CARMUSTINE Aurovitas 100 mg Powder and Solvent for Concentrate for Infusion Solution

Introduction

Package Leaflet: Information for the Patient

Carmustine Aurovitas 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, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

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

Carmustine Aurovitas 100 mg powder and solvent for concentrate for solution for infusion EFG is a medicine that contains carmustine. Carmustine belongs to a group of anticancer medicines, known as nitrosoureas, which act by slowing down the growth of cancer cells.

Carmustine is used as palliative therapy (relieving and preventing patient suffering) as a single agent or in established combination therapy with other approved anticancer substances in certain types of cancer, such as:

• Brain tumors; glioblastoma, brainstem gliomas, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors.
• MultIPLE myeloma (malignant tumor that develops from the bone marrow): in combination with other cytostatics and a hormone from the adrenal cortex, especially prednisone.
• Hodgkin's disease (lymphoid tumor).
• Non-Hodgkin's lymphoma (lymphoid tumor).
• Malignant tumors of the gastrointestinal tract: only in the case of advanced disease, when other cell growth inhibitors have failed.

Carmustine is also used as conditioning treatment before the transplantation of the patient's own blood stem cells (autologous hematopoietic stem cell transplantation) in malignant hematological diseases of the lymphatic system (Hodgkin's lymphoma and non-Hodgkin's lymphoma).

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

Do not use Carmustine Aurovitas

• If you are allergic to carmustine or any of the other ingredients of this medicine (listed in section 6).
• Carmustine must not be used in patients who have a reduced number of platelets (thrombocytes), 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.
• If the patient's age is under 18 years.
• If you are breastfeeding.

Warnings and precautions

Consult your doctor or pharmacist before starting to use carmustine:

Since the main adverse effect of this medicine is delayed bone marrow suppression, your doctor will monitor your blood counts every week for at least 6 weeks after each dose. At the recommended dose, carmustine cycles will not be administered more frequently than every 6 weeks. The dosage will be confirmed with the blood count.

Inform your doctor immediately if you experience any of the following symptoms:

• Signs of infection (fever, persistent sore throat).
• Increased tendency to bruising/bleeding.
• Unusual fatigue.
• Rapid/palpable heart rate.

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

During treatment, gastrointestinal symptoms may occur in the form of vomiting and nausea.

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").

Treatment with high doses of carmustine (up to 600 mg/m2) is only performed in combination with subsequent hematopoietic stem cell transplantation. These high doses may increase the frequency or severity of pulmonary, renal, hepatic, cardiac, and gastrointestinal toxicities, as well as infections and alterations in electrolyte balance (low blood levels of potassium, magnesium, and phosphate).

Stomach pain (neutropenic enterocolitis) may occur as an adverse event related to therapy after treatment with chemotherapeutic agents.

Patients who have multiple conditions simultaneously and have a worse disease state are at higher risk of adverse events. This is especially important for elderly patients.

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).

Women and men of childbearing age must use effective contraceptive methods during treatment and for at least 6 months after treatment (see also the section "Pregnancy, breastfeeding, and fertility").

Other medicines and Carmustine Aurovitas

Inform your doctor or pharmacist 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.
• Cimetidine, used for stomach problems such as indigestion.
• Digoxin, used if you have an abnormal heart rhythm.
• Melphalan, an anticancer medicine.
• Dexamethasone, used as an anti-inflammatory and immunosuppressant.
• Methotrexate, cyclophosphamide, procarbazine (nitrogen mustard), fluorouracil, vinblastine, actinomycin (dactinomycin), bleomycin, doxorubicin (adriamycin), used for the treatment of various types of cancer.

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 must 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 avoid becoming pregnant during treatment with this medicine. Women of childbearing age must use effective contraceptive methods to avoid becoming pregnant during treatment and for at least six months after the end of treatment.

Male patients must use adequate contraceptive measures during treatment with carmustine for at least 6 months to avoid getting their partners pregnant. The fertility of male patients may be affected by treatment with carmustine. They should seek adequate advice on fertility/family planning before starting treatment with carmustine.

Breastfeeding

You must not breastfeed while using this medicine and for 7 days after the end of treatment. The risk to newborns/infants cannot be excluded.

Driving and using machines

The effect of this medicine on the ability to drive and use machines is not known. You should consult your doctor before driving or using any tools or machines because the amount of alcohol in this medicine may impair your ability to drive or use machines.

Carmustine Aurovitas contains ethanol (alcohol)

This medicine contains 2.4 g of ethanol (alcohol) per vial, which is equivalent to 25.92 g per maximum dose (10% v/v). 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 contained in this medicine may affect your ability to drive and use machines because it can alter your judgment and reaction ability.

