Carmustine waymade

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Carmustine Waymade, 100 mg, powder and solvent for preparation of concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of powder for concentrate for solution for infusion contains 100 mg of carmustine.
After reconstitution and dilution (see section 6.6), 1 mL of solution contains 3.3 mg of carmustine.
Excipient with known effect
Each vial of solvent contains 3 mL of anhydrous ethanol (equivalent to 2.37 g).
For a complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for preparation of a concentrate for infusion solution.
Powder: lyophilized pale yellow flakes or solidified mass.
Solvent: colorless, clear liquid.
The pH of ready-to-use infusion solutions ranges from 4.0 to 6.8.

4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Carmustine is effective in the treatment of the following malignant neoplasms used as monotherapy or in combination with other antineoplastic agents or other therapeutic modalities (radiotherapy, surgery):

• Brain tumors (multiform glioblastoma, brain stem gliomas, embryonal carcinoma, astrocytoma, and ependymoma) and brain metastases
• Second-line treatment of non-Hodgkin's lymphoma and Hodgkin's disease
• As conditioning treatment prior to autologous hematopoietic stem cell transplantation in malignant hematological diseases (Hodgkin's disease/non-Hodgkin's lymphoma)
• Multiple myeloma – in combination with a glucocorticosteroid such as prednisone.

4.2. Dosage and method of administration

Carmustine Waymade must be administered only by specialists experienced in chemotherapy and under appropriate medical supervision.

Dosage:

Initial doses
The recommended dose of Carmustine Waymade for previously untreated patients receiving monotherapy is 150 to 200 mg/m² administered intravenously every 6 weeks. The drug may be given as a single dose or divided into daily infusions of 75 to 100 mg/m² on two consecutive days.

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

Monitoring and subsequent doses
The next course of treatment with Carmustine Waymade may be administered only after blood counts have returned to acceptable levels (platelet count above 100,000/mm³, white blood cell count above 4,000/mm³), which usually occurs within six weeks. Blood counts should be monitored frequently, and treatment should not be repeated before six weeks have elapsed due to the risk of delayed hematological toxicity.

Following the initial dose, subsequent doses should be adjusted according to the patient's hematological response to the previous dose, both in monotherapy and in combination therapy with other myelosuppressive medicinal products. The following dose adjustment guidelines are recommended:

In cases where the lowest value after administration of the initial dose is not in the same row for leukocytes and platelets (e.g., leukocyte count >4000 and platelet count <25,000), the dose corresponding to the lowest percentage of the previous dose should be used (e.g., platelet count <25,000 – apply a maximum of 50% of the previous dose).
There are no limitations regarding the duration of treatment with carmustine. If the tumor remains incurable or severe or intolerable adverse reactions occur, carmustine treatment should be discontinued.
Conditioning treatment prior to hematopoietic stem cell transplantation
Carmustine is administered intravenously at a dose of 300–600 mg/m² in combination with other chemotherapeutic agents to patients with malignant hematological disorders prior to hematopoietic stem cell transplantation.
Special patient groups:
Children and adolescents
Carmustine should not be administered to children or adolescents under 18 years of age (see section 4.3).
Elderly patients:
In elderly patients, doses should be selected cautiously, particularly starting at the lower end of the dose range, due to the higher frequency of impaired liver, kidney, or heart function; additionally, concomitant diseases and concomitant therapies with other medicinal products should be taken into account. Since elderly patients have a higher likelihood of impaired renal function, caution should be exercised when selecting the dose, glomerular filtration rate should be monitored, and the dose should be adjusted accordingly.
Renal impairment
In patients with renal impairment, the dose of the medicinal product Carmustine Waymade should be reduced if a decreased glomerular filtration rate is observed.
Method of administration
The product Carmustine Waymade is intended for intravenous administration after reconstitution and further dilution.
During reconstitution of the powder using the supplied solvent, the solution should be prepared by additionally adding 27 mL of water for injections. The reconstituted solution is a clear, colorless or pale yellow liquid. The reconstituted solution must then be diluted using 500 mL of sodium chloride 9 mg/mL (0.9%) solution for injection or dextrose 50 mg/mL (5%) solution for injection.
The resulting ready-to-use infusion solution should be administered immediately by intravenous infusion over one to two hours, protected from light. The infusion duration should not be shorter than one hour—otherwise, burning and pain at the site of administration may occur. The intravenous infusion site should be monitored during administration of the drug.
Instructions for reconstitution and dilution of the medicinal product prior to administration are provided in section 6.6.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Severe bone marrow depression.
• Severe (end-stage) renal impairment.
• Children and adolescents.
• Breast-feeding.

4.4. Special warnings and precautions for use

Pulmonary toxicity with pulmonary infiltrates and (or) pulmonary fibrosis has been observed, occurring with a frequency of up to 30%. This disorder may occur within 3 years after treatment administration and appears to be dose-dependent, with a cumulative dose of 1200–1500 mg/m associated with an increased risk of pulmonary fibrosis. Risk factors include tobacco smoking, pre-existing respiratory diseases, pre-existing abnormalities in radiological examinations, sequential or concurrent radiotherapy to the chest, and concomitant use of other drugs that may cause lung damage. Baseline pulmonary function tests and chest X-ray should be performed, followed by regular monitoring of pulmonary function during treatment. Patients with baseline values of forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) below 70% are at particular risk. Increased risk of pulmonary toxicity has been reported following conditioning regimens and after haematopoietic stem cell transplantation in women. To date, the increased risk has been described for the treatment itself, including conditioning regimens without carmustine (e.g. total body irradiation [TBI] or busulfan-cyclophosphamide) or with carmustine (BEAM chemotherapy: carmustine, etoposide, cytarabine, and melphalan or CBV: cyclophosphamide, carmustine, and etoposide).

