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

Patient Information Leaflet

Introduction

Patient Information Leaflet

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

Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist or nurse.
• If you experience any adverse reactions, consult your doctor or nurse, even if they are adverse reactions not listed in this leaflet. See section 4.

Package leaflet

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

1. What Carmustina Glenmark is and what it is used for

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

Carmustine is indicated in 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, meduloblastoma, astrocytoma, and ependymoma), brain metastases.
• Multiple myeloma (a malignant tumor originating in the bone marrow) in combination with other antineoplastic medicines and glucocorticoids, particularly prednisone.
• Second-line treatment in Hodgkin’s disease and non-Hodgkin lymphoma.
• As conditioning treatment prior to autologous hematopoietic stem cell transplantation (HSCT) in malignant hematological disorders (Hodgkin’s disease / non-Hodgkin lymphoma).
• Malignant gastrointestinal tract tumors at advanced stages, after failure of other cell growth-inhibiting medicines.

2. What you need to know before using Carmustine Glenmark

Do not use Carmustine Glenmark

• if you are allergic to carmustine (BCNU), other nitrosoureas, or any of the other ingredients of this medicine (listed in section 6).
• if you have bone marrow suppression resulting in low levels of platelets, white blood cells (leukocytes), or red blood cells (erythrocytes), whether due to chemotherapy or other causes.
• if you have severe renal 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 adverse effect of this medicine is delayed bone marrow suppression, which may present as fatigue, skin and mucosal bleeding, infections, and fever due to blood abnormalities. Therefore, your doctor will monitor your blood counts weekly 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 based on blood counts.

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

Since carmustine may cause lung injury, a chest X-ray and pulmonary function tests will be performed before starting treatment (see also section “Possible side effects”).

High-dose carmustine treatment (up to 600 mg/m²) is only performed in combination with subsequent stem cell transplantation. Such high doses 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 following treatment with chemotherapeutic agents.

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

Take special care when using Carmustine Glenmark

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

Carmustine may have harmful effects on genetic material. Male patients treated with carmustine will be advised to use effective contraception during treatment and for at least 6 months after completion of treatment. They should also be advised to seek information about sperm preservation before treatment due to the possibility of permanent (irreversible) infertility caused by carmustine therapy.

Women must not become pregnant during treatment with carmustine.

Carmustine must not be administered to patients with low platelet (thrombocyte), white blood cell (leukocyte), or red blood cell (erythrocyte) counts, whether due to chemotherapy or other causes.

In patients whose bone marrow reserve is depleted due to disease or prior treatments, an increased risk of adverse reactions such as reduced white blood cell and platelet counts (leukopenia or thrombocytopenia) may be expected.

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

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

Patients with serious concomitant diseases and advanced stages of illness are at higher risk of adverse effects. This is particularly important in elderly patients.

Special instructions before starting treatment

Patients should be warned about symptoms of low white blood cell count (fever with granulocytopenia) or low platelet count (skin bleeding (petechiae) and other bleeding with thrombocytopenia). You should contact your doctor if these effects occur.

Before starting carmustine treatment, patients should be informed about possible gastrointestinal disturbances such as nausea or vomiting.

Patients should be warned about possible pulmonary toxicity and allergic reactions and their symptoms. You should contact your doctor if these effects occur.

Children and adolescents

Carmustine must 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 need to 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.

An increased risk of adverse reactions such as reduced platelet or white blood cell counts (thrombocytopenia and leukopenia) may be expected when used in combination with other myelosuppressive medicines (medicines that suppress blood cell formation 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 for excessive gastric acid production).

Cross-resistance may be expected with concomitant treatment using other alkylating agents (cytostatic agents) such as chlorambucil and cyclophosphamide.

Use of 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 plan to become pregnant, consult your doctor or pharmacist before using this medicine.

Pregnancy

Carmustine may cause genetic damage and harm embryonic/fetal development.

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

Therefore, this medicine should not normally be given to pregnant women. If used during pregnancy, the patient must be aware of the potential risk to the fetus. Women of childbearing potential should use effective contraceptive methods to avoid pregnancy during treatment with this medicine and for at least 6 months after completion of treatment.

Male patients must use adequate contraception during carmustine treatment and for at least 6 months after completion of treatment to prevent their partners from becoming pregnant.

Breastfeeding

You must not breastfeed while taking this medicine and for 7 days after treatment. Risk to newborns/infants cannot be excluded.

Fertility

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

Driving and using machines

The influence of carmustine on the ability to drive and use machines is negligible or minor. You should consult your doctor before driving or operating tools or machinery, as the amount of alcohol in this medicine may affect your ability to drive or operate machines.

Carmustine Glenmark contains ethanol (alcohol)

This medicine contains 2.4 g of alcohol (ethanol) per vial, 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, as it may impair 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 are alcohol-dependent, consult your doctor or pharmacist before taking this medicine.

