Carmustine Accord 100 mg powder and solvent for solution for infusion EFG

Package leaflet: Information for the user

Introduction

Package leaflet: information for the patient

Carmustine Accord 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.

Contents of the leaflet

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

1. What Carmustine Accord 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 adults 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 gliomas, meduloblastoma, astrocytoma, ependymoma), brain metastases
• Second-line treatment of Hodgkin's disease and non-Hodgkin's lymphoma
• Gastrointestinal tract tumors
• Malignant melanoma (skin cancer)
• As conditioning treatment prior to autologous hematopoietic progenitor cell transplantation (HPCT) in malignant hematological disorders (Hodgkin’s disease / non-Hodgkin’s lymphoma).

2. What you need to know before using Carmustine Accord

Do not use Carmustine Accord

• if you are allergic to carmustine or to any of the other ingredients of this medicine (listed in section 6);
• if you have bone marrow suppression resulting in low blood cell counts, including low 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 Accord.

The main adverse effect of this medicine is delayed bone marrow suppression, which may present as fatigue, bleeding from the skin and mucous membranes, 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. Dosing will be confirmed based on 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 section "Possible side effects").

High-dose treatment with Carmustine Accordpharma (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).

Children and adolescents

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

Other medicines and Carmustine Accord

Inform 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.

Use of Carmustine Accord 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 become pregnant, consult your doctor or pharmacist before using this medicine.

Pregnancy and fertility

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 effective contraception during treatment with carmustine and for at least 6 months after the end of treatment to prevent their partners from becoming pregnant.

Breastfeeding

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

Driving and using machines

The influence of carmustine on the ability to drive and use machines is negligible or minor. However, 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 machinery.

Carmustine Accord contains ethanol (alcohol)

This medicine contains 2.37 g of ethanol (alcohol) per vial, 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 operate 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.

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

3. How to use Carmustine Accord

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 amount may be given as a single dose or divided into daily infusions of 75 to 100 mg/m2 on two consecutive days. The dosage will also depend on whether carmustine is administered together with other anticancer medicines.

Doses will be adjusted according to your response to treatment.

The recommended dose of carmustine administered in combination with other anticancer agents prior to autologous 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 will be monitored during administration.

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

If you use more Carmustine Accord than you should

Since this medicine will be administered by your doctor or nurse, it is unlikely that you will receive an incorrect dose. However, if you have any doubts about the amount of medicine you have received, inform your doctor or nurse.

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 redness of the eyes, 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 lung damage (possibly fatal). Lung damage 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/tiredness

• Severe nausea and vomiting

• When used on the skin, skin inflammation (dermatitis)

• Accidental skin contact 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 loss of 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 flushing

• Reactions at the injection site

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

• Veno-occlusive disease (progressive obstruction 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.
• Breathing problems caused by interstitial fibrosis (with lower doses)
• Kidney problems
• Gynaecomastia (breast enlargement in males)

Frequency not known (cannot be estimated from available data)

• Muscle pain
• Seizures (fits), including status epilepticus
• Tissue damage due to leakage at the injection site
• Any sign of infection
• Infertility
• Carmustine has been shown to have a negative effect on fetal development.
• Electrolyte abnormalities (and disturbances in electrolyte balance (low blood levels of potassium, magnesium and phosphate))

Reporting of adverse effects

If you experience any type of adverse effect, consult 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 System for Pharmacovigilance of Human Medicines: https://www.notificaRAM.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Carmustine Accord

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 the carton after “CAD” or “EXP”. The expiry date refers to the last day of the month indicated.

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

Keep in the original packaging to protect from light.

After reconstitution (reconstituted stock solution)

The physicochemical stability in use of the reconstituted stock solution has been demonstrated for 24 hours at 2–8 °C.

After dilution (solution diluted for infusion)

Chemical and physical in-use stability of the solution after dilution for infusion has been demonstrated for 4 hours at 20 to 25 °C when stored in glass or polypropylene containers, protected from light, in 500 ml of sodium chloride injection solution or 5% glucose injection solution. These solutions will also remain stable for 24 hours** when refrigerated (2 to 8 °C) and for an additional 3 hours at 20 to 25 °C, protected from light.