High-dose carmustine treatment (especially 600 mg/m) prior to haematopoietic stem cell transplantation has been shown to increase the risk and severity of pulmonary toxicity. Therefore, in patients with other risk factors for pulmonary toxicity, the use of carmustine should be considered in the context of risk assessment.

Following high-dose carmustine treatment, the risk and severity of infections, cardiotoxicity, hepatotoxicity, gastrointestinal toxicity, nephrotoxicity, neurological disorders, and electrolyte disturbances (hypokalaemia, hypomagnesaemia, and hypophosphataemia) are increased.

Patients with comorbidities and more advanced disease stages are at higher risk of adverse events. This should be particularly considered in elderly patients.

Liver and kidney function should also be assessed before starting treatment and regularly monitored during treatment (see section 4.8).

Neutropenic enterocolitis may occur as an adverse event related to therapy following administration of chemotherapeutic agents.

Carmustine has shown carcinogenic effects in rats and mice at doses lower than the recommended human dose based on body surface area (see section 5.3).

Myelosuppression is a common and severe adverse effect of carmustine. Complete blood counts should be frequently monitored for at least six weeks after administration of the product. In cases of reduced circulating platelets, leukocytes, or erythrocytes due to prior chemotherapy or other causes, the dose should be appropriately adjusted.

• See Table 1 in section 4.2. Liver, kidney, and lung function should be regularly monitored during treatment (see section 4.8).

Multiple doses of the medicinal product Carmustine Waymade should not be administered more frequently than every six weeks. The myelotoxic effect of carmustine is cumulative; therefore, dose adjustment should be considered based on the lowest blood count values (nadir) observed after previous doses (see section 4.2).

Direct administration of carmustine into the carotid artery is considered experimental and may be associated with ocular toxicity.

Administration of a dose of 200 mg/mg to an adult weighing 70 kg will result in exposure to 109.7 mg/kg of ethanol, which may increase blood alcohol concentration by approximately 18.3 mg/100 mL. For comparison, in an adult consuming a glass of wine or 500 mL of beer, blood alcohol concentration reaches about 50 mg/100 mL. Concomitant administration with medicines containing, for example, propylene glycol or ethanol may lead to ethanol accumulation and occurrence of adverse events. Since this product is usually administered slowly over 6 hours, the effect of alcohol may be limited.

4.5. Interactions with other medicinal products and other types of interactions

Phenytoin and dexamethasone
When chemotherapeutic agents are used concomitantly with anticonvulsants, reduced efficacy should be expected.
Cimetidine
Concomitant use of cimetidine leads to delayed, significant, expected increase in the toxic effects of carmustine (due to inhibition of carmustine metabolism).
Digoxin
Concomitant use with digoxin leads to delayed, moderate, expected reduction in digoxin efficacy (due to decreased digoxin absorption).
Melphalan
Concomitant use of melphalan leads to an increased risk of pulmonary toxicity.

4.6. Effects on fertility, pregnancy and lactation

Women of childbearing potential /contraception in men and women
Women should use effective contraception to avoid becoming pregnant during treatment and
for at least 6 months after its completion.
Men should be advised to use appropriate contraceptive methods during treatment with
carmustine and for at least 6 months after treatment ends.
Pregnancy
Carmustine should not be administered to pregnant patients. The safety of this product during
pregnancy has not been established, and therefore the benefits must be carefully weighed against
the risk of toxic effects. Carmustine shows embryotoxic effects in rats and rabbits and teratogenic
effects in rats when administered at doses equivalent to those used in humans (see section 5.3). If
the product is used during pregnancy or if a patient becomes pregnant while receiving methotrexate,
the patient should be informed of the potential risk to the fetus.
Breast-feeding
It is not known whether carmustine or its metabolites pass into human milk. A risk to newborns or
infants cannot be excluded. Carmustine Waymade is contraindicated during breast-feeding. Breast-feeding must not be initiated during treatment with the product and for seven days after its discontinuation (see section 4.3).
Fertility
Carmustine may impair fertility in men. Men should be informed of the potential risk of infertility and
should be advised to seek counselling on fertility/family planning before starting treatment with
carmustine.

4.7. Effects on ability to drive and use machines

Carmustine Waymade has no effect or has negligible effect on the ability to drive
and use machines. However, one should take into account the possibility that the amount of alcohol
contained in this medicinal product may impair the ability to drive and use machines.

4.8. Undesirable effects

Summary of safety profile
The table below lists undesirable effects observed during treatment with this medicinal product,
but these effects do not necessarily have a causal relationship with the medicinal product.
Since clinical trials are conducted under very different conditions, the frequency of undesirable
effects observed in clinical trials may not reflect the frequency observed in clinical practice.
Undesirable effects are generally included if they occurred in more than 1% of patients in the product monograph or in key studies and (or) if they were considered clinically significant. When placebo-controlled studies are available, undesirable effects are included if their frequency was ≥5% higher in the treated group.

Tabulated presentation of undesirable effects
The table below presents undesirable effects of carmustine listed by MedDRA system organ class and frequency of occurrence, ordered by decreasing severity, according to the following convention:

• very common (≥1/10),
• common (≥1/100 to <1/10),
• uncommon (≥1/1000 to <1/100),
• rare (≥1/10 000 to <1/1000),
• very rare (<1/10 000),
• frequency not known (frequency cannot be determined from available data)

Within each frequency group, undesirable effects are listed in order of decreasing severity:

* Increased risk of pulmonary toxicity has been reported following conditioning regimens and hematopoietic stem cell transplantation in women. To date, the increased risk has been described for the treatment itself, including conditioning regimens without carmustine (e.g., total body irradiation [TBI] or busulfan-cyclophosphamide) or with carmustine (BEAM chemotherapy: carmustine, etoposide, cytarabine, and melphalan or CBV: cyclophosphamide, carmustine, and etoposide).

