BICNU

Package leaflet: Information for the user

BICNU 100 mg powder and solvent for concentrate for solution for infusion

Carmustine
Equivalent medicine
Please read all of this leaflet carefully before you are given 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.
• If you get any side effects, talk to your doctor or nurse. This includes any side effects not listed in this leaflet. See section 4.
  Contents of this leaflet:
  1. What BICNU is and what it is used for
  2. What you need to know before being given BICNU
  3. How to use BICNU
  4. Possible side effects
  5. How to store BICNU
  6. Contents of the pack and other information

1. What BICNU is and what it is used for

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

• brain tumours, glioblastoma, medulloblastoma, astrocytoma, and metastatic brain tumours;
• multiple myeloma (a malignant tumour arising from the bone marrow);
• Hodgkin’s disease (a lymphoid tumour);
• non-Hodgkin’s lymphomas (lymphoid tumours);
• tumours of the gastrointestinal tract or digestive system;
• malignant melanoma (a skin tumour);

Carmustine is also used as conditioning therapy prior to autologous blood stem cell transplantation in malignant haematological disorders of the lymphatic system (Hodgkin’s lymphoma and non-Hodgkin’s lymphoma).

2. What you need to know before using BICNU

Do not use BICNU:

• if you are allergic to carmustine or to any of the other ingredients of this medicine (listed in section 6).
• BICNU must not be used in patients with reduced platelet (thrombocytes), white blood cell (leucocytes), or red blood cell (erythrocytes) counts, whether due to chemotherapy or other causes.
• in case of 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 taking BICNU.
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 doses, BICNU administrations should not occur more frequently than every 6 weeks. Dosing will be confirmed by complete blood count.
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 heartbeat/palpitations.

Your liver and kidney function will be checked before treatment and monitored regularly during treatment.
Gastrointestinal symptoms such as vomiting and nausea may occur during therapy.
Since the use of BICNU 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 administered only in combination with subsequent stem cell transplantation. Such high doses may increase the frequency or severity of toxicity affecting the lungs, kidneys, liver, heart, and gastrointestinal tract, as well as infections and electrolyte imbalances (low levels of potassium, magnesium, and phosphate in the blood).
Stomach pain (neutropenic enterocolitis) may occur as an adverse event during chemotherapy.
Patients with multiple concurrent medical conditions and more severe disease states 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).
Women and men 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 BICNU
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those not requiring a prescription, 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, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy and fertility
BICNU must not be used during pregnancy because it may cause harm to the fetus. Therefore, this medicine should normally not be administered to pregnant women. If used during pregnancy, the patient must be aware of the potential risks to the fetus. Women of childbearing potential are advised to avoid pregnancy during treatment with this medicine. Women of childbearing age are advised to use effective contraception during and for at least 6 months after treatment with this medicine.
Male patients must use adequate contraceptive methods during treatment with BICNU and for at least 6 months after the end of treatment to prevent their partner from becoming pregnant. Male fertility may be affected by treatment with BICNU. Adequate counseling regarding fertility/family planning should be obtained before starting treatment with BICNU.
Breastfeeding
Do not breastfeed during treatment with this medicine and for up to 7 days after treatment. Risk to newborns/infants cannot be excluded.

Driving and use of machines
The effect of this medicine on the ability to drive or operate machinery is unknown. Ask your doctor for advice before driving or using tools or machines, as dizziness is a reported adverse reaction with this medicine that may impair your ability to drive or use machinery.

BICNU contains propylene glycol
The propylene glycol in this medicine may produce effects similar to those of alcohol consumption and may increase the likelihood of side effects.
Do not use this medicine in children under 5 years of age.
Use this medicine only if recommended by your doctor. Your doctor may carry out additional monitoring during treatment.

3. How to use BICNU

BICNU will always be administered by a healthcare professional experienced in the use of antineoplastic agents.
Adults
The dosage depends on the medical condition, body size, and response to treatment. It is generally administered at least every 6 weeks. The recommended dose of BICNU as a single agent in previously untreated patients ranges from 150 to 200 mg/m² administered intravenously every 6 weeks. It may be given 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 BICNU is used in combination with other antineoplastic drugs.
Doses are adjusted according to the 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 intravenously.
Blood counts are monitored frequently to prevent bone marrow toxicity, and the dose is adjusted if necessary.
Route of administration
After reconstitution and dilution, BICNU 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 monitored 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)
BICNU must not be used in children and adolescents due to the high risk of pulmonary toxicity.
Use in the elderly
BICNU may be used with caution in elderly patients. In such cases, renal function should be closely monitored.
If you use more BICNU 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 concerns regarding the amount of medicine administered.
If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

