Carmustine Aurobindo

Patient Information Leaflet

Carmustine Aurobindo 100 mg powder and solvent for concentrate for solution for infusion

Generic medicine
Please read all of this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

1. What Carmustina Aurobindo is and what it is used for

Carmustina Aurobindo 100 mg powder and solvent for concentrate for solution for infusion is a
medicinal product containing carmustine. Carmustina Aurobindo belongs to a group of antineoplastic agents
known as nitrosoureas, which act by slowing the growth of tumour cells.
Carmustina Aurobindo is used as palliative therapy (to relieve and prevent patient suffering)
either as a single agent or in established combination therapy with other approved antineoplastic agents in
certain types of tumours, such as:

• brain tumours, glioblastoma, brain stem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumours;
• multiple myeloma (a malignant tumour arising from the bone marrow), in combination with other cytostatic agents and with an adrenal cortex hormone, particularly prednisone;
• Hodgkin's disease (a lymphoid tumour);
• non-Hodgkin lymphomas (lymphoid tumours);
• malignant gastrointestinal tract tumours: only in cases of advanced disease when other cell growth-inhibiting agents have failed. Carmustina Aurobindo is also used as conditioning therapy prior to autologous blood stem cell transplantation (autologous stem cell transplantation) in malignant haematological diseases of the lymphatic system (Hodgkin lymphoma and non-Hodgkin lymphoma).

2. What you should know before taking Carmustine Aurobindo

Do not take Carmustine Aurobindo

• if you are allergic to carmustine or to any of the other ingredients of this medicine (listed in section 6);
• Carmustine Aurobindo must not be used in patients with reduced platelet (thrombocyte), white blood cell (leukocyte), or red blood cell (erythrocyte) counts, whether due to chemotherapy or other causes;
• if you have severe impairment of kidney function;
• if the patient is under 18 years of age;
• if you are breastfeeding.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before receiving Carmustine Aurobindo.
Since the main side effect of this medicine is delayed bone marrow suppression, your doctor will monitor your blood counts weekly for at least 6 weeks after administration of a dose. At the recommended dosage, cycles of Carmustine Aurobindo should not be administered more frequently than every 6 weeks. Dosage will be confirmed based on complete blood count results.
Immediately inform your doctor if any of the following symptoms occur:

• signs of infection (fever, persistent sore throat);
• increased tendency to bruise or bleed;
• unusual tiredness;
• rapid or pounding heartbeat.

Your liver and kidney function will be checked before treatment and regularly monitored during treatment.
Gastrointestinal symptoms such as nausea and vomiting may occur during therapy.
Because use of Carmustine Aurobindo may cause lung damage, a chest X-ray and lung function tests will be performed before starting treatment (see also section “Possible side effects”).
High-dose carmustine treatment (up to 600 mg/m²) is performed only 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 disturbances in electrolyte balance (low blood levels of potassium, magnesium, phosphate).
Stomach pain (neutropenic enterocolitis) may occur as a therapy-related adverse event during treatment with chemotherapeutic agents.
Patients suffering from multiple concurrent conditions and with a more severe disease state are at higher risk of adverse events. This is particularly important for elderly patients.
Your doctor will inform you about the possibility of lung damage and allergic reactions, as well as the related symptoms. If such symptoms occur, contact your doctor immediately (see section 4).
Men and women of reproductive age must use an effective method of contraception during treatment and for at least 6 months after treatment (see also section “Pregnancy, breastfeeding and fertility”).

Other medicines and Carmustine Aurobindo
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including non-prescription medicines, such as:

• Phenytoin, used in epilepsy.
• Cimetidine, used for stomach problems such as indigestion.
• Digoxin, used for arrhythmia.
• Melphalan, an anticancer drug.
• Dexamethasone, used as an immunosuppressant and anti-inflammatory agent.
• Methotrexate, cyclophosphamide, procarbazine, chlorambucil (nitrogen mustard), fluorouracil, vinblastine, actinomycin (dactinomycin), bleomycin, doxorubicin (adriamycin), used in the treatment of various types of cancer.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine.