3. How to use Carmustine Glenmark

Carmustine will always be administered by a healthcare professional experienced 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 administered intravenously every 6 weeks. This dose may be given as a single infusion or divided into daily infusions of 75 to 100 mg/m² on two consecutive days. The dosage may also vary depending on whether carmustine is administered in combination with other anticancer medications.

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

The recommended dose of carmustine when administered in combination with other anticancer agents prior to hematopoietic 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.

Route of administration

After reconstitution and dilution, carmustine is administered intravenously via an infusion set (intravenous infusion) 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 should be monitored during administration.

The duration of treatment will be determined by the physician and may vary for each patient.

More Carmustine Glenmark than you should have

Since a doctor or nurse will administer 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 about the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

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

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

Carmustine may cause the following adverse effects:

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

• Delayed myelosuppression (reduction in blood cells in the bone marrow), which may increase the risk of infections if white blood cells are reduced

• Ataxia (lack of voluntary coordination of muscle movements)

• Dizziness

• Headaches

• Transient eye redness, blurred vision due to retinal haemorrhage

• Hypotension (low blood pressure)

• Phlebitis (inflammation of the veins) associated with pain, swelling, redness, sensitivity

• Respiratory disorders (lung-related disorders) with breathing difficulties;

This medicine may cause severe (possibly fatal) lung damage. Lung injury may occur years after treatment. Inform 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 may cause transient hyperpigmentation (darkening of an area of skin or nails)

Common (may affect up to 1 in 10 people)

• Acute leukaemias and bone marrow dysplasias (abnormal bone marrow development). Some symptoms include bleeding gums, bone pain, fever, frequent infections, frequent or severe nosebleeds, lumps caused by swelling of lymph nodes in and around the neck, armpits, abdomen or groin, paleness, difficulty breathing, weakness, fatigue, or general decrease in energy.
  • Anaemia (reduction in the number of red blood cells in the blood)
  • Encephalopathy (brain disorder). This may include symptoms such as muscle weakness in one area, reduced ability to make decisions or concentrate, involuntary contractions, tremors, difficulty speaking or swallowing, seizures
  • Anorexia
  • Constipation
  • Diarrhoea
  • Inflammation of the mouth and lips
  • Reversible hepatic toxicity with high-dose treatment. This may cause increased liver enzymes and bilirubin (detected by blood tests)
  • Alopecia (hair loss)
  • Skin erythema (redness)
  • Reactions at the injection site

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

• Veno-occlusive disease (progressive blockage of veins), in which very small (microscopic) veins in the liver become blocked. Symptoms may include: fluid accumulation in the abdomen, enlarged spleen, severe bleeding from the oesophagus, yellowing of the skin and whites of the eyes
• Respiratory problems caused by interstitial fibrosis (with lower doses)
• Kidney problems
• Gynaecomastia (breast enlargement in males)
• Neuroretinitis (inflammation of the retina and optic nerve of the eye)
• Gastrointestinal tract bleeding

Frequency not known (cannot be estimated from available data)

• Secondary malignant neoplasms (cancers caused by radiotherapy or chemotherapy)
• Muscle pain
• Seizures, 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 abnormalities (and disturbances in electrolyte balance (low blood levels of potassium, magnesium and phosphate))
• Abdominal pain (neutropenic enterocolitis)

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, pharmacist or nurse, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicinal Products: https://www.notificaRAM.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Carmustine Glenmark

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 stated on the label and carton after "EXP". The expiry date refers to the last day of the month indicated.

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

After reconstitution and dilution

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

The solution should be administered within 3 hours after reconstitution and dilution of the product. The solution must remain protected from light until administration is complete.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and containers you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of Carmustine 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, one milliliter of solution contains 3.3 mg of carmustine.

• Other ingredients are:
• Powder: contains no excipients
• Solvent: anhydrous ethanol

Appearance of the medicinal product and contents of the container

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

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

The solvent is a transparent, colourless, mobile, volatile liquid supplied in a 5 ml transparent tubular Type I glass vial closed with a 20 mm rubber stopper and sealed with a 20 mm aluminium cap with a polypropylene disc.

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

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Marketing Authorization Holder and Manufacturing Responsible

Marketing Authorization Holder:

Glenmark Arzneimittel GmbH

Industriestr. 31

82194 Gröbenzell

Germany

Manufacturer responsible:

Pharmadox Healthcare Ltd

KW20A Kordin Industrial Park

Paola, PLA3000

Malta

For further information regarding this medicinal product, please contact 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 European Economic Area member states under the following names:

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

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

Date of the most recent review of this leaflet: November 2024.

Detailed information about this medicine is available on the website of the Spanish Agency of Medicines and Medical Devices (AEMPS) (http://www.aemps.gob.es).

