Label: Information for the Patient

Carmustine Teva 100 mg Powder and Diluent for Concentrate for Solution for Infusion EFG

Read this label carefully before starting to use this medication, because

it contains important information for you.

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

Carmustina is a medication that contains carmustin. Carmustin belongs to a group of anticancer medications, known as nitrosoureas, which act by slowing the growth of cancerous cells.

Carmustina is indicated for the following malignant neoplasias in monotherapy or in combination with other antineoplastic agents and/or other therapeutic measures (radiation therapy, surgery):

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

Do not use Carmustina Teva

• if you are allergic to carmustine, other nitrosoureas 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 (leucocytes) or red blood cells (erythrocytes), either as a result of chemotherapy or for other reasons;
• if you have severe kidney failure;
• if you are breastfeeding.
• in children and adolescents;

Warnings and precautions

Consult your doctor, pharmacist or nurse before starting to use Carmustina.

The main side effect of this medicine is delayed bone marrow suppression, which may manifest as fatigue, skin and mucous membrane bleeding, infections and fever as a result of blood abnormalities. Therefore, your doctor will monitor your blood counts every week for at least 6 weeks after each dose. Following the recommended dosage, carmustine cycles will not be administered at a frequency greater than every 6 weeks. Dosage will be confirmed with blood counts.

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

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

High-dose treatment with carmustine (up to 600 mg/m2) is only performed in combination with subsequent stem cell transplantation. A dose this high 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, phosphate in the blood).

Neutropenic enterocolitis may occur as an adverse event related to chemotherapy after treatment with this medicine.

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).

Children and adolescents

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

Other medicines and Carmustina Teva

Inform your doctor if you are taking, have taken recently or may need to take any other medicine, including those purchased 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.
• Melfalan, a cancer medicine.

Use of Carmustina Teva with alcohol

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

Pregnancy,breastfeeding and fertility

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor or pharmacist before using this medicine.

Pregnancy and fertility

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

Therefore, this medicine should not be administered to pregnant women normally. 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 suitable contraceptive methods during treatment with carmustine and for at least 6 months after completing treatment to avoid their partners becoming pregnant.

Breastfeeding

You should not breastfeed while taking this medicine and for 7 days after treatment. The risk cannot be ruled out in newborns/lactants.

Driving and operating machinery

The influence of carmustine on the ability to drive and use machines is negligible or insignificant. You should consult 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.

Carmustina 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, as 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, consult your doctor or pharmacist before taking this medicine.

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

Carmustina will always be administered by a healthcare professional with experience in the use of cancer medications.

Adults

The dosage will depend on the disease, body size, and response to treatment. It is usually administered at least every 6 weeks. The recommended dose of carmustina 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, 75 to 100 mg/m², over 2 consecutive days. The dosage will also depend on whether carmustina is administered with other cancer medications.

The doses will be adjusted based on your response to treatment.

The recommended dose of carmustina administered in combination with other chemotherapeutic agents before hematopoietic stem cell transplantation is 300 to 600 mg/m² by intravenous route.

Frequent blood counts will be monitored to avoid bone marrow toxicity and the dose will be adjusted as necessary.

Route of Administration

For intravenous use

After reconstitution with anhydrous sterile alcohol (3 ml vial) and water for injection (27 ml) and subsequent dilution with 500 ml of 9 mg/ml sodium chloride (0.9%) injectable solution or 50 mg/ml glucose (5%) injectable solution, carmustina is administered intravenously through infusion (intravenously), over a period of 1 to 2 hours protected from light. The duration of the infusion should not be less than 1 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 the doctor and may vary in each patient.

If you use more Carmustina Teva than you should

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

If you have any other questions about the use of this medication, ask your doctor, pharmacist, or nurse.

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

Inform 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 entire body) and feeling like you are going to faint. These may be signs of a severe allergic reaction.