Description of selected adverse reactions:
Bone marrow suppression
Bone marrow suppression occurs very commonly, beginning 7–14 days after drug administration and resolving 42–56 days after administration. Bone marrow suppression is dose- and cumulative dose-dependent; it often follows a biphasic course.

Respiratory, thoracic and mediastinal disorders
Pulmonary fibrosis (with fatal outcome), pulmonary infiltrates.
Pulmonary toxicity has been observed in up to 30% of patients. In cases where pulmonary toxicity began early (within 3 years of treatment), pulmonary infiltrates and/or pulmonary fibrosis occurred, in some cases with fatal outcome. Patients were aged from 22 months to 72 years. Risk factors include tobacco smoking, pre-existing respiratory diseases, prior abnormalities on radiological examinations, sequential or concurrent thoracic irradiation, and concomitant use of other drugs that may cause lung damage. The frequency of adverse reactions is likely related to dose; cumulative doses of 1200–1500 mg/m² have been associated with an increased likelihood of pulmonary fibrosis. Pulmonary function tests (FVC, DLCO) should be performed regularly during treatment. Patients with baseline forced vital capacity or diffusing capacity for carbon monoxide values <70% of predicted are at particular risk.

Cases of very delayed pulmonary fibrosis (up to 17 years after treatment) have been reported in patients who received carmustine during childhood or adolescence.
Long-term follow-up of 17 patients who survived childhood brain tumors showed that 8 of them developed pulmonary fibrosis. Two of these 8 fatal cases occurred within the first 3 years of treatment, and 6 occurred 8–13 years after treatment. The median age of patients who died during treatment was 2.5 years (range 1–12 years), and the median age of long-term survivors after treatment was 10 years (range 5–16 years). All patients who were under 5 years of age at the time of treatment died due to pulmonary fibrosis; neither the dose of carmustine nor additional doses of vincristine or spinal irradiation influenced the risk of death.

Pulmonary fibrosis was diagnosed in all other individuals under observation. Carmustine should not be administered to children or adolescents under 18 years of age – see section 4.3.

Pulmonary toxicity has also been observed in the post-marketing period – as cases of pneumonia and interstitial lung disease. Pneumonia was observed after doses >450 mg/m², and interstitial lung disease occurred after long-term treatment and cumulative doses >1400 mg/m².

Potential to induce vomiting
The risk of vomiting is high following doses >250 mg/m² and high to moderate following doses ≤250 mg/m². Nausea and vomiting are severe and occur within 2–4 hours after administration of the medicinal product, persisting for 4–6 hours.

Nephrotoxicity
Renal toxicity is rare but may occur with cumulative doses <1000 mg/m².

Reporting of suspected adverse reactions
Following marketing authorization, it is important to report suspected adverse reactions. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, PL-02 222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl.
Adverse reactions can also be reported to the marketing authorization holder.

4.9. Overdose

The main symptom of poisoning is bone marrow suppression. Additionally, the following serious adverse reactions may occur: liver necrosis, interstitial pneumonitis, encephalitis, and myelitis.
No specific antidote is available.

5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agent, alkylating agents, nitrosourea derivatives, ATC code: L01AD01

Mechanism of action
Carmustine is a non-specific antineoplastic agent acting on cell cycle phases, exerting cytotoxic effects on tumors through multiple mechanisms. As an alkylating agent, it can alkylate reactive sites on nucleoproteins, thereby interfering with DNA and RNA synthesis and DNA repair. It is capable of forming cross-links between DNA strands, which prevents DNA replication and transcription. It is also known that carmustine can carbamylate lysine residues on proteins, leading to irreversible inactivation of enzymes, including glutathione reductase. The carbamylating activity of carmustine is generally considered less significant than its alkylating activity in its antitumor effect; however, carbamylation may inhibit DNA repair processes.

Pharmacodynamic effects
The antineoplastic and toxic effects of carmustine may be related to its metabolites. Carmustine and similar nitrosourea derivatives are unstable in aqueous solutions and undergo spontaneous decomposition into reactive intermediate compounds capable of alkylating and carbamylating. The intermediate alkylating species are believed to be responsible for the antitumor activity of carmustine. However, opinions differ regarding the role of carbamylating intermediates as mediators of the biological effects of nitrosourea derivatives. On one hand, their carbamylating activity has been observed to contribute to the cytotoxic properties of parent drugs by inhibiting DNA repair enzymes. On the other hand, carbamylating compounds may mediate certain toxic effects of carmustine.
Carmustine readily crosses the blood-brain barrier due to its lipophilic nature.

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

5.2. Pharmacokinetic properties

Distribution
Carmustine undergoes rapid degradation following intravenous administration – unchanged substance is not detectable after 15 minutes. Due to its high lipid solubility and lack of ionization at physiological pH, carmustine penetrates very well across the blood-brain barrier. The level of radioactivity in cerebrospinal fluid is at least 50% higher than that measured at the same time in plasma. The kinetics of carmustine in humans are characterized by a two-compartment model. After a 1-hour intravenous infusion, plasma concentrations of carmustine decline in a biphasic manner. The α half-life is 1–4 minutes, and the β half-life is 18–69 minutes.
Metabolism
It is believed that metabolites of carmustine are responsible for its antitumour and toxic effects.
Elimination
Approximately 60–70% of the total dose is excreted in urine within 96 hours, and about 10% as CO via the respiratory tract. The fate of the remaining portion is undefined.

5.3. Preclinical safety data

Carmustine showed embryotoxic and teratogenic effects in rats and embryotoxic effects in rabbits at doses equivalent to those used in humans. Carmustine impaired fertility in male rats at doses higher than those used in humans. Carmustine demonstrated carcinogenic effects in rats and mice at clinically relevant doses.
6. PHARMACEUTICAL DATA
6.1. List of excipients
Powder
The product does not contain excipients.
Solvent
Anhydrous ethanol.

