Label: Information for the Patient

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

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

it contains important information for you.

• Keep this label, as you may need to refer to it again.
• If you have any questions, consult your doctor, pharmacist, 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 carmustine. Carmustine belongs to a group of anticancer medications known as nitrosoureas, which act by slowing the growth of cancer cells.

Carmustina is indicated in adults for the following malignant neoplasms 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), cerebral metastases
• Second-line treatment in Hodgkin's disease and non-Hodgkin lymphoma
• Tumors of the gastrointestinal tract or digestive tract
• Malignant melanoma (skin cancer)
• As a conditioning treatment prior to autologous transplantation of hematopoietic progenitor cells (AHCT) in malignant hematological disorders (Hodgkin's disease/non-Hodgkin lymphoma).

No use Carmustina Accord

• if you are allergic to carmustine, or to any of the other ingredients of this medicine (listed in section 6);
• if you have a bone marrow suppression and, as a result, have a low number of platelets, white blood cells (leucocytes) or red blood cells (erythrocytes), whether due to chemotherapy or other causes;
• if you have severe kidney impairment;
• in children and adolescents;
• if you are breastfeeding.

Contraindications and Precautions

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

The main adverse 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. The 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 adverse effects").

High-dose treatment with Carmustina Accordpharma (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 and 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 Accord

Inform your doctor if you are taking, have taken recently or may 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 Accord 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. 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 pregnancy 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 partner becoming pregnant.

Breastfeeding

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

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

Carmustina Accord contains ethanol (alcohol)

This medicine contains 2.37 g of ethanol (alcohol) per vial, which is equivalent to 33.86 mg/kg. The amount in the maximum dose of this medicine (600 mg/m2) is equivalent to 640 ml of beer or 256 ml of wine.

The amount of alcohol in this medicine may affect your ability to drive or use machines, 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 or breastfeeding, 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.

Since this medicine is usually administered slowly over 1-2 hours, the effects of alcohol may be reduced.

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

Adults

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 carmustine in monotherapy for previously untreated patients is 150 to 200 mg/m2intravenously every 6 weeks. This amount can be administered as a single dose or divided into daily infusions of 75 to 100 mg/m2, over 2 consecutive days. Dosage will also depend on whether carmustine is administered with other cancer medications.

Doses will be adjusted based on your response to treatment.

The recommended dose of carmustine administered in combination with other anticancer substances before autologous stem cell transplantation is 300 to 600 mg/m2intravenously.

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

Route of administration

After reconstitution and dilution, carmustine is administered intravenously through a needle (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 your doctor and may vary for each patient.

If you use more Carmustina Accord 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 a feeling of fainting. They 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
• Ataxia (lack of voluntary coordination of muscle movements)
• Dizziness
• Headaches
• 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 disorders (pulmonary-related problems) with difficulty breathing;
• 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/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, decreased ability to make decisions orconcentration,involuntary contractions, tremors, difficultyspeakingorswallowing,seizures;
• Anorexia
• Constipation
• Dyspepsia
• Inflammation of the mouth and lips
• Reversible hepatotoxicity with high-dose treatment. This may cause an increase in liver enzymes and bilirubin (detected by blood analysis)
• 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), in which very small (microscopic) veins in the liver become blocked. It may include symptoms of: accumulation of fluid in the abdomen, enlargement of the spleen, severe bleeding from the esophagus, yellow discoloration of the skin and the white of the eyes.
• Respiratory problems caused by interstitial fibrosis (with lower doses)
• Renal problems
• Gynecomastia (breast growth in males)

Unknown frequency(cannot be estimated from available data)

• Muscle pain
• Seizures (crisis), including status epilepticus
• Tissue damage due to leakage at the injection site
• Any sign of infection
• Infertility
• Carmustine has been shown to negatively affect fetal development.
• Electrolyte anomalies (and alterations in electrolyte balance (low levels in blood of potassium, magnesium, and phosphate))

Reporting of side effects

If you experience any type of side effect, consult your doctor, pharmacistor nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the Spanish Systemof Pharmacovigilance of Medicines 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 stored 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” or “EXP”. The expiration date is the last day of the month indicated.

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

Store in the original packaging to protect it from light.

After reconstitution (reconstituted mother solution)

The physical and chemical stability in use of the reconstituted mother solution has been demonstrated for 24 hours at 2 ‑ 8 °C.

After dilution (solution after dilution for perfusion)

The chemical and physical stability in use of the solution after dilution for perfusion in 500 ml of sodium chloride injectable solution or 5% glucose injectable solution has been demonstrated for 4 hours at a temperature of 20 to 25 °C, protected from light. These solutions will also remain stable for 24 hours** in the refrigerator (2 to 8 °C) and an additional 3 hours between 20 and 25 °C, protected from light.

From a microbiological point of view, unless the opening, reconstitution, and dilution method excludes the risk of microbiological contamination, the product should be used immediately. If not used immediately, the storage times and conditions in use are the responsibility of the user.

The solution must be protected from light until the end of administration.

Medicines should not be thrown down the drain or in the trash. Ask your pharmacist how to dispose of the containers and medicines that you no longer need. This way, you will help protect the environment.

**The 24-hour storage time in use of the final diluted solution is the total time that carmustine is in solution, including the time when it is reconstituted using 3 ml of ethanol and 27 ml of water for injectable preparations.

Composition of Carmustine Accord

The active principle is carmustine.

Each vial of 30 ml of powder for concentrate for solution for infusion contains 100 mg of carmustine.

Each vial of solvent contains 3 ml of anhydrous ethanol.

After reconstitution with the solvent and dilution in 27 ml of water for injection, 1 ml of solution contains 3.3 mg of carmustine.