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

BICNU 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 coordination of muscle movements);
• dizziness;
• headache;
• temporary redness of the eyes, blurred vision due to retinal bleeding, inflammation of the iris and optic nerve;
• hypotension (low blood pressure) with high-dose therapy;
• phlebitis (inflammation of the veins) associated with pain, swelling, redness, and tenderness;
• respiratory disorders (lung problems) with breathing difficulties. This medicine can 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 or fatigue;
• severe nausea and vomiting; onset within 2–4 hours after administration, lasting 4–6 hours;
• skin inflammation (dermatitis) when applied to the skin;
• accidental contact with the skin 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), bone marrow dysplasia (abnormal development of the bone marrow) after prolonged use. The following symptoms may occur: bleeding gums, bone pain, fever, frequent infections, frequent or severe nosebleeds, lumps due to swelling of lymph nodes in the neck and around the neck, armpits, abdomen or groin, pale skin, shortness of breath, weakness, fatigue or general lack of energy;
• anemia (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;
• diarrhea;
• inflammation of the mouth and lips;
• reversible liver toxicity with high-dose therapy, delayed up to 60 days after administration, which may cause increased liver enzymes and bilirubin (detected in 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 liver veins become blocked. Possible symptoms include fluid accumulation in the abdomen, enlarged spleen, severe bleeding from the esophagus, yellowing of the skin and whites of the eyes (jaundice);
• breathing problems due to a type of lung disease characterized by scarring of lung tissue (interstitial fibrosis) (with lower doses); symptoms may include dry cough, shortness of breath, fatigue, weight loss;
• kidney problems;
• gynecomastia (breast enlargement in males);
• gastrointestinal bleeding;
• 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 tumors (malignant tumors caused by radiotherapy or chemotherapy);
• seizures, 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 imbalances (low levels of potassium, magnesium, phosphate in the blood);
• 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 BICNU and other nitrosoureas. Kidney damage has also been reported 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 or pharmacist. You can also report side effects directly via:
the national reporting system at
https://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 BICNU

Keep the medicine out of the sight and reach of children.
Store and transport in a refrigerator (2°C – 8°C).
Do not use the medicine after the expiry date stated on the vial and the carton after “EXP.”.
The expiry date refers to the last day of that month.
This medicine will be stored by the physician or healthcare personnel.
After reconstitution as recommended, injectable carmustine is stable for 480 hours when stored in a refrigerator (2°C – 8°C) and for 24 hours at room temperature (25°C ± 2°C) in glass containers. Before use, examine the vials after reconstitution to check for crystal formation. If crystals are observed, they can be dissolved by warming and gently agitating the vial at room temperature.
From a microbiological standpoint, the reconstituted solution should be used immediately.
Keep the vials in their outer packaging to protect them from light. The reconstituted solution must be further diluted to 500 ml with either 0.9% sodium chloride injection solution or 5% dextrose injection solution, in glass or polypropylene containers, and is physically and chemically stable for 8 hours at 25°C ± 2°C when protected from light. These diluted solutions are also stable for up to 48 hours in a refrigerator (2°C – 8°C) and for an additional 6 hours at 25°C ± 2°C, protected from light.
The solution must be protected from light until the end of administration.
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 BICNU contains
The active substance 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 propylene glycol.
After reconstitution with the provided solvent, one ml of solution contains 33.3 mg of carmustine.
The other excipients are:

• powder: no excipients.
• solvent: glycol

Description of the appearance of BICNU and the contents of the pack
BICNU is a powder and solvent for concentrate for solution for infusion.
The powder is pale yellow in colour and supplied in a type I amber glass vial (30 ml) closed with a dark grey bromobutyl rubber stopper and sealed with a polypropylene cap.
The solvent is a colourless, transparent, viscous liquid supplied in a clear type I glass vial (5 ml) closed with a grey bromobutyl rubber stopper and sealed with a polypropylene cap.
One pack contains one vial of 100 mg powder and one vial containing 3 ml of solvent.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Tillomed Italia Srl, viale G. Richard 1, Torre A, 20143 Milano, Italia
Manufacturer
SGS Pharma Magyarorszag Kft.
Derkovits Gyula Utca 53,
Budapest XIX, 1193,
Hungary
Tillomed Malta Limited,
Malta Life Sciences Park,
LS2.01.06 Industrial Estate,
San Gwann, SGN 3000, Malta

This medicinal product is authorised in the European Economic Area countries under the following names:
Belgium: Carmustine Tillomed 100 mg poudre et solvant pour solution à diluer pour perfusion
Czech Republic: Carmustine Zentiva
Denmark: Carmustin Macure
Finland: Carmustine Macure 100 mg kuiva-aine ja liuotin välikonsentraatiksi infuusionestettä varten, liuos
Greece: Carmustine/Tillomed 100 mg κόνις και διαλύτης για συμπύκνωμα για διάλυμα προς έγχυση
Hungary: Carmustine Tillomed 100 mg por és oldószer oldatos infúzióhoz való koncentrátumhoz
Ireland: Carmustine 100 mg powder and solvent for concentrate for solution for infusion
Italy: BICNU
Lithuania: Carmustine Zentiva 100 mg milteliai ir tirpiklis koncentratui
Netherlands: Carmustine Glenmark 100 mg poeder en oplosmiddel voor concentraat voor oplossing voor infusie
Norway: Carmustine Macure
Poland: Carmustine Zentiva
Portugal: Carmustine Tillomed 100 mg pó e solvente para concentrado para solução para perfusão
Slovakia: Carmustine Zentiva a rozpúšťadlo na infúzny koncentrát
Slovenia: Karmustin Tillomed 100 mg prašek in vehikel za raztopino za infundiranje
Sweden: Carmustine Macure

The following information is intended for healthcare professionals only.