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

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

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

**The 24-hour in-use storage time of the final diluted solution is the total time carmustine is in solution, including the time during reconstitution using 3 ml of ethanol and 27 ml of water for injections.

6. Contents of the pack and other information

Composition of Carmustine Accord

The active substance is carmustine.

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

Each solvent vial contains 3 ml of anhydrous ethanol.

After reconstitution with the solvent and dilution with 27 ml of water for injections, one ml of solution contains 3.3 mg of carmustine.

The other ingredients are:

• Powder: No 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 pale yellow flakes or solidified mass is supplied in a 30 ml amber glass vial closed with a grey bromobutyl rubber stopper coated with fluorotec and sealed with an aluminium cap with a polypropylene lid.

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

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 certain pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Accord Healthcare S.L.U.

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

Edifici Est, 6th floor. 08039, Barcelona.

Spain

Manufacturer:

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 single member S.A.

64th Km National Road Athens, Lamia,

Schimatari, 32009, Greece

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

Name of the Member State	Name of the medicine
Cyprus	Carmustine Accord
Czech Republic	Carmustine Accord
Germany	Carmustine Accord 100 mg Powder and solvent for a concentrate for infusion solution
Denmark	Carmustine Accord
Estonia	Carmustine Accord
Spain	Carmustine Accord 100 mg powder and solvent for concentrate for perfusion solution EFG
Finland	Carmustine Accord 100 mg Dry substance and solvent for intermediate concentrate for infusion solution, solution
France	Carmustine Accord 100 mg Powder and solvent for solution to be diluted for infusion
Ireland	Carmustine 100 mg powder and solvent for concentrate for solution for infusion
Italy	Carmustine Accord
Malta	Carmustine 100 mg powder and solvent for concentrate for solution for infusion
Netherlands	Carmustine Accord 100 mg powder and solvent for concentrate for infusion solution
Norway	Carmustine Accord
Poland	Carmustine Accord
Portugal	Carmustine Accord
Sweden	Carmustine Accord 100 mg powder and liquid for concentrate for infusion solution, solution
United Kingdom (Northern Ireland)	Carmustine 100 mg powder and solvent for concentrate for solution for infusion

Date of the latest review of this leaflet: September 2024

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

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This information is intended for healthcare professionals only

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

Carmustina Accord is a powder and solvent for concentrate for solution for infusion that contains no preservatives and is not designed as a multi-dose vial. It must be handled carefully, and contact between the medication and the skin should be avoided. Reconstitution and subsequent dilutions must be performed under aseptic conditions.

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

Storage of carmustine at 28°C or higher may cause liquefaction of the substance, as the melting point of carmustine is low (approximately 28.0 to 29.0°C). When inspected under bright light, an oily film visible at the bottom of the vial is a sign of degradation. Degraded medication must not be used. Flakes with sharp edges and a solid mass may be observed in unopened vials without carmustine having degraded.

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

Dissolve carmustine (100 mg of powder) with 3 ml of sterile refrigerated ethanol solvent supplied in the primary packaging (amber glass vial). Carmustine must be completely dissolved in ethanol before adding sterile water for injections. The dissolution of the powder may take up to 3 minutes. Then, aseptically add 27 ml of sterile water for injections to the alcoholic solution. The resulting 30 ml stock solution must be thoroughly mixed.

One ml of the reconstituted stock 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 from visible particles.

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

Method of administration:

Carmustina Accord is administered intravenously after reconstitution and subsequent dilution.

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

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

Pregnant personnel must not handle this medication.

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

Dosage and complementary laboratory tests

Initial doses

The recommended dose of Carmustina Accord 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 Carmustina Accord 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 doses

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

Subsequent doses after the initial dose should be adjusted based on the patient's hematological response to the previous dose, whether used as monotherapy or in combination with other myelosuppressive agents. The following scheme is suggested as a guide for dose adjustment:

Table

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).

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

Elderly patients

In general, the dose for elderly patients should be selected with caution, usually starting at the lower end of the dosing range, reflecting the higher frequency of impaired hepatic, renal, or cardiac function, concomitant diseases, or treatment with other medications. 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 Accord 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 non-PVC polyethylene; otherwise, glass containers should be used.