Carmustine Vaimade

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

Carmustine Waymade, 100 mg, powder and solvent for 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 effectEach vial of solvent contains 3 mL of anhydrous ethanol (equivalent to 2.37 g). A full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for concentrate for solution for infusion. Powder: Freeze-dried pale yellow flakes or a frozen mass. Solvent: Colorless, clear liquid. The pH of the 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 tumors in monotherapy or in combination with other anticancer drugs or other therapeutic measures (radiotherapy, surgical procedure):

• Brain tumors (glioblastoma multiforme, brainstem gliomas, medulloblastoma, astrocytoma, and ependymoma) and metastases to the brain;
• Second-line therapy for non-Hodgkin's lymphoma and Hodgkin's disease;
• As conditioning treatment before autologous hematopoietic stem cell transplantation in malignant hematological diseases (Hodgkin's disease/non-Hodgkin's lymphoma);
• Multiple myeloma - in combination with a glucocorticoid such as prednisone.

4.2. Posology and Method of Administration

Carmustine Waymade should only be administered by specialists with experience in chemotherapy and under appropriate medical supervision. Dosage: Initial dosesThe recommended dose of Carmustine Waymade as a single agent in previously untreated patients is 150 to 200 mg/m² intravenously every 6 weeks. The drug may be given as a single dose or divided into daily infusions of 75 to 100 mg/m² over two consecutive days. When Carmustine Waymade is used in combination with other myelosuppressive drugs or in patients with compromised bone marrow reserve, the doses should be adjusted accordingly based on the patient's hematologic profile, as presented below. Monitoring and subsequent dosesA subsequent course of Carmustine Waymade may be given only when the blood cell count has 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 cell counts should be frequently monitored, and a repeat course of treatment should not be given before six weeks have elapsed due to the possibility of delayed hematologic toxicity. After the initial dose, subsequent doses should be adjusted based on the patient's hematologic response to the previous dose, both in monotherapy and in combination therapy with other myelosuppressive drugs. The following dose adjustment scheme is suggested:

In cases where the lowest value after administration of the initial dose does not fall in the same row for white blood cells and platelets (e.g., white blood cell count >4000 and platelet count <25,000), the value corresponding to the lowest percentage of the previous dose should be used (e.g., platelet count <25,000 - maximum 50% of the previous dose). There are no restrictions on 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 before hematopoietic stem cell transplantationCarmustine is administered intravenously at a dose of 300-600 mg/m² in combination with other chemotherapeutic agents to patients with malignant hematological diseases before hematopoietic stem cell transplantation. Special patient populations: Children and adolescentsCarmustine should not be administered to children and adolescents under 18 years of age (see section 4.3). Elderly:In general, in elderly patients, doses should be selected cautiously, and it is recommended to start with the lower end of the dose range, due to the higher frequency of impaired hepatic, renal, or cardiac function; concomitant diseases and other medicinal products should also be taken into account. Since elderly patients are more likely to have impaired renal function, caution should be exercised when selecting the dose and monitoring the glomerular filtration rate, as well as appropriately reducing the dose. Renal impairmentIn patients with renal impairment, the dose of Carmustine Waymade should be reduced in case of decreased glomerular filtration rate. Method of administrationCarmustine Waymade is intended for intravenous administration after reconstitution and further dilution. During the reconstitution process of the powder using the supplied solvent, a solution is prepared by adding an additional 27 mL of water for injection. 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 glucose 50 mg/mL (5%) solution for injection. The resulting ready-to-use infusion solution should be administered immediately intravenously in a drip infusion over a period of one to two hours, protected from light. The infusion time should not be less than one hour - otherwise, burning and pain at the injection site may occur. During administration, the infusion site should be monitored. Instructions for reconstitution and dilution of the medicinal product before 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 (terminal) renal impairment.
• Children and adolescents.
• Breastfeeding.

