BICNU 100 mg Proszek I Rozpuszczalnik Do Koncentratu Do Roztworu Infuzyjnego

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1. BICNU 100 mg powder and solvent for concentrate for solution for infusion
   1. What is BICNU and what is it used for
   2. What you need to know before using BICNU
   3. How to use BICNU
   4. Possible side effects
   5. How to store BICNU
   6. Contents of the pack and other information

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

carmustine

Read this leaflet carefully before you use this medicine as 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.

consult your doctor or nurse. See section 4.

Contents of this leaflet:

• 1. What BICNU is and what it is used for
• 2. What you need to know before you use 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 is BICNU and what is it used for

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

• brain tumors glioblastoma, medulloblastoma, astrocytoma and metastatic brain tumors;
• multiple myeloma (malignant tumor that develops from the bone marrow);
• Hodgkin's disease (lymphoid tumor);
• non-Hodgkin lymphomas (lymphoid tumor);
• tumors of the gastrointestinal tract or digestive system;
• malignant melanoma (skin tumor);

Carmustine is also used as conditioning therapy before autologous 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 using BICNU

Do not use BICNU:

• if you are allergic to carmustine or any of the other ingredients of this medicine (listed in section 6).
• BICNU 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.
• In case of severe impairment of renal function.
• If the patient’s age is less than 18 years.
• if you are breastfeeding

Warnings and precautions
Consult your doctor, pharmacist or nurse before taking BICNU.
Because the main side effect of this medicine is delayed by suppression of the bone
marrow, the doctor will monitor the blood count weekly for at least 6 weeks after the
administration of a dose. At the recommended dosages, BICNU administrations would not
occur with a frequency of less than 6 weeks. The dosage will be confirmed with a complete blood count.
Immediately inform your doctor if you experience any of the following symptoms:

• signs of infection (fever, persistent sore throat);
• increased tendency to bruising/bleeding;
• unusual fatigue;
• rapid heartbeat/palpitations.

Your liver and kidney function will be checked before treatment and monitored regularly
during treatment.
During therapy, gastrointestinalsymptoms in the form of vomiting and nausea may occur.
Because the use of BICNU can cause lung damage, a chest X-ray will be performed and lung
function tests will be carried out before starting treatment (see also the section “Possible side effects”).
High-dose carmustine treatment (up to 600 mg/m²) is administered only in
combination with subsequent stem cell transplantation. Such a high dose may increase the
frequency or severity of toxicity to the lung, kidney, 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 therapy with
chemotherapeutic agents.
Patients who suffer from multiple conditions simultaneously and present a more severe disease state are at greater risk of adverse events. This is particularly important for elderly patients.
The doctor will inform you about the possibility of lung damage and allergic reactions as well as their related
symptoms. If such symptoms occur, contact your doctor immediately (see section 4).
Women and men of childbearing potential must use an effective contraceptive method during treatment and
for at least 6 months after treatment (see also the section “Pregnancy, breastfeeding and fertility”).

Other medicines and BICNU
Tell your doctor or pharmacist if you are taking, have recently taken or might take any
other medicines, including those available without a prescription, such as:

• Phenytoin, used for 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 for the treatment of various types of tumors.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you are pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy and fertility
BICNU must not be used during pregnancy because it can cause harm to the fetus. This
medicine should therefore normally not be administered to pregnant women. If used in
pregnancy, the patient should 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
potential are advised to use effective contraceptive methods to avoid becoming pregnant
during and for at least 6 months after the treatment period with this medicine.
Men must use adequate contraceptive methods during treatment with
BICNU and for at least 6 months after the end of treatment to avoid pregnancy of their partner. The
fertility of male patients may be affected by treatment with BICNU. Before
starting treatment with BICNU, adequate counseling regarding
fertility/family planning should be requested.
Breastfeeding
Do not breastfeed during the period of taking the medicine and up to 7 days after treatment. The
risk to newborns/infants cannot be excluded.