If you suffer from epilepsy or liver problems, consult your doctor or pharmacist before using this medicine.

The amount of alcohol contained in this medicine may alter the effect 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 using this medicine.

If you have an alcohol addiction, consult your doctor or pharmacist before using this medicine.

3. How to use Carmustine Aurovitas

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 may 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 autologous hematopoietic stem cell transplantation is 300-600 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 by infusion over a period of one to two hours. 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.

Use in children and adolescents (under 18 years of age)

Carmustine must not be used in children and adolescents due to the high risk of pulmonary toxicity.

Use in elderly patients

Carmustine can be used with caution in elderly patients. Kidney function will be closely monitored.

If you use more Carmustine Aurovitas than you should

Since a doctor or nurse will administer this medicine to you, it is unlikely that you will receive an incorrect dose. Inform your doctor or nurse if you have any doubts about the amount of medicine you have received.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, telephone 91 562 04 20, indicating the medicine and the amount administered.

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 it affects the whole body) and a feeling of fainting. 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 in the bone marrow).
• Ataxia (lack of voluntary muscle coordination).
• Dizziness.
• Headache.
• Transient eye redness, blurred vision, retinal hemorrhage, inflammation of the iris and optic nerve.
• Hypotension (low blood pressure) in high-dose treatments.
• 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 (potentially fatal) lung damage. Lung damage 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; start 2-4 hours after administration and last 4-6 hours.
• When used on the skin, skin inflammation (dermatitis).
• Accidental contact with the skin may cause transient hyperpigmentation (darkening of a skin or nail area).

Common(may affect up to 1 in 10 people)

• Acute leukemia (blood cancer) and bone marrow dysplasias (abnormal development of the bone marrow) after prolonged use. The following symptoms may occur: 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) in high-dose treatments. Symptoms may include muscle weakness in one area, decreased ability to make decisions or concentrate, involuntary contractions, tremors, difficulty speaking or swallowing, seizures.
• Loss of appetite (anorexia).
• Constipation.
• Diarrhea.
• Inflammation of the mouth and lips.
• Reversible liver toxicity with high-dose treatment. This may cause an increase in liver enzymes and bilirubin (detected by blood tests).
• Alopecia (hair loss).
• Redness of the skin.
• Reactions at the injection site.

Uncommon(may affect up to 1 in 100 people)

• Veno-occlusive disease (progressive blockage of small veins) in high-dose treatments, 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, yellowing of the skin and the whites of the eyes.
• Respiratory problems caused by interstitial fibrosis (with lower doses). Symptoms may include dry cough, difficulty breathing, fatigue, weight loss.
• Kidney problems.
• Gynecomastia (breast growth in males).
• Bleeding in the gastrointestinal tract.
• Inflammation of the optic nerve and adjacent retina in the eye.

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

• Inflammatory process that causes a blood clot to form and block one or more veins, usually in the legs. The affected vein may be near the surface of the skin or deep in a muscle (thrombophlebitis).

Very rare(may affect up to 1 in 10,000 people)

• Muscle pain.
• Secondary tumors (cancers caused by radiation or chemotherapy).
• Seizures (crises), including status epilepticus.
• Tissue damage due to leakage at the injection site.
• Infertility.
• Impaired development of the embryo/fetus in pregnant women.
• Any sign of infection.
• Rapid heart rate, chest pain.
• Allergic reaction.
• Electrolyte imbalance (low blood levels of potassium, magnesium, and phosphate).
• Abdominal pain (neutropenic enterocolitis).
• A decrease in kidney volume, progressive accumulation of some metabolic products in the blood (azotemia), and kidney failure have been observed after high cumulative doses and long-term treatment with carmustine and other nitrosoureas. Kidney damage has also been observed after lower total doses.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Carmustine Aurovitas

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 vial label and carton after EXP. The expiry date is the last day of the month stated.

Once prepared and diluted, this medicine should be used immediately or within 24 hours if stored in a refrigerator (between 2°C and 8°C).

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Container Contents and Additional Information

Composition ofCarmustina Aurovitas

• The active ingredient is carmustine.

Each vial 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, each ml of solution contains 3.3 mg of carmustine.

• The other components are:

Powder: does not contain excipients.

Solvent: anhydrous ethanol.

Appearance ofthe Productand Container Contents

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

Powder:

Type I molded glass vial of 30 ml with a 20 mm neck, closed with a 20 mm gray bromobutyl rubber stopper and sealed with an aluminum cap with a polypropylene disc.