Carmustine may cause the following side effects:

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

• Late myelosuppression (decrease in blood cells in the bone marrow) that may increase the risk of infections if white blood cells decrease
• Reduction of platelets in the blood, which may increase the risk of bleeding or bruising
• Ataxia (lack of voluntary coordination of muscle movements)
• Dizziness
• Headaches
• Eye problems, transient conjunctival redness, blurred vision due to retinal hemorrhage
• Hypotension (low blood pressure)
• Phlebitis (inflammation of veins) associated with pain, swelling, redness, and sensitivity
• Respiratory problems (related to the lungs) with respiratory difficulties

This medicine may cause a severe lung injury (possibly fatal). Lung injury may appear years after treatment. Inform your doctor immediately if you experience any of the following symptoms: difficulty breathing, persistent cough, chest pain, persistent weakness or fatigue

• Severe nausea and vomiting
• When used on the skin, inflammation of the skin (dermatitis)
• Accidental contact with the skin may 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 bone marrow)

Some symptoms include gum bleeding, bone pain, fever, frequent infections, frequent or severe nosebleeds, swollen lymph nodes in and around the neck, armpits, abdomen, or groin, pallor, 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 may include symptoms ofmuscle weaknessin a region, decrease in decision-making abilities orconcentration,involuntary contractions, tremors, difficultyspeakingorswallowing,seizures;
• Anorexia
• Constipation
• Dyspepsia
• Inflammation of the mouth and lips
• Reversible liver toxicity with high-dose treatment. This may cause an increase in liver enzymes and bilirubin (detected through blood tests)
• Alopecia (hair loss)
• Rubefaction of the skin
• Reactions at the injection site

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

• Thrombophlebitis (progressive obstruction of veins) at high doses, in which very small (microscopic) veins in the liver are blocked. It may include symptoms of: fluid accumulation in the abdomen, enlargement of the spleen, severe bleeding from the esophagus, yellow discoloration of the skin and white of the eyes.
• Respiratory problems caused by interstitial fibrosis (with lower doses)
• Renal problems
• Gynecomastia (breast growth in males)

Frequency not known(cannot be estimated from available data)

• Any sign of infection (opportunistic infections, including fatal outcome)
• Muscle pain
• Chest pain
• Accelerated heart rate (tachycardia)
• Seizures (crises), including status epilepticus
• Tissue damage due to leaks at the injection site
• Infertility
• Carmustine has been shown to negatively affect fetal development.
• Electrolyte anomalies (and alterations in electrolyte balance (low levels of potassium, magnesium, and phosphate in the blood))

Reporting of side effects

If you experience any type of side effect, consult your doctoror nurse, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through the Spanish Systemof Pharmacovigilance of Medicinal Products for Human Use:https://www.notificaRAM.es.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

This medication will be conserved by your doctor or healthcare professional.

Keep this medication out of sight and reach of children.

Do not use this medication after the expiration date that appears on the label and the box after “CAD”. The expiration date is the last day of the month indicated.

Unopened vials with dry powder:

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

Store in the original packaging to protect it from light.

After reconstitution and dilution

The solution must be administered within 4 hours after reconstitution and dilution of the medication at room temperature or within 2 hours if the prepared solution for use was kept refrigerated (2 - 8°C) for 18 hours.The solution must remain protected from light until the end of administration.

Medications should not be disposed of through drains or trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. This will help protect the environment.

Carmustine Teva Composition

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, 1 ml of solution contains 3.3 mg of carmustine.

Excipients:

Powder: No excipients

Solvent: Anhydrous ethanol

Appearance of the product and contents of the package

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

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

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

Each package contains a vial with 100 mg of powder (carmustine) and 1 vial with 3 ml of sterile solvent (anhydrous ethanol).

Marketing authorization holder and responsible manufacturer

Marketing authorization holder

Teva B.V.

Swensweg 5

2031GA Haarlem

Netherlands

Responsible manufacturer:

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

11 Ion Mihalache Ave., the 1st district

Bucarest, 011171,

Romania

For more information about this medicine, 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)

Last review date of this leaflet:February 2022

Other sources of information

The detailed information about this medicine is available on the website of theSpanish Agency for Medicines and Medical Devices (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 medicine, overdose or measures of vigilance and laboratory explorations based on the current technical file.

The Carmustine Teva powder for concentrate for solution for infusion does not contain preservatives and is not designed as a multi-dose vial. Reconstitution and subsequent dilutions must be performed in aseptic conditions.

