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

Introduction

Package Leaflet: Information for the Patient

Carmustine Teva 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 or nurse.

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

1. What is Carmustine Teva 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 neoplasms as monotherapy or in combination with other antineoplastic agents and/or other therapeutic measures (radiotherapy, surgery):

• brain tumors (glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma), brain metastases
• multiple myeloma (in combination with glucocorticoids such as prednisolone)
• second-line treatment in Hodgkin's disease and non-Hodgkin's lymphoma
• as conditioning treatment prior to autologous hematopoietic progenitor cell transplantation (HPCT) in malignant hematological diseases (Hodgkin's disease/non-Hodgkin's lymphoma)
• advanced tumors of the gastrointestinal tract after failure of other anticancer drugs.

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

Do not use Carmustine Teva

• if you are allergic to carmustine, other nitrosourea medicines or any of the other ingredients 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 problems;
• if you are breastfeeding.
• in children and adolescents;

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 changes in the blood. Therefore, your doctor will check 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 section "Possible side effects").

High-dose treatment with carmustine (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 disturbances (low potassium, magnesium, phosphate levels 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 should not be used in children and adolescents under 18 years of age.

Other medicines and Carmustine Teva

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.

Using Carmustine Teva 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 finishing treatment.

Male patients should use appropriate contraceptive methods during treatment with carmustine and for at least 6 months after finishing 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.

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 contained in this medicine may affect your ability to drive or use machines.

Carmustine Teva contains ethanol (alcohol)

This medicine contains 2.37 g of ethanol (alcohol) per vial, which is equivalent to 25.6 g per maximum dose (1080 mg). 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. 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, 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 use Carmustine Teva

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 by intravenous infusion 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 chemotherapeutic agents before hematopoietic progenitor cell transplantation is 300 to 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

For intravenous use

After reconstitution with sterile anhydrous alcohol (3 ml vial) and water for injections (27 ml) and subsequent dilution with 500 ml of sodium chloride 9 mg/ml (0.9%) injection solution or glucose 50 mg/ml (5%) injection solution, carmustine is administered intravenously by 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 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 Teva 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 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 get any of the following side effects:

Sudden wheezing, difficulty breathing, swelling of the eyelids, face or lips, rash or itching (especially if this affects your 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)

• Delayed bone marrow suppression (decrease in blood cells) which can increase the risk of infection if white blood cells are reduced
• Reduced platelet count in the blood, which can increase the risk of bleeding or bruising
• Ataxia (lack of voluntary coordination of muscle movements)
• Dizziness
• Headaches
• Eyelid problems, transient reddening of the eyes, 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 respiratory problems.

This medicine may cause severe lung damage (possibly fatal). Lung damage may 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).

Some of the symptoms are gum bleeding, bone pain, fever, frequent infections, frequent or severe nosebleeds, 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 (reduced red blood cell count)
• 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) at high doses, in which very small (microscopic) veins in the liver are blocked. This 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 (at lower doses)
• Kidney problems
• Gynecomastia (breast growth in males)

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

• Any sign of infection (opportunistic infections, including fatal outcome)
• Muscle pain
• Chest pain
• Fast heart rate (tachycardia)
• Seizures (fits), 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.
• Electrolyte disturbances (and electrolyte imbalance (low potassium, magnesium, phosphate levels in the blood))

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via 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 Teva

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.

Unopened vials with dry powder:

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

Store in the original packaging to protect from light.

After reconstitution and dilution

The solution should be administered within 4 hours after reconstitution and dilution of the medicine at room temperature or within 2 hours if the prepared solution is stored refrigerated (2 - 8°C) for 18 hours. 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 Content and Additional Information

Composition of Carmustina Teva

The active ingredient is: carmustine

Each vial of powder for concentrate for solution for infusion contains 100 mg of carmustine. After reconstitution with 3 ml of anhydrous ethanol and 27 ml of water for injectable preparations, 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 Content

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

Powder: Yellowish powder for reconstitution in a type I amber glass vial (30 ml) closed with a gray type I bromobutyl rubber stopper and sealed with a flip-off aluminum cap with a colored polypropylene disk.