6.2. Pharmaceutical incompatibilities

Compatibility/Incompatibility with containers
The intravenous solution is unstable in containers made of polyvinyl chloride. Carmustine solution may be administered only from glass vials or polypropylene containers.
Do not mix the medicinal product with other medicinal products, except those mentioned in section 6.6.

6.3. Shelf life

Unopened vial
3 years.
After reconstitution and dilution
After reconstitution according to the recommendations, Carmustine Waymade is stable for
24 hours when stored at 2°C - 8°C in a light-protective glass container.
The reconstituted solution must be diluted using 500 mL of sodium chloride 9 mg/mL (0.9%) or dextrose 50 mg/mL (5%) solution in a glass or polypropylene container. It should be stored at room temperature, protected from light, and used within 4 hours. These solutions are also stable for 24 hours when stored at 2°C – 8°C and for an additional 6 hours at room temperature, provided they are protected from light.
Considering the risk of microbial contamination, the product should be used immediately unless the method of opening / reconstitution / dilution excludes such risk.
If the product is not used immediately, the user is responsible for the storage duration and conditions.

6.4. Special storage precautions

Store in a refrigerator (2°C – 8°C). Do not freeze.
Vials containing powder and solvent should be stored in their outer cardboard packaging
to protect from light.
For storage conditions of the medicinal product after reconstitution and further dilution, see
section 6.3.

6.5. Type and content of container

Powder:
Type I glass vial made of amber glass (30 mL) with a 20 mm grey bromobutyl rubber stopper and
flip-off cap.
Solvent:
Colorless type I glass vial (5 mL) with a 13 mm grey chlorobutyl rubber stopper and flip-off cap.
One package contains one vial with 100 mg of concentrate powder for infusion solution and one
vial with 3 mL of solvent.

6.6. Special precautions for disposal and preparation of the medicinal product for administration
The product containing carmustine as a powder for preparation of concentrate solution for infusion
does not contain preservatives and is not intended for use in multidose vials. Reconstitution and
further dilution must be carried out under aseptic conditions.
The lyophilized product is supplied in a freeze-dried form without any preservatives and is intended
for single use only. The lyophilisate may appear as dry flakes or a dry solid mass. The presence of an
oily layer may indicate that the medicinal product has melted. Such products must not be used due
to the risk of exceeding 30°C. Do not use such medicinal products. In case of doubt whether the
product has been maintained under appropriate cooling conditions, inspect all vials in the carton
immediately. For verification, place the vial in bright light.

Reconstitution and dilution for infusion
Dissolve 100 mg of lyophilized carmustine powder in 3 mL of the supplied sterile cooled solvent
(anhydrous ethanol) included in the package. Carmustine must be completely dissolved in ethanol
before adding sterile water for injections. Then, aseptically add 27 mL of sterile water for injections
to the alcoholic solution. Mix the resulting 30 mL stock solution thoroughly. Reconstitution performed
according to these instructions yields a clear solution (colorless or pale yellow).

Before using vials containing reconstituted substance, check whether crystals have formed. If so, they
can be dissolved by warming the vial to room temperature and gently shaking it. After reconstitution,
Carmustine Waymade is stable for 24 hours provided it is stored at 2°C – 8°C in a light-protected glass
container.

The reconstituted solution must then be diluted using 500 mL of sodium chloride 9 mg/mL (0.9%)
solution or dextrose 50 mg/mL (5%) solution. The reconstituted and diluted solution (i.e., the ready-to-use
solution) must be shaken for at least 10 seconds prior to administration. The ready-to-use solution
should be stored at room temperature in a light-protected container made of glass or polypropylene and
used within 4 hours. These solutions are also stable for 24 hours if stored at 2°C – 8°C and for an
additional 6 hours at room temperature, provided they are protected from light.

The reconstituted and diluted solution (i.e., the ready-to-use solution) must be administered
intravenously as an infusion lasting 1 to 2 hours. The infusion should be administered using polyethylene
containers that are free from PVC. Only appropriate containers made of glass or polypropylene should
be used for administration of the medicinal product. Ensure that polypropylene containers do not
contain PVC or DEHP. Carmustine has a low melting point (30.5°C – 32.0°C or 86.9°F – 89.6°F).
Exposure of the drug to this temperature (or higher) will cause it to liquefy and form an oily layer in the
vials, indicating degradation of the substance—in such cases, the vials must be discarded.

Administering Carmustine Waymade infusion over a shorter period may cause severe pain and a burning
sensation at the injection site. The injection site should be monitored throughout the administration of
the drug (see section 4.2).

Follow recommendations for safe handling and disposal of cytotoxic medicinal products.
Any unused residues of the product or waste materials must be disposed of in accordance with local
regulations.

7. MARKETING AUTHORISATION HOLDER

Waymade B.V.
Herikerbergweg 88,
1101CM Amsterdam,
The Netherlands

8. NUMBERS OF MARKETING AUTHORISATIONS

9. DATE OF FIRST AUTHORISATION
Date of first authorisation:

10. DATE OF ADOPTION OR PARTIAL REVISION OF THE TEXT

PRODUCT CHARACTERISTICS

Package leaflet: Information for the user

Carmustine Waymade
100 mg, powder and solvent for concentrate for solution for infusion
carmustine
Please read this leaflet carefully before using this medicine, as it contains important
information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, please consult your doctor, pharmacist, or nurse.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor or nurse. See section 4.