Driving and operating machinery
The effect of this medicine on the ability to drive and operate machinery is unknown. Ask
your doctor for information before driving or using tools or machinery because the amount of alcohol
contained in this medicine may reduce the ability to drive or operate machinery.

BICNU contains ethanol (ethyl alcohol)
This medicine contains 0.57% vol of ethanol (alcohol), i.e. up to 7.68 g per dose, equivalent to 11.32 ml
of beer or 4.72 ml of wine per dose.
Harmful for those suffering from alcoholism. To be considered in high-risk groups such as patients with
liver disease or epilepsy.
The amount of alcohol in this medicine may alter the effects of other medicines.

3. How to use BICNU

BICNU will always be administered by a healthcare professional experienced in the use of
anticancer medicines.

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 patients not previously treated is between 150 and 200 mg/m intravenously
every 6 weeks. It can be administered as a single dose or divided into daily infusions of 75-
100 mg/m over two consecutive days. The dosage also varies depending on the possible use of BICNU in
combination with other anticancer drugs.
The doses are adjusted based on the response to treatment.
The recommended dose of carmustine administered in combination with other anticancer substances
before autologous stem cell transplantation is 300 - 600 mg/m intravenously.
The blood count is monitored frequently to avoid bone marrow toxicity and the dose is
adjusted, if necessary.

Route of administration
After reconstitution and dilution, BICNU is administered intravenously via infusion
for a period of 1-2 hours. The duration of the infusion 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 established by the doctor and may vary for each patient.

Use in children and adolescents (age < 18 years)
BICNU cannot be used in children and adolescents due to the high risk of pulmonary
toxicity.

Use in the elderly
BICNU can be used with caution in elderly patients. In such cases, renal function should be
carefully monitored.

If you use more BICNU than you should
Since a doctor or nurse will administer this medicine to you, it is unlikely that you will be
given 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 doubts about 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 everyone gets them.
manifest them.

Immediately inform your doctor or nurse if you notice the following:
sudden wheezing, difficulty breathing, swelling of the eyelids, face or lips,
skin rash or feeling of itching (especially all over the body) and feeling of fainting.
These may be signs of a serious allergic reaction.

BICNU may cause the following side effects:
Very common(may affect more than 1 in 10 people)

• delayed myelosuppression (decrease in blood cells in the bone marrow);
• ataxia (absence 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, tenderness;
• respiratory disorders (lung problems) with breathing difficulties. This medicine can cause severe (even fatal) lung damage that can develop years after treatment. See 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; starting 2-4 hours after administration and lasting 4-6 hours;
• if used on the skin, skin inflammation (dermatitis);
• Accidental contact with the skin can 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 swollen lymph nodes in the neck and around the neck, armpits, abdomen or groin, pale skin, shortness of breath, weakness, fatigue or general decrease in energy;
• anemia (decrease in the amount of red blood cells in the blood);
• encephalopathies (brain disorder) in high-dose therapy; Symptoms may include muscle weakness; in a specific area, impaired ability to make decisions or concentrate, involuntary contraction, tremor, difficulty speaking or swallowing, seizures;
• loss of appetite (anorexia);
• constipation;
• diarrhea;
• inflammation of the mouth and lips;
• reversible liver toxicity in high-dose therapy, delayed up to 60 days after administration, which can cause an increase in liver enzymes and bilirubin (shown by blood tests);
• alopecia (hair loss);
• skin redness;
• reactions at the injection site;

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

• veno-occlusive disease (progressive obstruction of the veins) in high-dose therapy, in which very small veins in the liver become blocked. The following symptoms are possible: accumulation of fluid in the abdomen, enlargement of the spleen, severe bleeding from the esophagus, yellowing of the skin and whites of the eyes;
• respiratory problems due to a type of lung disease in which the lung tissue is scarred (interstitial fibrosis) (with lower doses); symptoms may include dry cough, shortness of breath, fatigue, weight loss
• kidney problems;
• gynecomastia (development of breasts 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)