The other ingredients are:

• Powder: Does not contain excipients
• Solvent: Anhydrous ethanol

Appearance of Carmustine Accord and contents of the pack

Carmustine Accord is a powder and solvent for concentrate for solution for infusion. The lyophilized yellowish flakes or solidified dry mass are supplied in an amber glass vial (30 ml) closed with a grey rubber stopper and sealed with an aluminium cap with a polypropylene stopper.

The solvent is a colourless transparent liquid supplied in a transparent glass vial (5 ml) closed with a fluorotec-coated butyl rubber stopper and sealed with an aluminium cap with a polypropylene stopper.

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

The pack contains 10 vials with 100 mg of powder and 10 vials with 3 ml of solvent.

Only some pack sizes may be marketed.

Marketing authorisation holder and responsible person for manufacture

Marketing authorisation holder

Accord Healthcare S.L.U.

World Trade Center. Moll de Barcelona, s/n,

Edifici Est, 6th floor. 08039, Barcelona.

Spain

Responsible person for manufacture:

Accord Healthcare Polska Sp.z o.o.

ul. Lutomierska 50,

95-200 Pabianice, Poland

Or

Laboratori Fundació Dau

C/ C, 12-14 Pol. Ind.

Zona Franca, Barcelona, 08040, Spain

Or

Accord Healthcare B.V.

Winthontlaan 200, 3526KV Utrecht

Netherlands

This medicinal product has been authorised in the Member States of the European Economic Areawith the following names

Last update of this leaflet:September 2024

The detailed information on this medicinal product is available on the website of theSpanish Agency of Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es

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This information is intended solely for healthcare professionals

This information is a brief description of the preparation and/or handling, incompatibilities, dosage of the medicinal product, overdose or measures of vigilance and complementary laboratory explorations based on the current technical file.

Carmustine Accord is a powder and solvent for concentrate for solution for infusion that does not contain preservatives and is not designed as a multi-dose vial. It must be handled with care and avoid skin contact with the medicinal product. 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 expiry date indicated on the packaging.

The storage of carmustine at 28 °C or more may cause the substance to liquefy, since the melting point of carmustine is low (around 28.0 to 29.0 °C). When inspected under bright light, the oily film seen at the bottom of the vial is a sign of deterioration. The medicinal product must not be used if it is deteriorated. Scales with sharp edges and a solid mass may be seen in unopened vials without the carmustine having degraded.

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

Dissolve the carmustine (100 mg of powder) with 3 ml of the anhydrous ethanol refrigerated sterile supplied in the primary packaging (amber glass vial). The carmustine must be completely dissolved in ethanol before adding sterile water for injection. The dilution of the powder may take 3 minutes. Subsequently, add aseptically 27 ml of sterile water for injection to the alcoholic solution. The 30 ml mother solution must be mixed well.

1 ml of the reconstituted mother solution contains 3.3 mg of carmustine in 10% ethanol, and has a pH of 4.0 to 6.8.

Reconstitution, following the recommendations, results in a yellowish solution, practically free of visible particles.

The 30 ml mother solution must be immediately diluted by adding the 30 ml mother solution or in 500 ml of sodium chloride 9 mg/ml (0.9%) injection solution or in 500 ml of 5% glucose injection solution.

Administration form:

Carmustine Accord is administered intravenously after reconstitution and subsequent dilution.

When reconstituting the powder with the sterile solvent (3 ml vial) provided, a solution must be prepared by adding an additional 27 ml of sterile water for injection, resulting in a yellowish mother solution. The mother solution must be diluted further with 500 ml of sodium chloride 9 mg/ml (0.9%) injection solution or with 500 ml of 5% glucose injection solution.

The resulting infusion solution ready for use must be administered immediately by intravenous drip over a period of one to two hours protected from light. The duration of the infusion must not be less than one hour to avoid burning and pain at the injection site. The injection site must be monitored during administration.

Pregnant personnel must not handle this medicinal product.

Proper handling and disposal of antineoplastics must be followed.

Dosage and complementary laboratory explorations

Initial doses

The recommended dose of Carmustine Accord in monotherapy in untreated patients is 150 to 200 mg/m2by intravenous route every 6 weeks. This amount may be administered in a single dose or divided into daily infusions, 75 to 100 mg/m2, over two consecutive days.

Carmustine Accord may be used in combination with other myelosuppressive drugs or in patients in whom the bone marrow reserve is exhausted. The doses must be adjusted according to the patient's hematological profile, as shown below.

Vigilance and subsequent doses

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

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

Table

In cases where the nadir of leucocytes and platelets after the initial dose is not in the same row (e.g. leucocytes >4,000 and platelets <25,000), the value corresponding to the lowest percentage of the previous dose (e.g. if the platelet value is <25,000, a maximum of 50% of the previous dose must be administered).

Pre-transplant conditioning treatment

Carmustine is administered in combination with other chemotherapeutic agents in patients with malignant hematological diseases before TCHP at a dose of 300 mg/m2to 600 mg/m2by intravenous route.

Special populations

Pediatric population

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

Geriatric population

In general, the dose for an elderly patient must be selected with caution, starting with the lower end of the dose range, which reflects the higher frequency of hepatic, renal or cardiac dysfunction, and concomitant diseases or treatment with other drugs. Since elderly patients have a higher likelihood of presenting a decrease in renal function, care must be taken when selecting the dose, and glomerular filtration must be monitored and the dose reduced accordingly.

Renal insufficiency

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

Compatibility/Incompatibility with containers

The intravenous solution is unstable in PVC chloride containers. All plastics that come into contact with the carmustine infusion solution (e.g. infusion equipment, etc.) must be made of polyethylene without PVC; otherwise, glass containers must be used.