Leaflet contents:

1. What Carmustine Waymade is and what it is used for
2. What you need to know before using 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 Carmustine Waymade is and what it is used for

Carmustine Waymade is a medicine containing carmustine as the active substance. Carmustine
belongs to a group of anticancer drugs known as nitrosourea derivatives, which work by slowing the growth of cancer cells.
Carmustine is effective in treating the following malignant tumours, either as monotherapy or in combination with other anticancer drugs or other therapeutic modalities (radiotherapy, surgery):

• Brain tumours (glioblastoma multiforme, brainstem gliomas, medulloblastoma, astrocytoma, and ependymoma) and brain metastases;
• Second-line treatment of non-Hodgkin's lymphoma and Hodgkin's disease;
• As conditioning therapy prior to autologous haematopoietic stem cell transplantation in malignant haematological diseases (Hodgkin’s disease/non-Hodgkin’s lymphoma);
• Multiple myeloma (a malignant tumour developing in the bone marrow) – in combination with a glucocorticosteroid such as prednisone.

2. What you need to know before using Carmustine Waymade

When not to use Carmustine Waymade:

• If you are allergic to carmustine or any of the other ingredients of this medicine (listed in section 6);
• If you have bone marrow suppression leading to low numbers of platelets, white blood cells (leukocytes), or red blood cells (erythrocytes), due to previous chemotherapy or other causes;
• If you have severe kidney dysfunction;
• In children and adolescents;
• If you are pregnant or breastfeeding.

Warnings and precautions
Before starting treatment with Carmustine Waymade, discuss this with your doctor, pharmacist, or nurse.
The main adverse effect of this medicine is delayed bone marrow suppression, which may manifest as fatigue, bleeding from the skin and mucous membranes, and infections with fever due to blood changes. Therefore, your doctor will monitor your blood count weekly for at least 6 weeks after each dose. Treatment courses with Carmustine Waymade should not be administered more frequently than every 6 weeks. Your doctor will check your blood count before each administration.
Before starting treatment, liver, lung, and kidney function tests will be performed and repeated regularly during therapy.
Because Carmustine Waymade 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 treatment with Carmustine Waymade (up to 600 mg/m²) is used exclusively in combination with subsequent stem cell transplantation. High doses may increase the risk and severity of toxic effects on the lungs, kidneys, liver, heart, and gastrointestinal tract, as well as infections and electrolyte imbalances (low levels of potassium, magnesium, and phosphorus in the blood).
Abdominal pain (neutropenic colitis) may occur as an adverse reaction associated with therapy following chemotherapy.
Your doctor will inform you about the possibility of lung damage and allergic reactions, including their symptoms. If such symptoms occur, contact your doctor immediately (see section 4).

Children and adolescents
Carmustine Waymade must not be given to children and adolescents under 18 years of age.

Carmustine Waymade with other medicines
Inform your doctor or pharmacist about all medicines you are currently taking or have recently taken, including those obtained without a prescription, such as:

• Phenytoin used for epilepsy;
• Dexamethasone used as an anti-inflammatory and immunosuppressive agent;
• Cimetidine used for stomach problems such as indigestion;
• Digoxin used for irregular heart rhythm;
• Melphalan – an anticancer drug.

Using Carmustine Waymade with alcohol
The amount of alcohol in this medicine may affect the action of other drugs.

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

Pregnancy and fertility
Carmustine Waymade should not be used during pregnancy, as it may harm the unborn child. Therefore, this medicine should generally not be given to pregnant women. If used during pregnancy, the patient must be aware of potential risks to the unborn child. Women of childbearing potential must be advised to use effective contraception to prevent pregnancy during treatment and for at least 6 months after treatment ends.
Men should use appropriate contraceptive measures during treatment with Carmustine Waymade and for at least 6 months thereafter to prevent pregnancy in their partners.

Breastfeeding
Do not breastfeed during treatment with this medicine and for 7 days after treatment. Risk to newborns or infants cannot be excluded.

Driving and operating machinery
Carmustine Waymade has no or negligible influence on the ability to drive or operate machinery. However, consult your doctor before driving or operating tools or machines, as the alcohol content in this medicine may impair your ability to drive or operate machinery.

Carmustine Waymade contains anhydrous ethanol (alcohol)
One vial of this medicine contains 2.4 g of alcohol (ethanol), equivalent to 7.68 g at the maximum dose (320 mg). The alcohol content at the maximum dose (200 mg/m² for patients weighing 70 kg) corresponds to the alcohol content in 192 mL of beer or 76.8 mL of wine.
The medicine is usually administered slowly over 6 hours, which may help reduce the effect of alcohol.
The alcohol content in this medicine may affect the ability to drive or operate machinery and may impair judgment and reaction speed.
Patients with epilepsy or liver disease should consult their doctor or pharmacist before taking this medicine.
The alcohol content in this medicine may alter the effect of other medicines. If you are taking other medicines, consult your doctor or pharmacist.
Pregnant women should consult their doctor or pharmacist before taking this medicine.
Alcohol-dependent individuals should consult their doctor or pharmacist before taking this medicine.

3. How to use Carmustine Waymade

Carmustine Waymade will always be administered by medical personnel experienced in handling anticancer drugs.
This medicine is intended for intravenous infusion.

Adults
Dosage depends on health status, body surface area, and response to treatment. The medicine is usually administered no more frequently than every 6 weeks. The recommended dose of Carmustine Waymade for previously untreated patients is 150–200 mg/m² intravenously every 6 weeks. The dose may be given as a single infusion or split into two consecutive daily infusions of 75–100 mg/m². Dosing also depends on whether Carmustine Waymade is used in combination with other anticancer drugs. Doses may be adjusted based on the patient's response to treatment.
The recommended dose of Carmustine Waymade administered intravenously in combination with other chemotherapeutic agents prior to haematopoietic stem cell transplantation is 300–600 mg/m².
To avoid toxic effects on the bone marrow, blood counts will be monitored frequently, and the dose will be adjusted if necessary.

