CARMUSTINE GLENMARK 100 mg POWDER AND SOLVENT FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Carmustine Glenmark 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.

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

1. What is Carmustine Glenmark 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 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.
• Multple myeloma (malignant tumor originating in the bone marrow) in combination with other antineoplastic medications and glucocorticoids, especially prednisone.
• Second-line treatment in Hodgkin's disease and non-Hodgkin's lymphoma.
• As conditioning treatment prior to autologous hematopoietic stem cell transplantation (HSCT) in malignant hematological disorders (Hodgkin's disease / non-Hodgkin's lymphoma).
• Malignant tumors of the gastrointestinal tract, in advanced stages, after failure of other cell growth inhibitor medications.

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

Do not use Carmustine Glenmark

• if you are allergic to carmustine (BCNU), other nitrosoureas, or any of the other components of this medicine (listed in section 6).
• if you have bone marrow suppression and, therefore, have 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 failure.
• in children and adolescents.
• if you are breastfeeding.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before you start using carmustine.

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 blood alterations. Therefore, your doctor will monitor your blood counts every week for at least 6 weeks after each dose. Following the recommended posology, carmustine cycles will not be administered more frequently than every 6 weeks. The posology 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").

Treatment with carmustine at high doses (up to 600 mg/m2) is only performed in combination with subsequent stem cell transplantation. Such a high dose can 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).

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

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

Be careful when using Carmustine Glenmark

The benefit versus the risk of toxicity should be carefully weighed, as with other antitumor agents.

Carmustine may have a harmful effect on genetic material. Male patients treated with carmustine should use effective contraceptive methods during treatment and for at least 6 months after completing treatment, as well as seek information about sperm preservation before treatment due to the possibility of permanent infertility (irreversible) caused by carmustine treatment.

Women should not become pregnant during treatment with carmustine.

Carmustine should not be administered to patients with a reduced platelet count (thrombocytes), white blood cells (leukocytes), or red blood cells (erythrocytes), either due to chemotherapy or for other reasons.

In patients whose bone marrow reserve is depleted due to the disease or previous treatments, an increase in adverse reactions such as a reduction in the number of white blood cells and platelets (leukopenia or thrombocytopenia) can be expected.

The injection site should be carefully monitored during infusion due to the risk of extravasation (loss of infusion solution from the vein to the surrounding tissues).

Your doctor will discuss with you the possibility of allergic reactions and their symptoms. You should contact your doctor immediately if these symptoms appear (see section "Possible side effects").

Patients with severe concomitant diseases and in advanced stages of the disease have a higher risk of presenting adverse effects. This is especially important in elderly patients.

Special instructions before starting treatment

Patients should be warned of the symptoms of a reduction in the number of white blood cells (fever with granulocytopenia) or a reduction in the number of platelets (bleeding in the skin (petechiae) and other bleeding with thrombocytopenia). They should see their doctor if these effects occur.

Before starting treatment with carmustine, patients should be warned of possible gastrointestinal discomfort such as nausea or vomiting.

Patients should be warned of possible lung toxicity and allergic reactions and their symptoms. They should see their doctor if these effects occur.

Children and adolescents

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

Other medicines and Carmustine Glenmark

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, a cancer medicine.

A increase in adverse reactions such as a reduction in the number of platelets or white blood cells (thrombocytopenia and leukopenia) can be expected in combination with other myelosuppressive medicines (medicines that suppress the formation of blood cells in the bone marrow) such as vincristine, methotrexate, cyclophosphamide, procarbazine, chlorambucil (nitrogen mustards), fluorouracil, vinblastine, actinomycin (dactinomycin), bleomycin, doxorubicin (adriamycin).

The myelosuppressive effect of carmustine may be increased by cimetidine (a medicine used in excessive gastric acid production).

A cross-resistance can be expected in concomitant treatment with other alkylating agents (cytostatic agents) such as chlorambucil and cyclophosphamide.

Using Carmustine Glenmark 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

Carmustine may cause genetic damage and harm to the fetus.

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 should use effective contraceptive methods to avoid becoming pregnant during treatment with this medicine and for at least 6 months after completing treatment.

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

Breastfeeding

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

Fertility

Carmustine may have a harmful effect on genetic material. Men treated with carmustine should seek information about sperm preservation before treatment due to the possibility of permanent infertility (irreversible) caused by carmustine treatment.

Driving and using machines

Carmustine has no or negligible influence on the ability to drive and use machines. You should consult 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 Glenmark contains ethanol (alcohol)

This medicine contains 2.4 g of alcohol (ethanol) per vial, which is equivalent to 25.92 g per maximum dose (10% volume). The amount in the maximum dose of this medicine (600 mg/m2 in a 70 kg patient) 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. This is because it may affect your judgment and reaction speed.

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

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

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

If you have a history of alcoholism, consult your doctor or pharmacist before taking this medicine.

3. How to use Carmustine Glenmark

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

Adults

The posology depends on the disease, body size, and response to treatment. It is usually administered at least every 6 weeks. The recommended dose of carmustine in monotherapy in previously untreated patients is 150 to 200 mg/m2 by intravenous route 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 posology 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 hematopoietic stem cell transplantation is 300 to 600 mg/m2 by intravenous route.

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

Route of administration

After reconstitution and dilution, carmustine is administered intravenously through a 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 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 Glenmark 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. Inform 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 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.