Solvent: Transparent type I glass vial (4 ml) closed with a gray type I butyl rubber stopper and sealed with a metal aluminum cap with a colored polypropylene disk.

Each container contains one vial with 100 mg of powder (carmustine) and one vial with 3 ml of sterile solvent (anhydrous ethanol).

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Teva B.V.

Swensweg 5

2031GA Haarlem

Netherlands

Manufacturer:

S.C. Sindan Pharma, S.R.L.

11 Ion Mihalache Ave., the 1st district

Bucharest, 011171,

Romania

For further information about this medicinal product, please contact the local representative of the marketing authorization holder:

Teva Pharma, S.L.U

C/ Anabel Segura, 11, Edifício Albatros B, 1ª planta,

Alcobendas, 28108, Madrid (Spain)

Date of the last revision of this leaflet:February 2022

Other Sources of Information

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

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 summary of product characteristics.

The Carmustina Teva powder 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 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 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 supplied sterile anhydrous ethanol refrigerated solvent 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 to the alcohol solution in a sterile manner. The 30 ml mother solution should be mixed well. Reconstitution, following the recommendations, results in a clear, colorless or pale yellow mother solution, free from visible particles, which should be diluted immediately in 500 ml of 9 mg/ml (0.9%) sodium chloride injectable solution or 50 mg/ml (5%) glucose injectable solution in polypropylene containers. The diluted solution (i.e., the solution ready for use) should be mixed for at least 10 seconds before administration.

Prior to application, the infusion solution should be checked for precipitates. If precipitates are observed, they can be redissolved by warming the vial to room temperature with gentle agitation.

Carmustine has a low melting point (approximately 30.5-32.0 °C). Exposure of this medicinal product to this temperature or higher will cause the medicinal product to melt and appear as an oil film at the bottom of the vials. This is a sign of decomposition, and the vials should be discarded.

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

pH: 4.0 to 6.8

The osmolarity of the ready-to-use infusion solutions (if diluted in 50 mg/ml (5%) glucose injectable solution) or in 9 mg/ml (0.9%) sodium chloride injectable solution) is in the range of 360-390 mOsm/l.

Method of Administration

The ready-to-use solution should be administered intravenously by intravenous infusion over a period of one to two hours.

Administration should be completed within 4 hours of reconstitution/dilution of the medicinal product at room temperature or within 2 hours if the ready-to-use solution has been refrigerated (2-8°C) for 18 hours.

The infusion should be administered with a PVC-free PE infusion set. Additionally, the ready-to-use solutions should be protected from light (e.g., by wrapping the ready-to-use solution container with aluminum foil) and stored preferably at temperatures below 20-22 °C, as carmustine degrades more rapidly at higher temperatures.

Infusion of Carmustina Teva 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 antineoplastic agents should be followed.

Dosage and Laboratory Tests

Initial Doses

The recommended dose of Carmustina Teva 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 Teva is used in combination with other myelosuppressive agents or in patients in whom the bone marrow reserve is depleted, the doses should be adjusted based on the patient's hematologic profile, as shown below.

Monitoring and Subsequent Doses

A new cycle of Carmustina Teva 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 repeated cycles should not be administered before six weeks due to delayed hematologic toxicity.

Subsequent doses after the initial dose should be adjusted based on the patient's hematologic response to the previous dose, both as 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 treatment period with carmustine. If the tumor remains incurable or severe or intolerable adverse reactions occur, treatment with carmustine should be discontinued.

Conditioning Treatment before HPCT

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

Special Populations

Pediatric Population

Carmustina is contraindicated in children and adolescents under 18 years of age.

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 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 necessary.

Renal Impairment

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

Compatibility/Incompatibility with Containers

The intravenous solution is unstable in polyvinyl chloride containers. The carmustine solution can only be administered from glass vials or polypropylene containers. All plastics that come into contact with the carmustine infusion solution (e.g., infusion equipment, etc.) should be PVC-free polyethylene.