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This information is intended for healthcare professionals only:

This information is a brief description of the preparation and/or handling, incompatibilities, dosage, overdose, or monitoring measures and supplementary laboratory tests based on the current summary of product characteristics.

Carmustine Glenmark is a powder for concentrate for solution for infusion that contains no preservatives and is not designed for multiple-dose use. Reconstitution and subsequent dilutions must be carried out under aseptic conditions.

If stored under the recommended storage conditions, degradation of the unopened vial can be avoided until the expiry date indicated on the packaging.

The lyophilized product contains no preservatives and is suitable for single use only. The lyophilized material may appear as a fine powder, but manipulation may cause it to appear as a heavier, clumped lyophilisate rather than a powdery form, due to mechanical instability of the lyophilized aggregate. The presence of an oily film may indicate melting of the medicinal product.

These products are not suitable for use due to the risk of temperature deviations above 30°C. This medicinal product should no longer be used. When there is any doubt regarding whether the product has been properly refrigerated, each vial in the pack should be inspected immediately. For verification, hold the vial up to a bright light.

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

Dissolve 100 mg of carmustine powder for concentrate for solution for infusion with 3 ml of sterile refrigerated ethanol solvent supplied in the primary packaging (brown glass vial). Carmustine must be completely dissolved in ethanol before adding sterile water for injections. Then, aseptically add 27 ml of sterile water for injections to the alcoholic solution. The resulting 30 ml stock solution must be thoroughly mixed. When reconstituted according to recommendations, a clear, colorless to pale yellow stock solution is obtained.

The 30 ml stock solution must be diluted immediately by adding 30 ml of the stock solution to either 500 ml of 50 mg/ml (5%) glucose injection solution or to 500 ml of 9 mg/ml (0.9%) sodium chloride injection solution in glass containers. The resulting 530 ml diluted solution (i.e., the ready-to-use solution) must be mixed for at least 10 seconds prior to administration.

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

pH 4.0 to 5.0 and 385–397 mOsmol/l (when diluted in 50 mg/ml [5%] glucose injection solution), and pH 4.0 to 6.8 and 370–378 mOsmol/l (when diluted in 9 mg/ml [0.9%] sodium chloride injection solution).

Method of administration

The reconstituted and diluted solution (i.e., the ready-to-use solution) must be administered intravenously as an intravenous infusion over a period of one to two hours; administration must be completed within 3 hours of reconstitution/dilution of the medicinal product. The infusion must be administered using a polyethylene (PE) infusion set free of PVC. During administration, the container must be made of suitable glass. In addition, ready-to-use solutions must be protected from light (e.g., by wrapping the container of the ready-to-use solution in aluminum foil) and preferably stored at temperatures below 20–22°C, as carmustine degrades more rapidly at higher temperatures.

The infusion must be administered using a polyethylene (PE) infusion set free of PVC.

Shorter infusion durations of carmustine may cause intense pain and burning at the injection site. The infusion site must be monitored during administration.

Standard guidelines for the safe handling and disposal of antineoplastic agents must be followed.

Dosage and supplementary laboratory tests

Initial dosing

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

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

Monitoring and subsequent dosing

A new cycle of carmustine must not be administered until circulating blood elements have recovered to acceptable levels (platelets above 100,000/mm³, white blood cells above 4,000/mm³), which generally occurs after six weeks. Blood counts should be monitored frequently, and repeated cycles must not be administered before six weeks due to delayed hematological toxicity.

Subsequent doses following the initial dose should be adjusted based on 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:

Nadir after previous dose	Percentage of previous dose to administer
Leukocytes/mm 3	Platelets/mm 3
> 4,000	>100,000	100%
3,000 – 3,999	75,000 – 99,999	100%
2,000 – 2,999	25,000 – 74,999	70%
<2,000	<25,000	50%

In cases where the nadir of leukocytes and platelets after the initial dose does not fall within the same row (e.g., leukocytes >4,000 and platelets <25,000), the value corresponding to the lower percentage of the previous dose should be used (e.g., if the platelet count is <25,000, a maximum of 50% of the previous dose should be administered).

There are no limits regarding the duration of carmustine treatment. If the tumor remains incurable or if severe or intolerable adverse reactions occur, carmustine treatment should be discontinued.

Preparative regimen prior to HSCT

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

Special populations

Pediatric population

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

Elderly patients

In general, dose selection for elderly patients should be cautious, usually starting at the lower end of the dosing range, reflecting the higher frequency of impaired hepatic, renal, or cardiac function, and of concomitant diseases or concomitant medication use. Since elderly patients are more likely to have decreased renal function, care should be taken when selecting the dose, glomerular filtration should be monitored, and the dose adjusted accordingly.

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 (PVC) containers. All plastics coming into contact with the carmustine infusion solution (e.g., infusion sets, etc.) must be made of polypropylene; otherwise, glass containers should be used.