4.4. Special Warnings and Precautions for Use

Pulmonary toxicity with pulmonary infiltrates and/or pulmonary fibrosis has been observed with a frequency of up to 30%. This condition may occur within 3 years of treatment and appears to be dose-dependent, with a cumulative dose of 1200-1500 mg/m² associated with an increased risk of pulmonary fibrosis. Risk factors include smoking, respiratory diseases, pre-existing radiological abnormalities, sequential or concurrent chest irradiation, and concurrent use of other drugs that may cause pulmonary damage. Baseline pulmonary function tests and chest X-ray should be performed, and pulmonary function tests should be frequently repeated during treatment. Patients with a baseline forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) below 70% are at particular risk. There have been reports of increased risk of pulmonary toxicity after treatment with conditioning regimens and after hematopoietic stem cell transplantation in women. To date, increased risk has been reported for treatment itself, including conditioning regimens without carmustine (e.g., total body irradiation [TBI] or busulfan-cyclophosphamide) or with carmustine (chemotherapy BEAM: carmustine, etoposide, cytarabine, and melphalan or CBV: cyclophosphamide, carmustine, and etoposide). High-dose carmustine (especially 600 mg/m²) before hematopoietic stem cell transplantation increases the risk of pulmonary toxicity. Therefore, the use of carmustine should be considered in the context of risk in patients with other risk factors for pulmonary toxicity. After high-dose carmustine treatment, there is an increased risk of infections, toxic effects on the heart, liver, gastrointestinal tract, and kidneys, neurological disorders, and electrolyte disturbances (hypokalemia, hypomagnesemia, and hypophosphatemia). Patients with concomitant diseases and advanced disease are at higher risk of adverse events. This should be taken into account, especially in elderly patients. Liver and kidney function should also be monitored before starting treatment and regularly during treatment (see section 4.8). Neutropenic enterocolitis may occur as an adverse event related to chemotherapy. Carmustine has been shown to be carcinogenic in rats and mice at doses lower than the recommended dose for humans based on body surface area (see section 5.3). Bone marrow toxicity is a common and severe adverse effect of carmustine. Blood cell counts should be frequently performed for at least six weeks after administration of the dose. In case of decreased platelet count, white blood cell count, or red blood cell count due to previous chemotherapy or for other reasons, the dose should be adjusted accordingly (see Table 1 in section 4.2). Liver, kidney, and lung function should be regularly monitored during treatment (see section 4.8).

• 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 Carmustine Waymade should not be administered more frequently than every six weeks. The toxic effect of carmustine on the bone marrow is cumulative, and therefore, the dose should be adjusted based on the lowest values of blood cell count parameters (nadir) after administration of previous doses (see section 4.2). Direct administration of carmustine into the carotid artery is considered experimental and may be associated with toxic effects on the eyes. Administration of a dose of 200 mg/m² to an adult weighing 70 kg will result in exposure to 109.7 mg/kg of ethanol, which may increase blood alcohol levels by approximately 18.3 mg/100 mL. For comparison, for an adult who consumes a glass of wine or 500 mL of beer, the blood alcohol level will be 50 mg/100 mL. Concurrent administration with drugs containing, for example, propylene glycol or ethanol may lead to accumulation of ethanol and adverse events. Since this product is usually administered slowly over 6 hours, the effect of alcohol may be limited.

4.5. Interaction with Other Medicinal Products and Other Forms of Interaction

Phenytoin and dexamethasoneWhen anticancer drugs are used concurrently with antiepileptic drugs, a decrease in their efficacy should be expected. CimetidineConcurrent use of cimetidine leads to delayed, significant, expected, increased toxic effects of carmustine (due to inhibition of carmustine metabolism). DigoxinConcurrent use with digoxin leads to delayed, moderate, expected, decreased effects of digoxin (due to decreased absorption of digoxin). MelphalanConcurrent use of melphalan leads to increased risk of toxic effects on the lungs.

4.6. Fertility, Pregnancy, and Lactation

Women of Childbearing Potential / Contraception in Males and FemalesWomen 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 measures during treatment with carmustine and for at least 6 months after its completion. PregnancyCarmustine should not be administered to pregnant women. The safety of this product during pregnancy has not been established, and therefore, the benefits should be carefully weighed against the risk of toxic effects. Carmustine has been shown to be embryotoxic and teratogenic in rats and embryotoxic in rabbits at doses equivalent to those used in humans (see section 5.3). If the product is used during pregnancy or if the patient becomes pregnant while taking carmustine, the patient should be informed of the potential risk to the fetus. BreastfeedingIt 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 breastfeeding. Breastfeeding should not be initiated during treatment and up to 7 days after its completion (see section 4.3). FertilityCarmustine may impair fertility in males. Men should be informed of the potential risk of infertility and advised to seek counseling on fertility/planning a family before starting treatment with carmustine.