Route of administration
After reconstitution and dilution, Carmustine Waymade is administered intravenously by infusion over 1 to 2 hours, protected from light. The infusion duration should not be less than 1 hour, as shorter durations may cause burning and pain at the injection site. The infusion site will be monitored during administration.
The duration of treatment will be determined by the doctor and may vary between patients.

Overdose of Carmustine Waymade
Since the medicine will be administered by a doctor or nurse, incorrect dosing is unlikely. Inform your doctor or nurse if you have any concerns about the amount of medicine received.
If you have further questions about using this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine may cause side effects, although not everyone will experience them.
Immediately inform your doctor or nurse if you experience any of the following symptoms:
wheezing, breathing difficulties, eyelid, facial, or lip swelling, rash or itching (especially if widespread), or 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 (reduced blood cell production by the bone marrow), increasing the risk of infections due to low white blood cell count;
• Ataxia (lack of voluntary muscle coordination);
• Dizziness;
• Headache;
• Transient eye redness, blurred vision due to retinal haemorrhage;
• Hypotension (low blood pressure);
• Phlebitis (vein inflammation) with pain, swelling, redness, and tenderness;
• Respiratory disorders (lung-related problems) causing breathing difficulties; This medicine may cause severe (potentially fatal) lung damage. Lung damage may occur years after treatment. Inform your doctor immediately if you experience any of the following: shortness of breath, persistent cough, chest pain, prolonged weakness, or fatigue;
• Severe nausea and vomiting;
• Skin inflammation upon contact with the medicine;
• Accidental skin contact may cause transient skin or nail discoloration (darkening).

Common (may affect up to 1 in 10 people):

• Acute leukaemias and bone marrow dysplasias (abnormal bone marrow development). Possible symptoms include: gum bleeding, bone pain, fever, frequent infections, frequent or severe nosebleeds, lumps caused by swollen lymph nodes in the neck or surrounding areas, under the arms, abdomen, or groin, pale skin, shortness of breath, weakness, fatigue, or general loss of energy;
• Anaemia (reduced number of red blood cells in the blood);
• Encephalopathy (brain disease). Possible symptoms include: muscle weakness in one area, inability to make decisions or poor concentration, involuntary muscle twitching, tremors, difficulty speaking or swallowing, seizures;
• Loss of appetite;
• Constipation;
• Diarrhoea;
• Inflammation of the mouth and lips;
• Reversible hepatotoxicity with high-dose treatment. This may lead to increased liver enzyme activity and bilirubin levels (parameters measured 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) causing obstruction of very small (microscopic) veins in the liver. Possible symptoms include: fluid accumulation in the abdomen, enlarged spleen, severe bleeding from the oesophagus, yellowing of the skin and whites of the eyes;
• Breathing problems due to interstitial fibrosis (with lower doses);
• Kidney disorders;
• Gynaecomastia (enlargement of breast tissue in men).

Frequency not known (frequency cannot be estimated from available data):

• Muscle pain;
• Seizures, including status epilepticus;
• Tissue damage due to leakage at the infusion site;
• Infertility;
• Carmustine has been shown to have harmful effects on unborn children;
• Electrolyte imbalances (including low levels of potassium, magnesium, and phosphorus in the blood).

Reporting of adverse reactions
If you experience any adverse reactions, including those not listed in this leaflet, inform your doctor or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, PL-02 222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl .
Reporting adverse reactions helps provide more information on the safety of this medicine.
Adverse reactions can also be reported to the marketing authorisation holder.

5. How to store Carmustine Waymade

The medicine will be stored by your doctor or other healthcare professional.
Keep the medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after EXP. The expiry date refers to the last day of the specified month.
Store in a refrigerator (2°C – 8°C). Do not freeze.
Both vials (active substance and solvent) should be stored in the outer cardboard packaging to protect from light.

After reconstitution and dilution
After reconstitution, Carmustine Waymade is stable for 24 hours if stored at 2°C – 8°C in a light-protected glass container.
The reconstituted solution must be diluted using 500 mL of 9 mg/mL (0.9%) sodium chloride solution or 50 mg/mL (5%) dextrose solution in a glass or polypropylene container. It should be stored at room temperature, protected from light, and used within 4 hours. These solutions are also stable for 24 hours if stored at 2°C – 8°C and an additional 6 hours at room temperature, provided they are protected from light.
Considering the risk of microbial contamination, the product should be used immediately unless the method of opening/reconstitution/dilution excludes such risk.
If the product is not used immediately, the user is responsible for storage conditions and duration.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist or doctor how to dispose of medicines safely, to protect the environment.

6. Contents of the pack and other information

What Carmustine 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: The product contains no excipients.
• Solvent: Anhydrous ethanol.

What Carmustine Waymade looks like and contents of the pack
One pack of Carmustine Waymade (powder and solvent for preparation of concentrate for infusion solution) contains one vial with 100 mg of carmustine powder and one vial with 3 mL of solvent (anhydrous ethanol).
The powder is in the form of lyophilised pale yellow flakes or a solidified mass in an amber glass vial.
The solvent is a colourless, clear liquid in a transparent glass vial.
Lyophilised pale yellow flakes or solidified mass for reconstitution.
Appearance of the solution: The reconstituted solution is clear and colourless or pale yellow.
Powder: Type I glass vial (30 mL), amber glass, with a 20 mm grey bromobutyl rubber stopper and flip-off seal.
Solvent: Type I glass vial (5 mL), colourless glass, with a 13 mm grey chlorobutyl rubber stopper and flip-off seal.