Pregnancy and fertility
Carmustine Aurobindo must not be used during pregnancy because it may harm the unborn baby. Therefore, this medicine should generally not be given to pregnant women. If used during pregnancy, the patient must be aware of the potential risks to the fetus. Women of childbearing age are advised to avoid pregnancy during treatment with this medicine. Women of childbearing age are advised to use effective contraception methods to prevent pregnancy during and for at least 6 months after treatment with this medicine.
Male patients must use adequate contraception during treatment with Carmustine Aurobindo and for at least 6 months after the end of treatment to prevent pregnancy of their partner. Male fertility may be affected by treatment with Carmustine Aurobindo. Appropriate counseling regarding fertility/family planning should be obtained before starting treatment with Carmustine Aurobindo.

Breastfeeding
Do not breastfeed while taking this medicine and for at least 7 days after treatment. Risk to newborns/infants cannot be excluded.

Driving and using machines
The effect of this medicine on the ability to drive or operate machinery is unknown. Ask your doctor for advice before driving or operating tools or machines, as the amount of alcohol contained in this medicine may impair your ability to drive or use machinery.

Carmustine Aurobindo contains ethanol (alcohol)
This medicine contains 2.4 g of ethanol (alcohol) per vial, equivalent to 25.92 g per maximum dose (10 vol%). The amount of alcohol in the maximum dose (600 mg/m² in a 70 kg patient) is equivalent to 648 ml of beer or 259 ml of wine.
The amount of alcohol in this medicine may affect your ability to drive or use machinery, as alcohol may impair 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. Speak with 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 before taking this medicine.

3. How to use Carmustina Aurobindo

Carmustina Aurobindo will always be administered by a healthcare professional experienced in the use of antineoplastic medicinal products.
Adults
The dosage depends on the medical condition, body size and response to treatment. It is generally administered at intervals of at least 6 weeks. The recommended dose of Carmustina Aurobindo as a single agent in previously untreated patients is 150–200 mg/m² given intravenously every 6 weeks. It may be administered as a single dose or divided into daily infusions of 75–100 mg/m² on two consecutive days. Dosage may also vary depending on whether Carmustina Aurobindo is used in combination with other antineoplastic agents.
Doses will be adjusted according to response to treatment.
The recommended dose of carmustine administered in combination with other antineoplastic agents prior to autologous stem cell transplantation is 300–600 mg/m² given 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, Carmustina Aurobindo is administered intravenously by infusion over a period of 1–2 hours. The infusion duration should not be less than one hour to avoid burning and pain at the injection site. The injection site is checked during administration.
The duration of treatment is determined by the physician and may vary for each patient.
Use in children and adolescents (age < 18 years)
Carmustina Aurobindo must not be used in children and adolescents due to the high risk of pulmonary toxicity.
Use in the elderly
Carmustina Aurobindo may be used with caution in elderly patients. In such cases, renal function should be closely monitored.
If you use more Carmustina Aurobindo than you should
Since this medicine will be administered by a doctor or nurse, it is unlikely that you will receive an incorrect dose. Inform your doctor or nurse if you have any doubts regarding the amount of medicine administered to you.
If you have any questions about the use of this medicine, consult your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Immediately inform your doctor or nurse if you notice any of the following:
Sudden wheezing, difficulty breathing, swelling of the eyelids, face or lips, skin rash or itching (especially all over the body), and feeling faint. These may be signs of a severe allergic reaction.

Carmustine Aurobindo may cause the following side effects:

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

• Delayed myelosuppression (reduction in blood cells in the bone marrow);
• Ataxia (lack of voluntary muscle coordination);
• Dizziness;
• Headache;
• Temporary eye redness, blurred vision due to retinal bleeding, inflammation of the iris and optic nerve;
• Hypotension (low blood pressure) with high-dose therapy;
• Phlebitis (vein inflammation) associated with pain, swelling, redness, tenderness;
• Respiratory disorders (lung problems) with breathing difficulties; this medicine may cause severe (even fatal) lung damage, which may appear years after treatment. Contact your doctor immediately if you experience any of the following symptoms: shortness of breath, persistent cough, chest pain, persistent weakness/fatigue;
• Severe nausea and vomiting; onset within 2–4 hours after administration and lasting 4–6 hours;
• Skin inflammation (dermatitis) when used on the skin;
• 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 leukemia (blood cancer) and myelodysplasia (abnormal bone marrow development) after prolonged use. The following symptoms may occur: bleeding gums, bone pain, fever, frequent infections, frequent or severe nosebleeds, lumps due to swollen lymph nodes in the neck, forearm, abdomen or groin, pallor, shortness of breath, weakness, fatigue, or general lack of energy;
• Anaemia (reduction in the number of red blood cells in the blood);
• Encephalopathy (brain disorder) with high-dose therapy; symptoms may include muscle weakness in a specific area, poor decision-making or concentration, involuntary muscle contractions, tremors, difficulty speaking or swallowing, seizures;
• Loss of appetite (anorexia);
• Constipation;
• Diarrhoea;
• Inflammation of the mouth and lips;
• Reversible liver toxicity with high-dose therapy, delayed up to 60 days after administration. This may cause increased liver enzymes and bilirubin (detected by blood tests);
• Alopecia (hair loss);
• Skin redness;
• Injection site reactions.

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

• Veno-occlusive disease (progressive blockage of veins) with high-dose therapy, in which very small veins in the liver become blocked. Possible symptoms include: fluid accumulation in the abdomen, enlarged spleen, severe esophageal bleeding, yellowing of the skin and whites of the eyes;
• Breathing problems caused by interstitial fibrosis (with lower doses); symptoms may include dry cough, shortness of breath, fatigue, weight loss;
• Kidney problems;
• Gynaecomastia (breast development in men);
• Bleeding in the gastrointestinal tract;
• Inflammation of the optic nerve and adjacent retina in the eye.

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

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

Not known (frequency cannot be estimated from available data)

• Muscle pain;
• Secondary tumours (caused by radiation or chemotherapy);
• Seizures (fits), including status epilepticus;
• Tissue damage due to leakage at the injection site;
• Infertility;
• Impairment of embryo/fetal development in pregnant women;
• Any signs of infection;
• Rapid heartbeat, chest pain;
• Allergic reaction;
• Electrolyte imbalance disorders (low blood levels of potassium, magnesium, phosphate);
• Abdominal pain (neutropenic enterocolitis);
• Reduced kidney volume, progressive accumulation of certain metabolic products in the blood (azotemia), and kidney failure have been observed after high cumulative doses and prolonged treatment with Carmustine Aurobindo and other nitrosoureas. Kidney damage has also been observed after lower total doses.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system at www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Carmustina Aurobindo

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and outer packaging following EXP. The expiry date refers to the last day of that month.
Once reconstituted and diluted, Carmustina Aurobindo must be used immediately or within 24 hours if stored in a refrigerator (between 2°C and 8°C).
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Carmustina Aurobindo contains

• The active substance is carmustine. Each 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, each ml of solution contains 3.3 mg of carmustine. The other components are:
  Powder: no excipients.
  Solvent: anhydrous ethanol.

Description of the appearance of Carmustina Aurobindo and package contents
Carmustina Aurobindo consists of powder and solvent for concentrate for solution for infusion.
Powder
30 ml amber glass vial of type I with 20 mm neck, with grey bromobutyl rubber stopper 20 mm, aluminium seal and polypropylene disc.
Solvent
10 ml transparent tubular glass vial of type I with 13 mm neck, with grey chlorobutyl rubber stopper 13 mm, aluminium seal and polypropylene disc.
Pack sizes: 1, 5, 8 and 10 vials.
One pack contains one vial of 100 mg powder and one vial of 3 ml solvent.

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
Generis Farmacêutica, S.A.
Rua Joao De Deus, no 19,
Venda Nova, 2700-487 Amadora
Portugal
Arrow Génériques,
26 Avenue Tony Garnier,
Lyon, 69007
France

This medicinal product is authorized in the Member States of the European Economic Area under the following names:
France: Carmustine Arrow 100 mg, powder and solvent for solution for dilution for infusion
Germany: Carmustin Puren 100 mg powder and solvent for preparation of a concentrate for infusion solution
Italy: Carmustina Aurobindo
Portugal: Carmustina Generis
Spain: Carmustina Aurovitas 100 mg powder and solvent for concentrate for solution for perfusion EFG

The following information is intended for healthcare professionals only:

A brief description of the preparation and/or handling, interactions, dosage, medicinal product, overdose, or monitoring measures and laboratory tests is provided, based on the current product characteristics summary.

