CARMUSTINE ACCORDPHARMA 50 mg POWDER AND SOLVENT FOR CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

Carmustine Accordpharma 50 mg powder and solvent for concentrate for solution for infusion

Carmustine Accordpharma 300 mg powder and solvent for concentrate for solution for infusion

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.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor or nurse, even if it is not listed in this leaflet. See section 4.

Contents of the pack

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

1. What is Carmustine Accordpharma and what is it used for

Carmustine Accordpharma 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 effective in the following malignant neoplasias in monotherapy or in combination with other antineoplastic agents and/or other therapeutic measures (radiotherapy, surgery):

• Brain tumors (glioblastoma, brainstem gliomas, medulloblastoma, astrocytoma, and ependymoma), brain metastases
• Second-line treatment in non-Hodgkin lymphoma and Hodgkin's disease
• Tumors of the gastrointestinal or digestive tract
• Malignant melanoma (skin cancer)
• As conditioning treatment prior to autologous hematopoietic progenitor cell transplantation (APBSCT) in malignant hematological disorders (Hodgkin's disease / non-Hodgkin lymphoma)

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

Do not use Carmustine Accordpharma

• if you are allergic to carmustine 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 failure;
• 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 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 monitor your blood counts every week for at least 6 weeks after each dose. Following the recommended dosage, Carmustine Accordpharma 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 the 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 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 levels of potassium, magnesium, and phosphate 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 Accordpharma

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, an anticancer medicine.

Using Carmustine Accordpharma 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 taking this medicine.

Pregnancy and fertility

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

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

The fertility of male patients may be affected by treatment with carmustine. Before starting treatment with carmustine, they should receive adequate counseling on fertility and family planning.

Breastfeeding

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

Driving and using machines

Carmustine has a minor influence on the ability to drive and use machines. You should talk to your doctor before driving or using any tool or machine, as the amount of alcohol in this medicine may impair your ability to drive or use machines.

Carmustine Accordpharma contains ethanol (alcohol)

This medicine contains 2.37 g of ethanol (alcohol) per 50 mg vial and 7.11 g of ethanol (alcohol) per 300 mg vial, which is equivalent to a maximum of 25.596 g per maximum dose (600 mg/m2 in a 70 kg patient). The amount in the maximum dose of this medicine 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 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 or breastfeeding, 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.

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

3. How to use Carmustine Accordpharma

Carmustine will always be administered by a healthcare professional with experience in the use of anticancer medicines.

Recommended dose for adults

The dosage will depend on your medical condition, body size, and response to treatment. It is usually administered at least every 6 weeks. The recommended dose of carmustine as a single agent in patients who have not been previously treated is 150 to 200 mg/m2 by intravenous infusion every 6 weeks. This can be administered as a single dose or divided into daily infusions, such as 75 to 100 mg/m2 over 2 consecutive days. The dose 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

After reconstitution and dilution, carmustine is administered intravenously through a drip (intravenously) over a period of 1 to 2 hours, protected from light. The infusion duration 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 Carmustine Accordpharma 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 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 whole body) and feeling faint. These may be signs of a severe allergic reaction.

Carmustine can cause the following side effects:

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

• Delayed bone marrow suppression (decrease in blood cells in the bone marrow) which can increase the risk of infections if white blood cells decrease
• Ataxia (lack of voluntary muscle coordination)
• Dizziness
• Headaches
• Transient eye redness, 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 breathing difficulties;

This medicine can cause severe lung damage (possibly fatal). Lung damage can 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 or nail area)

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, lumps caused by 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 (decrease in the number of red blood cells in the blood)
• 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
• Inflammation of the mouth and lips
• 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 obstruction of small veins) in the liver, which 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 (with lower doses)
• Kidney problems
• Gynecomastia (breast growth in males)

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

• Muscle pain
• 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 levels of potassium, magnesium, and phosphate in the blood))

Reporting of side effects

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

5. Storing Carmustine Accordpharma

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 refers to the last day of the month stated.

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

Store in the original packaging to protect from light.

After reconstitution (reconstituted mother solution)

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

After dilution (solution after dilution for infusion)

The chemical and physical stability of the solution after dilution for infusion in sodium chloride injection solution or 5% glucose injection solution at a final concentration of 0.2 mg/ml and stored in a glass or polypropylene container for 4 hours at a temperature of 20 to 25 °C, protected from light, has been demonstrated. These solutions will also remain stable for 24 hours** in the refrigerator (2 to 8 °C) and for another 3 hours at 20 to 25 °C, protected from light.

From a microbiological point of view, unless the method of opening, reconstitution, and dilution excludes the risk of microbial 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 24-hour in-use storage time for the final diluted solution is the total time that carmustine is in solution, including the time it is reconstituted using ethanol and water for injectable preparations.

The solution should be 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. Contents of the pack and additional information

Composition of Carmustina Accordpharma

The active substance is carmustine.

Carmustina Accordpharma 50 mg

A 20 ml vial of powder for concentrate for solution for infusion contains 50 mg of carmustine.

A 5 ml vial of solvent contains 3 ml of anhydrous ethanol.

Carmustina Accordpharma 300 mg

A 100 ml vial of powder for concentrate for solution for infusion contains 300 mg of carmustine.

A 10 ml vial of solvent contains 9 ml of anhydrous ethanol.

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

The other ingredients are:

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

Appearance of Carmustina Accordpharma and pack contents

Powder and solvent for concentrate for solution for infusion.