• inflammatory process causing the formation of a blood clot and blockage of one or more veins, usually in the legs. The affected vein may be near the surface of the skin or deep within a muscle (thrombophlebitis). Not known(frequency cannot be estimated based on available data)
• muscle pain;
• secondary tumors (malignant tumors caused by radiotherapy or chemotherapy); seizures (attacks) including status epilepticus;
• tissue damage due to leakage at the injection site;
• infertility;
• Impairment of embryo/fetal development in pregnant women;
• any sign of infection;
• fast heartbeat, chest pain;
• allergic reaction;
• electrolyte imbalances (low levels of potassium, magnesium, phosphate in the blood);
• abdominal pain (neutropenic enterocolitis);
• decreased renal volume, progressive accumulation of certain metabolic products in the blood (azotemia) and renal failure have been observed after high cumulative doses and after prolonged treatment with BICNU and other nitrosoureas. Kidney damage has also been observed after lower total doses;

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, tell your
doctor or pharmacist. You can also report side effects directly through:
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 this 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 which is 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 doctor or designated healthcare professional.
Store the vials in the outer packaging to protect them from light. The reconstituted mother liquor
further diluted with 500 ml of sodium chloride injectable solution or 5% glucose injectable solution, in glass or polypropylene containers, is physically and chemically stable for 4 hours at 15
°C - 25 °C when protected from light. These solutions are also stable for 24 hours in a refrigerator (2 °C -
8 °C) and for another 3 hours at 15 °C - 25 °C, when protected from light.
The solution must be protected from light until the end of administration.
Do not dispose of any medicine in waste water or household waste. Ask your pharmacist how to
dispose of medicines you no longer use: in this way you will help protect the environment.

6. Contents of the pack and other information

What BICNU contains
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 with the provided solvent and further dilution with 27 ml of sterile water, one ml of
solution contains 3.3 mg of carmustine.
The other excipients are:

• powder: no excipients.
• solvent: anhydrous ethanol.

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

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Tillomed Italia Srl, viale G. Richard 1, Torre A, 20143 Milan, Italy
Manufacturer
MIAS Pharma Limited
Suite 2, Stafford House, Strand Road
Portmarnock, Co. Dublin
Ireland

This medicinal product is authorised in the Member States of the European Economic Area with the following
denominations:
Belgium: Carmustine Tillomed 100 mg powder and solvent for solution to
dilute for infusion
Czech Republic: Carmustine Zentiva
Denmark: Carmustin Macure
Finland: Carmustine Macure 100 mg dry powder and solvent
for intermediate concentrate for infusion solution
Greece: Carmustine/Tillomed 100 mg powder and solvent for concentrate
for solution for infusion
Hungary: Carmustine Zentiva 100 mg powder and solvent for solution for infusion
Ireland: Carmustine 100 mg powder and solvent for concentrate for solution
for infusion
Italy: BICNU
Lithuania: Carmustine Zentiva 100 mg powder and solvent for concentrate
for infusion solution
Netherlands: Carmustine Tillomed 100 mg powder and solvent for
concentrate for solution for infusion
Norway: Carmustine Macure
Poland: Carmustine Zentiva
Portugal: Carmustine Tillomed 100 mg powder and solvent for concentrate for
solution for perfusion
Slovakia: Carmustine Zentiva 100 mg powder
and solvent for infusion concentrate
Slovenia: Karmustin Tillomed 100 mg powder and vehicle for solution for
infusion
Sweden: Carmustine Macure

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The following information is intended exclusively for healthcare professionals.