The lyophilized dosage formulation contains no preservatives and is not intended for use as a multi-dose vial. The medicinal product is strictly for single use. It must be handled with care, and contact with the skin should be avoided. Reconstitution and further dilutions must be carried out under aseptic conditions.

Following the product's storage instructions ensures that the intact vial remains stable until the expiry date indicated on the packaging.

Storage of carmustine at 27°C or higher temperatures may cause the substance to liquefy, as carmustine has a low melting point (approximately 30.5°C to 32°C). A sign of decomposition is the presence of an oily film at the bottom of the vial. In such cases, the medicinal product must not be used. If there is uncertainty regarding proper cooling of the product, each vial within the package should be inspected immediately. To perform this check, expose the vial to bright light.

Reconstitution and dilution of the powder for concentrate for solution for infusion from each vial must be prepared as follows:

Dissolve carmustine (100 mg of powder) with 3 ml of the sterile solvent supplied, and add to the alcoholic solution 27 ml of sterile water for injections under aseptic conditions. The resulting 30 ml stock solution must be thoroughly mixed.

Each ml of the reconstituted stock solution will contain 3.3 mg of carmustine in 10% ethanol, with a pH between 4.0 and 6.8.

The 30 ml stock solution must be immediately diluted by adding 500 ml of sodium chloride 0.9% injection solution or 500 ml of 5% glucose injection solution.

Route of administration

Carmustine is intended for intravenous use after reconstitution and further dilution.

Reconstitution and dilution using the sterile solvent supplied (3 ml vial) and 27 ml of sterile water for injections yield a yellowish stock solution. This stock solution must be further diluted with 500 ml of sodium chloride 9 mg/ml (0.9%) injection solution or 500 ml of 5% glucose injection solution. The resulting infusion solution ready for use must be administered immediately by intravenous infusion over one to two hours, protected from light. The infusion duration should not exceed one hour to minimize the risk of burning and pain at the injection site. The infusion site must be monitored during administration.

Appropriate guidelines for the safe handling and disposal of cytotoxic anticancer agents must be followed.

Dosage and laboratory monitoring

Initial doses

The recommended dose of Carmustine Aurobindo as a single agent in patients who have not been previously treated is 150–200 mg/m² administered intravenously every 6 weeks. This dose may be given as a single infusion or divided into daily infusions of 75–100 mg/m² on two consecutive days.

When Carmustine Aurobindo is used in combination with other myelosuppressive medicinal products or in patients with depleted bone marrow reserve, doses should be adjusted according to the patient's hematological profile, as outlined below.

Monitoring and subsequent doses

A new cycle of Carmustine Aurobindo must not be administered until circulating blood cells have returned to acceptable levels (platelets above 100,000/mm³, white blood cells above 4,000/mm³), which typically occurs within six weeks. Blood counts must be monitored frequently, and repeated cycles must not be administered at intervals shorter than six weeks due to delayed hematological toxicity.

Subsequent doses following 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 medicinal products. The following table is provided as a guide for dose adjustment.

Table 1

In cases where the nadir following the initial dose does not fall within the same row for leukocytes and platelets (e.g., leukocytes > 4,000 and platelets < 25,000), the lower percentage of the previous dose should be used (e.g., with platelets < 25,000, at most 50% of the previous dose should be administered).
There are no limitations regarding the duration of carmustine therapy. If the tumor remains incurable or severe or intolerable adverse reactions occur, carmustine therapy should be discontinued.

Conditioning regimen prior to SCT
Carmustine is administered in combination with other chemotherapeutic agents in patients with hematological neoplasms prior to SCT at an intravenous dose of 300–600 mg/m².

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

Elderly patients
In general, dose selection for elderly patients should be cautious, usually starting at the lower end of the dosing range, considering the higher likelihood of decreased hepatic, renal, or cardiac function, and taking into account concomitant diseases or therapies with other medicinal products.
Since reduced renal function is more likely in elderly patients, careful attention should be paid to dose selection, renal function should be monitored, and the dose reduced as necessary.

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. Carmustine solution may only be administered from glass vials or polypropylene containers.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.