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

Manufacturer
Drehm Pharma GmbH
Grünbergstraße 15/3/3,
Wien, 1120, Austria

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Information intended exclusively for healthcare professionals:

Below is a brief description of the preparation and/or administration, pharmaceutical incompatibilities, dosing, overdose or required monitoring actions, as well as laboratory tests, based on the current product characteristics.
The medicinal product Carmustine Waymade, powder for concentrate for solution for infusion, does not contain preservatives and is not intended for use in multidose vials. Reconstitution and further dilution must be performed under aseptic conditions.
By adhering to the recommended storage conditions, degradation of the substance contained in the unopened vial can be avoided until the expiry date indicated on the packaging.
The lyophilized product contains no preservatives and is intended for single use only. The lyophilisate may appear as dry flakes or a dry solid mass. The presence of an oily layer may indicate that the medicinal product has melted. Such products are unsuitable for use due to the risk of exceeding 30°C. Do not use such medicinal products. If there is any doubt whether the product has been maintained under appropriate cooling conditions, inspect all vials in the carton immediately. For verification, place the vial in bright light.

Reconstitution and dilution of the powder for concentrate for solution for infusion:
Dissolve 100 mg of Carmustine Waymade powder for concentrate for solution for infusion in 3 mL of the sterile cooled solvent (anhydrous ethanol) supplied in the package. Carmustine must be completely dissolved in anhydrous ethanol before sterile water for injection can be added. Then, aseptically add 27 mL of sterile water for injection to the alcoholic solution. Mix the 30 mL stock solution thoroughly.
Proper reconstitution according to instructions results in a clear solution (colorless or pale yellow).

Before using vials containing reconstituted substance, check whether crystals have formed. If so, they can be dissolved by warming the vial to room temperature and gently shaking it. After reconstitution, Carmustine Waymade is stable for 24 hours when stored at 2°C–8°C in a light-protected glass container.

The reconstituted solution must then be diluted using 500 mL of sodium chloride 9 mg/mL (0.9%) solution or dextrose 50 mg/mL (5%) solution. The reconstituted and diluted solution (i.e., the ready-to-use solution) must be shaken for at least 10 seconds prior to administration. The ready-to-use solution should be stored at room temperature in a light-protected container made of glass or polypropylene and used within 4 hours. These solutions are also stable for 24 hours when stored at 2°C–8°C and an additional 6 hours at room temperature, provided they are protected from light.

pH and osmolarity of ready-to-use infusion solutions:
The pH of ready-to-use infusion solutions ranges from 4.0 to 6.8.

Route of administration:
The reconstituted and diluted solution (i.e., the ready-to-use solution) must be administered intravenously as an infusion lasting 1 to 2 hours. The infusion should be delivered using PVC-free polyethylene containers. Only appropriate containers made of glass or polypropylene should be used for administration. Ensure that polypropylene containers do not contain PVC or DEHP. Carmustine has a low melting point (30.5°C–32.0°C or 86.9°F–89.6°F). Exposure of the drug to this temperature (or higher) will cause it to liquefy and form an oily layer on the vials, indicating degradation of the substance—in such cases, vials must be discarded.

Administering the Carmustine Waymade infusion over a shorter period may cause severe pain and burning at the injection site. The intravenous infusion site should be monitored during administration.

Strict adherence to safety guidelines for handling and disposal of cytotoxic anticancer drugs is required.

Dosing and laboratory monitoring

Initial dosing
The recommended dose of the medicinal product Carmustine Waymade when used as monotherapy in previously untreated patients is 150 to 200 mg/m² intravenously every 6 weeks. The drug may be administered as a single dose or divided into daily infusions of 75 to 100 mg/m² on two consecutive days.

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

Monitoring and subsequent doses
The next course of treatment with Carmustine Waymade may only be administered once blood counts have returned to acceptable levels (platelet count above 100,000/mm³, white blood cells above 4,000/mm³), which typically occurs within six weeks. Blood counts should be monitored frequently, and treatment should not be repeated before six weeks have elapsed due to the risk of delayed hematological toxicity.

After the initial dose, subsequent doses should be adjusted according to the patient's hematological response to the previous dose, both in monotherapy and in combination therapy with other myelosuppressive medicinal products. The following dose adjustment guidelines are recommended:

In cases where the lowest value after administration of the initial dose is not in the same row for leukocytes and platelets (e.g., leukocyte count >4000 and platelet count <25,000), the dose corresponding to the lowest percentage of the previous dose should be used (e.g., platelet count <25,000 – maximum 50% of the previous dose should be administered).
There are no limitations regarding the duration of treatment with carmustine. However, if the malignancy remains untreatable or severe or intolerable adverse reactions occur, carmustine treatment should be discontinued.
Conditioning treatment prior to hematopoietic stem cell transplantation
Carmustine is administered intravenously at a dose of 300–600 mg/m² in combination with other chemotherapeutic agents to patients with malignant hematological disorders prior to hematopoietic stem cell transplantation.
Special patient groups
Children and adolescents
Carmustine should not be used in children under 18 years of age due to safety concerns.
Elderly patients
In elderly patients, doses should be selected cautiously, particularly starting at the lower end of the dose range, due to the higher prevalence of impaired liver, kidney, or heart function; concomitant diseases and concomitant medications should also be considered. Since elderly patients have a higher likelihood of impaired kidney function, caution should be exercised when selecting the dose, glomerular filtration rate should be monitored, and the dose should be appropriately reduced.
Renal impairment
In patients with impaired renal function, the dose of the medicinal product Carmustine Waymade should be reduced if a decreased glomerular filtration rate is observed.
Compatibility or incompatibility with containers
The intravenous solution is unstable in containers made of polyvinyl chloride (PVC). Containers made of PVC should not be used. Carmustine solution may only be administered from glass or polypropylene containers. Ensure that polypropylene containers do not contain PVC or DEHP.
INFORMATION ON OUTER AND PRIMARY PACKAGING
CARDBOARD BOX

1. NAME OF THE MEDICINAL PRODUCT

Carmustine Waymade, 100 mg, powder and solvent for preparation of a concentrate solution for infusion
carmustine

2. ACTIVE SUBSTANCE CONTENT

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

3. LIST OF EXCIPIENTS

Contains anhydrous ethanol.
Each solvent vial contains 3 ml of anhydrous ethanol (equivalent to 2.37 g).
For more information, see the package leaflet.