The powder consists of a pale yellow powder or lyophilized flakes in a closed amber glass vial with a rubber stopper and sealed with an aluminum cap with a polypropylene top.

The solvent is a clear, colorless liquid supplied in a transparent glass vial closed with a rubber stopper and sealed with an aluminum cap with a polypropylene top.

Package sizes: The package contains 1 vial with 50 mg of powder and 1 vial with 3 ml of solvent.

The package contains 10 vials with 50 mg of powder and 10 vials with 3 ml of solvent.

The package contains 1 vial with 300 mg of powder and 1 vial with 9 ml of solvent.

The package contains 10 vials with 300 mg of powder and 10 vials with 9 ml of solvent.

Only some package sizes may be marketed.

Marketing authorization holder

Accord Healthcare S.L.U.

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

Edifici Est, 6ª planta. 08039, Barcelona. Spain

Manufacturer

Accord Healthcare Polska Sp.z o.o.

ul. Lutomierska 50,

95-200 Pabianice, Poland

This medicinal product has been authorized in the Member States of the European Economic Areaunder the following names

Date of last revision of this leaflet:May 2023

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

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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 of the medicinal product, overdose or monitoring measures and laboratory tests based on the current technical data sheet.

Carmustina Accordpharma is a powder and solvent for concentrate for solution for infusion that 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 packaging.

The lyophilized product does not contain preservatives and is intended for single use. The lyophilized product may appear as a fine powder; however, handling may make it appear as a heavier and more granular lyophilized product than a powdered lyophilized product due to the mechanical instability of the freeze-dried cake. The presence of an oily film may be an indication of drug melting. Such products are not accepted for use due to the risk of temperature excursions above 30°C. This medicinal product should not be used anymore. When in doubt whether the product has cooled adequately, each vial in the box should be inspected immediately. For verification, hold the vial under a bright light.

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

Dissolve the carmustine (powder) with the necessary amount of sterile refrigerated ethanol solvent supplied in the primary packaging (amber glass vial). The carmustine must be completely dissolved in ethanol before adding sterile water for injections. Then, aseptically add the required amount of sterile water for injection to the alcohol solution. The mother solution should be mixed well.

1 ml of the reconstituted mother solution contains 3.3 mg of carmustine in 10% ethanol. Reconstitution, as recommended, results in a clear, colorless to pale yellow mother solution, practically free from visible particles, which should be diluted immediately to the required amount of sodium chloride 9 mg/ml (0.9%) or glucose 5% solution for injection to obtain a final concentration of 0.2 mg/ml. The diluted solution (i.e., the solution for use) should be mixed for at least 10 seconds before administration. The solution for use should be administered over 1 to 2 hours.

The pH and osmolality of the diluted solutions for infusion are

pH: 3.2 to 7.0 diluted in sodium chloride 9 mg/ml (0.9%) or glucose 5% solution for injection.

Osmolality: 340 to 400 mOsmol/l (diluted in glucose 50 mg/ml [5%] or sodium chloride 9 mg/ml [0.9%] solution for injection).

Method of administration

For intravenous use after reconstitution and dilution.

The reconstituted and diluted solution (i.e., the solution for use) should be administered intravenously and should be administered by intravenous drip over a period of one to two hours. The infusion administration should be performed using a PVC-free PE infusion set; during the administration of the medicinal product, a glass or polypropylene container should be used. In addition, the solution for use should be protected from light (e.g., using aluminum foil wrapped around the solution for use container) and preferably kept at temperatures below 20-25°C, as carmustine degrades more rapidly at higher temperatures.

Infusion of carmustine over shorter periods may produce intense pain and burning at the injection site. The injected area should be monitored during administration.

Guidelines for the safe handling and disposal of antineoplastic agents should be followed.

Dosage and laboratory tests

Initial doses

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

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

Follow-up and subsequent doses

A repeated cycle of carmustine should not be administered until the circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3, white blood cells above 4,000/mm3), and this is usually at six weeks. Blood counts should be monitored frequently and cycles should not be repeated before six weeks due to late hematological toxicity.

Subsequent doses to the initial dose should be adjusted according to the patient's hematological response to the previous dose, both in monotherapy and in combination therapy with other myelosuppressive agents. The following program is suggested as a guide for dose adjustment:

Table 1

In cases where the nadir after the initial dose does not fall in the same row for white blood cells and platelets (e.g., white blood cells > 4,000 and platelets < 25,000), the value given with the lowest percentage of the previous dose should be used (e.g., platelets < 25,000 and then a maximum of 50% of the previous dose should be administered).

There are no limits to the treatment period with carmustine. In case the tumor remains incurable or severe or intolerable adverse reactions appear, treatment with carmustine should be discontinued.

Preparative treatment 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 - 600 mg/m2 intravenously.

Special populations

Pediatric population

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

Elderly patients

In general, the selection of the dose for an elderly patient should be cautious, 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 the glomerular filtration rate should be monitored, and the dose reduced accordingly.

Renal impairment

In patients with renal impairment, the dose of carmustine should be reduced if the glomerular filtration rate is reduced.

Compatibility/Incompatibility with containers

The intravenous solution is unstable in polyvinyl chloride containers. All plastic that comes into contact with the carmustine infusion solution (e.g., infusion equipment, etc.) should be PVC-free polyethylene; otherwise, glass material should be used.