Solvent:

Transparent type I glass tubular vial of 10 ml with a 13 mm neck, closed with a 13 mm gray chlorobutyl rubber stopper and sealed with an aluminum cap with a polypropylene disc.

Package sizes: 1, 5, 8, and 10 vials.

Only some package sizes may be marketed.

A package contains one vial with 100 mg of powder and one vial with 3 ml of solvent.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Eugia Pharma (Malta) Limited

Vault 14, Level 2, Valletta Waterfront

Floriana, FRN 1914

Malta

Manufacturer

APL Swift Services (Malta) Limited

HF26, Hal Far Industrial Estate, Hal Far

Birzebbugia, BBG 3000

Malta

Or

Generis Farmacêutica, S.A.

Rua João de Deus, nº 19, Venda Nova

2700-487 Amadora

Portugal

Or

Arrow Génériques

26 Avenue Tony Garnier

69007 Lyon

France

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

Aurovitas Spain, S.A.U.

Avda. de Burgos, 16-D

28036 Madrid

Spain

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Germany: Carmustin PUREN 100 mg Powder and solvent for concentrate for solution for infusion

Spain: Carmustina Aurovitas 100 mg powder and solvent for concentrate for solution for infusion EFG

France: Carmustine Arrow 100 mg, powder and solvent for solution to be diluted for infusion

Italy: Carmustina Aurobindo

Portugal: Carmustina Generis

Date of last revision of this leaflet: November 2022

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

The lyophilized formulation does not contain preservatives and is not designed as a multiple-dose vial. The medicinal product is for single use. It should be handled with caution and skin contact with the medicinal product should be avoided. 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.

Storage of carmustine at a temperature equal to or above 27°C may cause liquefaction of the substance due to carmustine having a low melting point (approx. 30.5°C to 32.0°C). An indication of decomposition is the appearance of an oil film at the bottom of the vial. This medicinal product should no longer be used. When there are doubts about whether the product is properly refrigerated, each vial in the box should be inspected immediately. For verification, the vial should be held under intense light.

Reconstitution and dilution of each vial of powder for concentrate for solution for infusion should be performed as follows

Dissolve carmustine (100 mg of powder) with 3 ml of the supplied sterile solvent and 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.

Each ml of the reconstituted mother solution will contain 3.3 mg of carmustine in 10% ethanol and will have a pH of 4.0 to 6.8.

The reconstituted 30 ml solution should be diluted immediately by adding the 30 ml of the mother solution to 500 ml of sodium chloride 0.9% injectable solution or to 500 ml of 5% glucose injectable solution.

Mode of administration

Carmustine is administered intravenously after reconstitution and subsequent dilution.

Reconstitution and dilution with the provided sterile solvent (3 ml vial) and sterile water for injectable preparations (27 ml) results in a yellowish mother solution. This reconstituted solution should be subsequently diluted with 500 ml of sodium chloride 9 mg/ml (0.9%) injectable solution or 500 ml of 5% glucose injectable solution. The resulting infusion solution ready for use should be administered immediately by intravenous drip over a period of one to two hours, protected from light. The infusion duration should not be less than one hour, otherwise, it causes burning and pain at the injection site. The injection site should be monitored during administration.

The guidelines for the correct handling and disposal of antineoplastics should be followed.

Posology and laboratory monitoring

Initial doses

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

Monitoring and subsequent doses

A new cycle of carmustine 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), which usually occurs in six weeks. Blood counts should be monitored frequently, and repeated cycles should not be administered before six weeks 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, both as monotherapy and in combination with other myelosuppressive medications. The following scheme is suggested as a guide for dose adjustment:

Table 1

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.

Pre-treatment conditioning for hematopoietic stem cell transplantation (HSCT)

In patients with malignant hematological disorders, carmustine is administered in combination with other chemotherapeutic agents before HSCT, at a dose of 300-600 mg/m2 intravenously.

Special populations

Patients with renal impairment

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

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 treatment with other medications.

Since elderly patients are more likely to have decreased renal function, the dose should be selected with caution, and glomerular filtration should be monitored, and the dose reduced accordingly.

Children and adolescents

Carmustine is contraindicated in children and adolescents under 18 years of age (see section 4.3) due to the high risk of pulmonary toxicity (see section 4.4).

Compatibility/incompatibility with containers

The infusion solution is unstable in polyvinyl chloride (PVC) containers. The carmustine solution can only be administered in glass or polypropylene containers.

This medicinal product should not be mixed with other medications, except those mentioned in section 6.6.