Carmustine Waymade

Package leaflet: Information for the user

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

Equivalent medicine
Please 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 questions, ask your doctor, pharmacist or nurse.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

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

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

Carmustina Waymade is a medicine containing carmustine as the active substance. Carmustine
belongs to a group of anticancer drugs known as nitrosoureas, which work by slowing down the
growth of tumour cells.
Carmustina Waymade is effective in the following malignant tumours as a single agent or in combination
with other antineoplastic agents and/or other therapeutic measures (radiotherapy, surgery):

• brain tumours (glioblastoma, brainstem gliomas, medulloblastoma, astrocytoma and ependymoma), brain metastases;
• secondary therapy in non-Hodgkin lymphoma and Hodgkin’s disease;
• as conditioning treatment prior to autologous haematopoietic progenitor cell transplantation (HPC) in malignant haematological disorders (Hodgkin’s disease / non-Hodgkin lymphoma).
• Multiple myeloma (a malignant tumour arising from the bone marrow) – in combination with glucocorticoids such as prednisone.

2. What you need to know before using Carmustina Waymade

Do not use Carmustina Waymade:

• if you are allergic to carmustine or to any of the other ingredients of this medicine (listed in section 6);
• if you have bone marrow suppression leading to reduced numbers of platelets, white blood cells (leucocytes), or red blood cells (erythrocytes), whether due to previous chemotherapy or other causes;
• if you have severe renal dysfunction;
• in children and adolescents;
• during pregnancy or breastfeeding.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before receiving Carmustina Waymade.
The main adverse effect of this medicine is delayed myelosuppression, which may manifest as fatigue, bleeding of the skin and mucous membranes, infections, and fever due to changes in blood counts. Therefore, your doctor will monitor your blood counts weekly for at least 6 weeks after each dose. Treatment cycles with Carmustina Waymade should not occur more frequently than every 6 weeks at recommended doses. Dosing will be confirmed based on blood counts.
Liver, lung, and kidney function will be assessed before treatment and monitored regularly during treatment.
Since the use of Carmustina Waymade may cause lung damage, a chest X-ray and pulmonary function tests will be performed before starting treatment (see also section “Possible side effects”).
High-dose Carmustina Waymade 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 related to therapy following treatment with chemotherapeutic agents.
Your doctor will inform you about the possibility of lung damage and allergic reactions, as well as their associated symptoms. If such symptoms occur, contact your doctor immediately (see section 4).

Children and adolescents
Carmustina Waymade must not be used in children and adolescents under 18 years of age.

Other medicines and Carmustina Waymade
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;
• dexamethasone, used as an immunosuppressive and anti-inflammatory agent;
• cimetidine, used for stomach problems such as indigestion;
• digoxin, used for heart rhythm disorders (arrhythmia);
• melphalan, an anticancer drug.

Carmustina Waymade and alcohol
The amount of alcohol contained in this medicine may alter the effect of other medicines.

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

Pregnancy and fertility
Carmustina Waymade must not be used during pregnancy because it may harm the unborn baby. Therefore, this medicine should normally 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 potential should use effective contraception to avoid becoming pregnant during treatment and for at least 6 months after treatment ends.
Male patients must use adequate contraception during treatment with Carmustina Waymade and for at least 6 months after treatment ends to prevent pregnancy in their partner.

Breastfeeding
You must not breastfeed during treatment and for up to 7 days after treatment. Risk to newborns/infants cannot be excluded.

Driving and using machines
Carmustina Waymade does not affect or affects negligibly the ability to drive or use machines. However, you should consult your doctor before driving or operating tools or machinery, as the alcohol content in this medicine may impair your ability to drive or use machines.

Carmustina Waymade contains anhydrous ethanol (alcohol)
This medicine contains 2.4 g of alcohol (ethanol) per vial, equivalent to 7.68 g at the maximum dose (320 mg). The amount of alcohol in the maximum dose (200 mg/m² in patients weighing 70 kg) corresponds to the amount found in 192 ml of beer or 76.8 ml of wine.
Since this medicine is usually administered slowly over 6 hours, the effects of alcohol may be reduced.
The alcohol content in this medicine may impair your ability to drive or use machinery, as alcohol can affect judgment and reaction speed.
If you have epilepsy or liver problems, talk to your doctor or pharmacist before using this medicine.
The alcohol in this medicine may alter the effects of other medicines. Talk to your doctor or pharmacist if you are taking other medicines.
If you are pregnant, talk to your doctor or pharmacist before using this medicine.
If you are alcohol-dependent, talk to your doctor or pharmacist before using this medicine.