4. PHARMACEUTICAL FORM AND PACKAGING CONTENTS

Powder and solvent for solution for concentrate for infusion
1 vial containing 100 mg powder: code 08720865197173
1 vial containing 3 ml solvent: code 08720865197173

5. METHOD AND ROUTE OF ADMINISTRATION

For single use only.
For intravenous administration after reconstitution and dilution.
Read the instructions in the leaflet before using the medicine.

6. WARNING ON STORAGE OF THE MEDICINAL PRODUCT

KEEP OUT OF SIGHT AND REACH OF CHILDREN
Keep the medicinal product out of sight and reach of children.

7. OTHER SPECIAL WARNINGS, IF NECESSARY

Cytotoxic product. Exercise caution during administration.
Avoid contact of the concentrate for solution for infusion with the skin.
May cause congenital malformations.

8. MANUFACTURING AND EXPIRY DATE

Expiry date (EXP)
After reconstitution/dilution: Duration of stability of the product after reconstitution – see the package leaflet.

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2°C – 8°C). Do not freeze.
Keep both vials in the outer packaging to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED

MEDICINAL PRODUCT OR WASTE DERIVING FROM IT, IF
APPLICABLE
Follow recommendations for the safe disposal of antineoplastic drugs.

11. NAME OF THE MANUFACTURER

Waymade B.V.
Herikerbergweg 88,
1101CM Amsterdam,
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

MARKETING AUTHORISATION NUMBER
Authorisation number:

13. LOT NUMBER

Lot number (Lot)

14. GENERAL AVAILABILITY CATEGORY

Rpz – Prescription-only medicine
15. INSTRUCTIONS FOR USE
16. INFORMATION PROVIDED IN BRAILLE
Justification for the absence of information in Braille has been accepted.

17. UNIQUE IDENTIFIER – 2D CODE

Includes a 2D code serving as a carrier of the unique identifier.

18. UNIQUE IDENTIFIER – HUMAN-READABLE INFORMATION

PC
SN
NN
INFORMATION ON OUTER AND IMMEDIATE PACKAGING
VIAL CONTAINING POWDER

1. NAME OF THE MEDICINAL PRODUCT

Carmustine Waymade, 100 mg powder for solution for infusion concentrate
carmustine

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of powder for solution for infusion contains 100 mg of carmustine.
After reconstitution and dilution, 1 ml of solution contains 3.3 mg of carmustine.
3. LIST OF EXCIPIENTS
4. PHARMACEUTICAL FORM AND CONTENTS OF THE CONTAINER
Powder for solution for infusion
100 mg

5. METHOD AND ROUTE OF ADMINISTRATION

For single use only.
For intravenous administration after reconstitution and dilution.
Read the instructions in the leaflet before using the medicine.

6. WARNING ON STORAGE OF THE MEDICINAL PRODUCT

KEEP OUT OF SIGHT AND REACH OF CHILDREN
Store in a place out of sight and reach of children.

7. OTHER SPECIAL WARNINGS, IF NECESSARY

Cytotoxic product. Handle with caution during administration.
Avoid contact of the concentrate for infusion solution preparation with skin.
May cause congenital malformations.

8. MANUFACTURING AND EXPIRY DATE

EXP

9. SPECIAL STORAGE INSTRUCTIONS

Store in a refrigerator (2°C – 8°C). Do not freeze.
Keep the vial in the outer packaging to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED

MEDICINAL PRODUCT OR WASTE DERIVING FROM IT, IF
APPLICABLE
Follow recommendations for the safe disposal of antineoplastic drugs.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Carmustine Waymade
Waymade plc
Waymade Park
Ashton Road
Wigan
WN4 0AA
United Kingdom
Tel: +44 1942 683333
Fax: +44 01942 683344
Website: www.waymade.com
Email: [email protected]

12. MARKETING AUTHORISATION NUMBER
13. BATCH NUMBER
Lot

14. GENERAL AVAILABILITY CATEGORY

Rpz – Prescription-only medicine
15. INSTRUCTIONS FOR USE
16. INFORMATION PROVIDED IN BRAILLE
Justification for absence of Braille information has been accepted.

17. UNIQUE IDENTIFIER – 2D CODE

Not applicable

18. UNIQUE IDENTIFIER – HUMAN-READABLE DATA

Not applicable
INFORMATION TO BE PRINTED ON OUTER PACKAGING AND
PRIMARY PACKAGING
VIAL WITH SOLVENT

1. NAME OF THE MEDICINAL PRODUCT

Carmustine Waymade medicinal product solvent
absolute ethanol
iv .

2. CONTENT OF ACTIVE SUBSTANCE

Each vial of solvent contains 3 ml of anhydrous ethanol (equivalent to 2.37 g).

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. METHOD AND ROUTE OF ADMINISTRATION

For dissolution only.
Please refer to the enclosed patient leaflet for instructions on use.

6. WARNINGS ON STORAGE OF THE MEDICINAL PRODUCT

KEEP OUT OF SIGHT AND REACH OF CHILDREN
7. OTHER SPECIAL WARNINGS, IF NECESSARY
8. SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C - 8°C). Do not freeze.
Keep the vial in the outer packaging to protect from light.

9. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Carmustine Waymade
Waymade Plc
Chester
CH3 7AN
United Kingdom
Tel: +44 (0)151 350 4000
Fax: +44 (0)151 350 4001
Website: www.waymade.com
Email: [email protected]

10. OTHERS