatures below 20-22 °C, as carmustine degrades more rapidly at higher temperatures.

The infusion should be administered with a PE infusion set without PVC.

Infusion of Carmustina medac over shorter periods may produce intense pain and burning at the injection site. The injection site should be monitored during administration.

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

Dosage and Laboratory Tests

Initial Doses

The recommended dose of Carmustina medac 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 medac 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 medac 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 hematological 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:

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).

There are no limits to the treatment period with carmustine. In case the tumor remains incurable or severe or intolerable adverse reactions occur, treatment with carmustine should be discontinued.

Preparative Treatment before HSCT

In patients with malignant hematological disorders, before HSCT, carmustine is administered in combination with other chemotherapeutic agents at a dose of 300-600 mg/m2 intravenously.

Special Populations

Pediatric Population

Carmustina should not be used in children under 18 years of age for safety reasons.

Elderly Patients

Generally, 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 concomitant disease or other medicinal product treatment. Since elderly patients are more likely to have decreased renal function, the dose should be selected with caution, and glomerular filtration should be monitored, and the dose reduced accordingly.

Renal Impairment

In patients with renal impairment, the dose of Carmustina medac 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 made of PVC-free polyethylene; otherwise, glass containers should be used.