3. How to use Carmustina Waymade

Carmustina Waymade will always be administered by a healthcare professional experienced in the use of antineoplastic medicinal products.
This medicine is intended for intravenous infusion.
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 Waymade as a single agent in previously untreated patients ranges between 150 and 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 Carmustina Waymade is used in combination with other antineoplastic agents.
Doses will be adjusted according to response to treatment.
The recommended dosage of Carmustina Waymade when administered in combination with other chemotherapeutic agents prior to hematopoietic progenitor cell transplantation is 300–600 mg/m² 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 Waymade is administered intravenously via infusion over a period of 1–2 hours, protected from light. 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.
If you use more Carmustina Waymade 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 everyone will experience them.
Immediately contact your doctor or nurse if you notice the following:
sudden wheezing, difficulty breathing, swelling of the eyelids, face or lips, skin rash or itching sensation (especially widespread over the body), and feeling faint. These may be signs of a severe allergic reaction.

Carmustine Waymade 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), which may increase the risk of infections if white blood cells (leukocytes) are reduced;
• ataxia (lack of voluntary muscular coordination);
• dizziness;
• headache;
• temporary reddening of the eyes, blurred vision due to retinal bleeding;
• hypotension (low blood pressure);
• phlebitis (vein inflammation) associated with pain, swelling, redness, and 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 or fatigue;
• nausea and severe vomiting;
• when used on the skin, skin inflammation (dermatitis);
• 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 and myelodysplasia (abnormal bone marrow development). Symptoms may include bleeding gums, bone pain, fever, frequent infections, frequent or severe nosebleeds, nodules due to swelling of lymph nodes in the neck and surrounding areas, armpits, abdomen or groin, pale skin, shortness of breath, weakness, fatigue or general loss of energy;
• anemia (reduction in the number of red blood cells in the blood);
• encephalopathy (brain disorder). Symptoms may include muscle weakness in a specific area, poor decision-making or concentration, involuntary contractions, tremors, difficulty speaking or swallowing, seizures;
• anorexia;
• constipation;
• diarrhea;
• inflammation of the mouth and lips;
• reversible liver toxicity during high-dose therapy, which may cause increased liver enzymes and bilirubin levels (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), in which very small liver veins (microscopic in size) become blocked. Symptoms may include: fluid accumulation in the abdomen, enlarged spleen, severe bleeding from the esophagus, yellowing of the skin and whites of the eyes;
• respiratory problems caused by interstitial fibrosis (with lower doses);
• kidney problems;
• gynecomastia (development of breast tissue in men);

Not known (frequency cannot be estimated from the available data):

• muscle pain;
• seizures (attacks), including status epilepticus;
• tissue damage due to leakage at the injection site;
• any signs of infection;
• infertility;
• carmustine has been shown to have a negative impact on fetal development;
• electrolyte disturbances (and electrolyte imbalances (low levels of potassium, magnesium and phosphate in the blood)).

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 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 Carmustine Waymade

This medicine will be stored by the doctor or healthcare personnel.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and the carton after "EXP.". The expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C). Do not freeze.
Store both vials (active and solvent) in the outer packaging to protect the medicine from light.

After reconstitution and dilution
After reconstitution, Carmustine Waymade is stable for 24 hours under refrigerated conditions (2°C - 8°C), stored in a glass container and protected from light.

The reconstituted solution is further diluted with 500 ml of sodium chloride 9 mg/ml (0.9%) solution or 500 ml of dextrose 50 mg/ml (5%) solution in a glass or polypropylene container. It must be stored at room temperature, protected from light, and used within 4 hours. These diluted solutions are also stable for 24 hours under refrigerated conditions (2°C - 8°C) and for a further 6 hours at room temperature and protected from light.

From a microbiological standpoint, unless the method of opening/reconstitution/dilution excludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the responsibility for the storage conditions and duration of use lies with the user.

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 Waymade contains
The active substance is carmustine.
Each vial of powder for concentrate for solution for infusion contains 100 mg of carmustine. After reconstitution and dilution, 1 ml of solution contains 3.3 mg of carmustine.

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

Description of the appearance of Carmustina Waymade and contents of the pack
A pack of Carmustina Waymade is a powder and solvent for concentrate for solution for infusion and contains one vial with 100 mg of Carmustine powder and one vial with 3 ml of solvent, anhydrous ethanol.
The powder is a pale yellow lyophilised flakes or cake supplied in an amber glass vial.
The solvent is a colourless transparent liquid supplied in a clear glass vial.
Pale yellow lyophilised flakes or cake for reconstitution.
Appearance of the solution: The reconstituted solution is a transparent, colourless to slightly yellowish solution.
Powder: 30 ml type I amber glass vial with a 20 mm grey bromobutyl rubber stopper and a blue opaque flip-off seal.
Solvent: 5 ml type I glass vial with a 13 mm grey chlorobutyl rubber stopper and sealed with a blue opaque flip-off seal.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Waymade B.V.
Herikerbergweg 88,
1101CM Amsterdam,
The Netherlands

Manufacturer
Drehm Pharma GmbH
Grünbergstraße 15/3/3,
Wien, 1120, Austria
Waymade B.V.
Herikerbergweg 88,
1101CM Amsterdam,
The Netherlands

The following information is intended for healthcare professionals only:

A brief description of the preparation and/or handling, incompatibilities,
dosage of the medicinal product, overdose or control measures and laboratory investigations
is provided, based on the current summary of product characteristics.
Carmustina Waymade powder for concentrate for solution for infusion contains no preservatives and
is not a multi-dose vial. Reconstitution and further dilutions must be performed under aseptic
conditions.
By following the product storage instructions, degradation of the intact vial can be prevented until
the expiry date indicated on the packaging.
The lyophilized product contains no preservatives and is for single use only. The lyophilized powder
may appear as flakes or a clumped mass. The presence of an oily film may indicate melting of the
medicinal product. In such cases, the product must not be used due to the risk of temperature excursions exceeding 30°C.
The medicinal product must not be used any further. If there is uncertainty regarding proper cooling of
the product, each individual vial in 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:
Dissolve 100 mg of Carmustina Waymade powder for concentrate for solution for infusion with 3 ml of
refrigerated sterile anhydrous ethanol provided in the package. Carmustine must be completely
dissolved in anhydrous ethanol before sterile water for injections is added. Then, under aseptic
conditions, add 27 ml of sterile water for injections to the alcoholic solution. The resulting 30 ml stock
solution should be mixed thoroughly. Reconstitution, when performed as recommended, results in a
clear, colourless to slightly yellow solution.
Before use, inspect reconstituted vials for crystal formation. If crystals are observed, they may be
redissolved by warming the vial to room temperature with agitation. After reconstitution, Carmustina
Waymade is stable for 24 hours under refrigeration (2°C - 8°C), when stored in a glass container and
protected from light.
The reconstituted solution must be further diluted with either 500 ml of sodium chloride 9 mg/ml (0.9%)
solution or 500 ml of dextrose 50 mg/ml (5%) solution. The reconstituted and diluted solution (i.e., the
ready-to-use solution) must be mixed for at least 10 seconds prior to administration. The ready-to-use
solution should be stored at room temperature in a glass or polypropylene container, protected from
light, and used within 4 hours. These solutions are also stable for 24 hours under refrigeration (2°C -
8°C) and for an additional 6 hours at room temperature protected from light.
pH and osmolarity of ready-to-use infusion solutions:
The pH of ready-to-use infusion solutions ranges between 4.0 and 6.8.
Method of administration
The reconstituted and diluted solution (i.e., the ready-to-use solution) must be administered by
intravenous infusion and should be infused over a period of one to two hours. The infusion must be
administered using a PVC-free infusion set or containers made of PE. During administration, the
container must be made exclusively of glass or polypropylene. Ensure that polypropylene containers
used are free of PVC and DEHP. Carmustine has a low melting point (30.5°C - 32.0°C or 86.9°F -
89.6°F). Exposure of this drug to this temperature or higher will cause liquefaction of the drug, which
will appear as an oily film on the vials. This is a sign of decomposition and the vials must be discarded.
Infusion of Carmustina Waymade over shorter intervals may cause severe pain and burning at the
injection site. The injection site must be monitored during administration.
Appropriate guidelines for the handling and safe disposal of cytotoxic anticancer agents must be
followed.
Dosage and laboratory investigations
Initial doses
The recommended dose of Carmustina Waymade as a single agent in previously untreated patients is
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.
When Carmustina Waymade 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
haematological profile as indicated below.
Monitoring and subsequent doses
A new cycle of Carmustina Waymade must not be administered until circulating blood elements have
returned to acceptable levels (platelets above 100,000/mm³, leukocytes above 4,000/mm³), which
usually occurs within six weeks. Blood values must be monitored frequently, and repeated cycles must
not be administered earlier than six weeks apart due to delayed haematological toxicity.
Subsequent doses following the initial dose must be adjusted based on the patient’s haematological
response to the previous dose, whether used as monotherapy or in combination with other
myelosuppressive medicinal products. The table below is provided as a guide for dose adjustment:

In cases where the nadir following the initial dose does not fall within the same line for leukocytes and platelets (e.g., leukocytes >4,000 and platelets <25,000), the lower percentage of the previous dose must be used (e.g., with platelets <25,000, a maximum of 50% of the previous dose should be administered).
There are no limitations regarding the duration of treatment with carmustine. However, if the tumor remains incurable or severe or intolerable adverse reactions occur, carmustine therapy must be discontinued.
Conditioning treatment prior to HPCT
Carmustine is administered intravenously in combination with other chemotherapeutic agents in patients with malignant hematological disorders prior to HPCT at a dosage of 300–600 mg/m².
Special populations
Paediatric population
For safety reasons, carmustine must not be used in individuals under 18 years of age.
Elderly
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, as well as concomitant diseases or therapies with other medicinal products. Since reduced renal function is more likely in elderly patients, careful attention must be paid when selecting the dosage, monitoring glomerular filtration rate, and adjusting the dose accordingly.
Renal impairment
For patients with renal impairment, the dose of Carmustina Waymade must be reduced if there is a reduction in glomerular filtration rate.
Compatibility/Incompatibility with containers
The intravenous solution is unstable in polyvinyl chloride (PVC) containers. Do not use PVC containers. Carmustine solution may only be administered from glass or polypropylene containers. Ensure that polypropylene containers used are free of PVC and DEHP.