A brief description of preparation and/or handling, interactions,

dosage of the medicinal product, overdose or control measures and laboratory investigations based

on the current summary of product characteristics is provided.
The lyophilised dosage form does not contain preservatives and is not intended as a multi-dose vial. The medicinal product is for single use only. It must be handled with caution; avoid contact of the
medicinal product with skin. Reconstitution and further dilutions must be carried out under aseptic conditions.
Following the storage instructions of the product, deterioration of the intact vial can be avoided until the expiry date indicated on the pack.
Storage of carmustine at 27 °C or higher 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 this case, the medicinal
product must no longer be used. If you are unsure about adequate cooling of the product, you should
immediately check each vial contained in the pack. To perform this check,
expose the vial to intense light.
Prepare the reconstitution and dilution of the powder for concentrate for solution for infusion of each
vial as follows
Dissolve carmustine (100 mg of powder) with 3 ml of the provided sterile ethanol solvent in the
primary packaging (brown glass vial). Carmustine must dissolve completely
in ethanol before sterile water for injection is added. Dissolution of the powder may
take up to 2 minutes. Subsequently, aseptically add 27 ml of sterile water for injection
to the alcoholic solution. The 30 ml mother liquor must be mixed thoroughly.
Each ml of the reconstituted solution will contain 3.3 mg of carmustine in 10% ethanol and will have a pH
between 4.0 and 6.8.
Reconstitution, as indicated, results in a yellowish solution.
The 30 ml mother liquor must be immediately diluted by adding the 30 ml mother liquor
to 500 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or to 500 ml of glucose 5% solution
for injection. The diluted 530 ml solution (i.e. the solution ready for use) must be
mixed for at least 10 seconds before administration.
Route of administration:
For intravenous use after reconstitution and dilution.
The reconstituted and diluted solution must be administered immediately as an intravenous infusion
over 1-2 hours, protected from light. The duration of the infusion should not be less than one hour, in order
to avoid the occurrence of burning and pain in the injection area. The injection area must be monitored during
administration. Administration must be completed within 3 hours of reconstitution/dilution
of the medicinal product.
A PVC-free PE infusion set must be used for administration of the infusion.
Guidelines for handling and safe disposal of antineoplastic agents must be followed.
Dosage and laboratory investigations

Initial doses
The recommended dose of BICNU as a single agent in previously untreated patients is between
150 and 200 mg/m intravenously every 6 weeks. This dose should be given as a single
administration or divided into daily infusions of 75-100 mg/m over two consecutive days.
When BICNU is used in combination with other myelosuppressive medicinal products or in patients with
depleted bone marrow reserve, the doses must be adjusted to the patient's haematological profile
as indicated below.

Monitoring and subsequent doses
A new cycle of BICNU should not be administered until the circulating blood elements have
returned to acceptable levels (platelets above 100,000/mm , leukocytes above 4,000/mm ),
which usually occurs within six weeks. Blood values must be monitored frequently
and repeated cycles must not be administered before six weeks due to late haematological toxicity.
Subsequent doses to the initial dose must be adjusted based on the patient's haematological response
to the previous dose, both in monotherapy and in combination therapy with other myelosuppressive
medicinal products. The table below is provided as a guide for dosage adjustment.
Table 1

In cases where the nadir after the initial dose does not fall within the same row for leukocytes and platelets (e.g.
leukocytes >4,000 and platelets <25,000), the value with the lowest percentage of the previous dose must be used (e.g. with platelets <25,000, a maximum of 50% of the previous dose must be administered).
Conditioning treatment prior to SCT
Carmustine is administered intravenously in combination with other chemotherapeutic agents in
patients with malignant haematological diseases prior to SCT at a dosage of 300 - 600 mg/m
Special populations

Patients with impaired renal function
In patients with impaired renal function, the dose of carmustine must be reduced based on
glomerular filtration rate.

Elderly
In general, dose selection for an elderly patient should be cautious, usually starting with the
lower end of the range, considering the greater frequency of decreased hepatic, renal or cardiac function and taking into account any concomitant diseases or therapies with other
medicinal products.
As elderly patients are more likely to have reduced renal function, care should be taken in dose selection, renal function should be monitored and the dose should be reduced if necessary.

Children and adolescents
Carmustine is contraindicated in children and adolescents under the age of 18 (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
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.