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 may 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) that can increase the possibility 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 (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 (possibly fatal). Lung damage may appear 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 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, lumps caused by swelling of the 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). It can include symptoms of muscle weakness in an 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 obstruction of the veins), in which very small (microscopic) veins in the liver are blocked. It 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)
• Neuroretinitis (inflammation of the retina and optic nerve of the eye)
• Gastrointestinal tract bleeding

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

• Secondary malignant neoplasms (cancers caused by radiotherapy or chemotherapy)
• Muscle pain
• Seizures (crises), including status epilepticus
• Tissue damage due to leakage at the injection site
• Infertility
• Carmustine has been shown to have a negative effect on fetal development
• Signs of infection
• Tachycardia, chest pain
• Electrolyte disturbances (and alterations in electrolyte balance (low levels of potassium, magnesium, and phosphate in the blood))
• Abdominal pain (neutropenic enterocolitis)

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 Pharmacovigilance System for Human Use Medicines: https://www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Carmustina Glenmark

This medicinal product will be stored by your doctor or healthcare professional. Keep this medicinal product out of the sight and reach of children.

Do not use this medicinal product 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 refrigerated (between 2°C and 8°C).

After reconstitution and dilution

After reconstitution, Carmustina Glenmark 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 the packaging and any unused medicinal products. This will help protect the environment.

6. Package contents and additional information

Composition of Carmustina Glenmark

• The active substance is carmustine.

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

After reconstitution and dilution, 1 ml of solution contains 3.3 mg of carmustine.

• The other ingredients are:
• Powder: does not contain excipients
• Solvent: anhydrous ethanol

Appearance of the product and package contents

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

The powder is a pale yellow flake or solidified mass that is supplied in a 30 ml type I amber glass vial closed with a 20 mm rubber stopper and sealed with a 20 mm flip-off aluminum cap with a polypropylene disc.

The solvent is a clear, colorless, mobile, volatile liquid supplied in a 5 ml type I tubular clear glass vial closed with a 20 mm rubber stopper and sealed with a 20 mm aluminum cap with a polypropylene disc.

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

Marketing authorization holder and manufacturer

Marketing authorization holder:

Glenmark Arzneimittel GmbH

Industriestr. 31

82194 Gröbenzell

Germany

Manufacturer:

Pharmadox Healthcare Ltd

KW20A Kordin Industrial Park

Paola, PLA3000

Malta

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

Glenmark Farmacéutica, S.L.U.

C/ Retama 7, 7th floor

28045 Madrid

Spain

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

Germany Carmustin Glenmark 100 mg Powder and solvent for concentrate for solution for infusion

Spain Carmustina Glenmark 100 mg powder and solvent for concentrate for solution for infusion EFG

Date of last revision of this leaflet:November 2024.

Detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Healthcare 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, posology of the medicinal product, overdose or monitoring and laboratory tests based on the current summary of product characteristics.

Carmustina Glenmark is a powder for concentrate for solution for infusion that does not contain preservatives and is not designed as a multiple-dose vial. Reconstitution and subsequent dilutions should be carried out under aseptic conditions.

Following the recommended storage conditions, it is possible to avoid decomposition of the unopened vial until the expiry date stated on the packaging.

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 cause it to appear as a heavier and more granular lyophilized product instead of a powdered lyophilized product due to the mechanical instability of the lyophilized aggregate. 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 sterile refrigerated ethanol solvent supplied in the primary packaging (amber glass vial). The carmustine should be completely dissolved in ethanol before adding the sterile water for injectable preparations. Then, add 27 ml of sterile water for injectable preparations aseptically to the alcohol solution. The 30 ml mother solution should be mixed well. Reconstitution, following the recommendations, results in a clear, colorless to pale yellow mother solution.

The 30 ml mother solution should be diluted immediately by adding 30 ml of mother solution to either 500 ml of glucose 50 mg/ml (5%) injectable solution or 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 mOsmol/l (if diluted in glucose 50 mg/ml [5%] injectable solution) and pH 4.0 to 6.8 and 370-378 mOsmol/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 by intravenous infusion over a period of 1 to 2 hours; administration should be completed within 3 hours of reconstitution/dilution of the medicinal product. The infusion should be administered with a PVC-free PE infusion set. 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 PVC-free PE infusion set.

Infusion of carmustine 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 proper handling and disposal of cytotoxics should be followed.

Posology and laboratory tests

Initial doses

The recommended dose of carmustine in monotherapy in previously untreated patients is 150 to 200 mg/m2 by intravenous infusion every 6 weeks. This dose may be administered in a single dose or divided into daily infusions of 75 to 100 mg/m2 over 2 consecutive days.

When carmustine is used in combination with other myelosuppressive agents 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 carmustine 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 6 weeks. Blood counts should be monitored frequently, and repeat cycles should not be administered before 6 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 in monotherapy and in combination with other myelosuppressive agents. 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 duration of treatment with carmustine. If the tumor remains incurable or severe or intolerable adverse reactions occur, treatment with carmustine should be discontinued.

Pre-treatment conditioning for HSCT

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

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 drug therapy. 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 as appropriate.

Renal impairment

In patients with renal impairment, the dose of carmustine 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 set, etc.) should be made of polypropylene; otherwise, glass containers should be used.