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

The lyophilized product does not contain preservatives and is only suitable for single use. The lyophilized product may have the appearance of a fine powder, but handling may make it appear as a heavier and more lumpy lyophilized product instead of a powder lyophilized for suspension due to the mechanical instability of the lyophilized powder for suspension. The presence of an oily film may be an indication of the fusion of the medicine. These products are not valid for use due to the risk of temperature deviations greater than 30 °C.

This medicine is no longer to be used. When there are doubts about whether the product is correctly refrigerated, each vial in the box must be inspected immediately. For verification, hold the vial in a bright 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 anhydrous ethanol provided in the primary packaging (amber type I glass vial). Carmustine must be dissolved completely in ethanol before adding sterile water for injectable preparations.

Subsequently, add 27 ml of sterile water for injectable preparations to the alcohol solution. The 30 ml mother solution must be mixed well. Reconstitution, following the recommendations, results in a transparent, colorless, or light yellow mother solution, free of visible particles, which must be diluted immediately in 500 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or in glucose 50 mg/ml (5%) solution for injection in polypropylene containers. The diluted solution (i.e., the ready-to-use solution) must be mixed for at least 10 seconds before administration.

Before application, the infusion solution must 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 medicine to this temperature or higher will cause the medicine to liquefy and appear as an oily film at the bottom of the vials. This is a sign of degradation, and the vials must be discarded.

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

pH: 4.0-6.8

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

Administration form

The ready-to-use solution must be administered by intravenous infusion via a PE infusion set without PVC during a period of 1 to 2 hours.

Administration must be completed within 4 hours after reconstitution/dilution of the medicine at room temperature or within 2 hours if the ready-to-use solution was kept refrigerated (2-8°C) for 18 hours.

The infusion must be administered with a PE infusion set without PVC. In addition, the ready-to-use solutions must be protected from light (e.g., wrapping the container of the ready-to-use solution with aluminum foil) and preferably stored at temperatures below 20-22 °C, as carmustine degrades more rapidly at higher temperatures.

Infusion of Carmustine Teva for shorter periods may cause intense pain and burning at the injection site. The injection site must be monitored during administration.

Proper handling and disposal of antineoplastics must be followed.

Dosage and laboratory explorations

Initial doses

The recommended dose of Carmustine Teva in monotherapy in 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 2 consecutive days.

Carmustine Teva may be used in combination with other myelosuppressive drugs or in patients in whom the bone marrow reserve is exhausted. Doses must be adjusted based on the patient's hematological profile, as shown below.

Vigilance and subsequent doses

No new cycle of Carmustine Teva should be administered until the circulating blood elements have recovered to acceptable levels (platelets above 100,000/mm3, leukocytes above 4,000/mm3), and this occurs, in general, in 6 weeks. Blood counts must be monitored frequently, and no repeated cycles should be administered before 6 weeks due to delayed hematological toxicity.

Subsequent doses after the initial dose must be adjusted based on the patient's hematological response to the previous dose, both in monotherapy and in combination with other myelosuppressive drugs. The following scheme is suggested as a guide for adjusting the dose:

In cases where the nadir of leukocytes and platelets after the initial dose is not in the same row (e.g., leukocytes > 4,000 and platelets <25,000), the dose must be adjusted accordingly.

No limits are set for the duration of treatment with carmustine. If the tumor remains incurable or if severe or intolerable adverse reactions occur, treatment with carmustine must be discontinued.

Pre-transplant conditioning 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 by intravenous infusion.

Special populations

Pediatric population

Carmustine is contraindicated in children and adolescents under 18 years.

Geriatric population

In general, the dose for an elderly patient must be selected with caution, usually starting with the lower end of the dose range, which reflects the higher frequency of deterioration of liver, renal, or cardiac function, and concomitant diseases or treatment with other medications. Since elderly patients are more likely to have a decrease in renal function, care must be taken when selecting the dose, and renal filtration must be monitored and the dose reduced accordingly.

Renal insufficiency

In patients with renal insufficiency, the dose of Carmustine Teva must be reduced if glomerular filtration is decreased.

Compatibility/incompatibility with containers

The intravenous solution is unstable in PVC chloride containers. The carmustine solution may only be administered from glass vials or polypropylene containers. All plastics that come into contact with the carmustine infusion solution (e.g., infusion set, etc.) must be made of polyethylene without PVC.