A brief description of the preparation and/or handling, interactions, dosage, overdose, or monitoring measures and laboratory investigations is provided, based on the current Summary of Product Characteristics.
The lyophilized dosage formulation contains no preservatives and is not intended for use as a multiple-dose vial. The medicinal product is for single use only. It must be handled with care; avoid skin contact with the medicinal product. Reconstitution and further dilutions must be performed under aseptic conditions.
By following the product storage instructions, degradation of the intact vial can be prevented up to the expiry date indicated on the packaging.
Storage of carmustine at 27°C or higher temperatures may lead to liquefaction of the substance, as carmustine has a low melting point (from 30.5°C to 32°C). An indication 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 any doubt about proper cooling of the product, each vial within the package must be checked immediately. To perform this check, expose the vial to bright light.

Prepare the reconstitution and dilution of the powder for concentrate for infusion solution from each vial as follows:
Dissolve carmustine (100 mg of powder) with 3 mL of the provided sterile diluent (propylene glycol for injection) until a clear solution is obtained. Use the vial of propylene glycol for reconstitution only after it has reached room temperature, and use a larger gauge needle (smaller than 22 gauge) to withdraw the diluent from the vial. A detailed guide for reconstitution is provided below.

Step 1: Remove both vials from the packaging and allow them to reach room temperature (at least 10 minutes)

Step 2: Aseptically withdraw 3 mL of sterile diluent from the diluent vial using a sterile syringe. Ensure that exactly 3 mL of sterile diluent are withdrawn into the syringe.

Step 3: Inject the sterile diluent into the vial containing 100 mg of carmustine and allow the product to soak for at least 10 minutes.

Step 4: Gently swirl the vial (using circular motions) continuously for at least 60 seconds until a clear solution is obtained.

Step 5: Hold the reconstituted vial in an inverted position for 5 minutes.

Step 6: Aseptically withdraw the reconstituted solution only while the vial is in an inverted position, and prepare the infusion solution after further dilution.

Each mL of the reconstituted concentrate solution will contain 33.3 mg of carmustine.
Reconstitution as directed results in a yellowish solution.
The reconstituted solution must be further diluted to 500 mL with either 0.9% sodium chloride injection solution or 5% dextrose injection solution. The resulting solution contains a final concentration of 0.2 mg/mL of carmustine and must be protected from light.
Before use, examine the vials after reconstitution to check for crystal formation. If crystals are observed, they may be dissolved by warming and gently agitating the vial at room temperature. Reconstituted vials must be visually inspected for the presence of particulate matter and discoloration prior to administration.

Route of administration:
For intravenous use after reconstitution and dilution.
The reconstituted and diluted solution must be administered immediately as an intravenous infusion within 1–2 hours, protected from light. The infusion duration must not be less than one hour to avoid the occurrence of burning and pain at the injection site. The injection site must be monitored during administration. Administration must be completed within 3 hours of reconstitution/dilution of the medicinal product.
A polyethylene (PE) infusion set free of PVC must be used for the administration of the infusion.
Standard guidelines for the safe handling and disposal of antineoplastic agents must be followed.

Dosage and laboratory monitoring
Initial doses
The recommended dose of BICNU as a single agent in previously untreated patients is 150–200 mg/m² administered intravenously every 6 weeks. This dose may be given as a single administration or divided into daily infusions of 75–100 mg/m² on two consecutive days.
When BICNU 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 outlined below.

Monitoring and subsequent doses
A new cycle of BICNU must not be administered until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm³, white blood cells above 4,000/mm³), which typically occurs within six weeks. Blood values 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 must be adjusted according to the patient's hematological response to the previous dose, whether used as monotherapy or in combination with other myelosuppressive agents. The table below 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 dose percentage from the previous dose should be used
(e.g., with platelets <25,000, at most 50% of the previous dose should be administered).

Preparative treatment regimen prior to SCT
Carmustine is administered intravenously in combination with other chemotherapeutic agents in patients with malignant hematological disorders prior to SCT at a dosage of 300–600 mg/m².

Special populations

Patients with impaired renal function
In patients with impaired renal function, the dose of carmustine should be reduced according to 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, taking into account the higher prevalence of decreased hepatic, renal, or cardiac function, as well as concomitant diseases or therapies with other medicinal products.

Since elderly patients are more likely to have reduced renal function, careful attention should be paid to dose selection, renal function should be monitored, and dose reduction should be considered 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 polyvinylchloride (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.