4.7. Effects on Ability to Drive and Use Machines

Carmustine Waymade has no or negligible influence on the ability to drive and use machines. However, 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 ProfileThe table presents undesirable effects observed during treatment with this medicinal product, but they may not necessarily have a causal relationship with this medicinal product. Due to the fact that 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 is ≥5% higher in the treated group. Tabular List of Undesirable EffectsThe following table presents the undesirable effects of carmustine listed by system organ class and MedDRA and frequency, according to decreasing severity, in accordance with the following convention:

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

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

* There have been reports of increased risk of pulmonary toxicity after treatment with conditioning regimens and after hematopoietic stem cell transplantation in women. To date, increased risk has been reported for treatment itself, including conditioning regimens without carmustine (e.g., total body irradiation [TBI] or busulfan-cyclophosphamide) or with carmustine (chemotherapy BEAM: carmustine, etoposide, cytarabine, and melphalan or CBV: cyclophosphamide, carmustine, and etoposide). Description of selected undesirable effects: Suppression of bone marrow functionSuppression of bone marrow function occurs very frequently and begins 7-14 days after administration of the drug and resolves 42-56 days after its administration. Suppression of bone marrow function is dose-dependent and often has a biphasic course. Disorders of the respiratory system, thorax, and mediastinum Pulmonary fibrosis (with fatal outcome), pulmonary infiltrates. Pulmonary toxicity has been observed in up to 30% of patients. In cases where pulmonary toxicity started early (within 3 years of treatment), pulmonary infiltrates and/or pulmonary fibrosis occurred, sometimes with fatal outcome. Patients were between 22 months and 72 years old. Risk factors include smoking, respiratory diseases, pre-existing radiological abnormalities, sequential or concurrent chest irradiation, and concurrent use of other drugs that may cause pulmonary damage. The frequency of undesirable effects is probably related to the dose; cumulative doses of 1200-1500 mg/m² were associated with an increased risk of pulmonary fibrosis. During treatment, pulmonary function tests (FVC, DLCO) should be regularly performed. Patients with a baseline forced vital capacity or carbon monoxide diffusing capacity below 70% are at particular risk. In patients who received carmustine in childhood or adolescence, cases of very delayed pulmonary fibrosis (up to 17 years after treatment) have been reported. Long-term follow-up of 17 patients who survived brain tumors in childhood showed that 8 of them developed pulmonary fibrosis. Two of these 8 fatal cases occurred within the first 3 years of treatment, and 6 of them occurred 8-13 years after treatment. The median age of patients who died during treatment was 2.5 years (1-12 years), and the median age of long-term survivors was 10 years (5-16 years). All patients under 5 years of age at the time of treatment died due to pulmonary fibrosis; neither the dose of carmustine nor the additional dose of vincristine or spinal irradiation affected the risk of death. Pulmonary fibrosis was diagnosed in all remaining patients. Carmustine should not be administered to children and 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 - after prolonged treatment and cumulative dose >1400 mg/m². Possible induction of vomitingThe risk of vomiting is high after administration of doses >250 mg/m² and high to moderate after administration of doses ≤250 mg/m². Nausea and vomiting are severe and occur within 2-4 hours of administration of the medicinal product and last for 4-6 hours. NephrotoxicityNephrotoxicity occurs rarely but may occur at cumulative doses <1000 mg m². reporting of suspected adverse reactions after authorization the medicinal product, it is important to report any reactions. this allows for continued monitoring benefit risk balance product. healthcare professionals are asked via national system [insert website]. can also be reported marketing holder.< p>

4.9. Overdose

The main symptom of overdose is suppression of bone marrow function. In addition, the following severe adverse reactions may occur: liver necrosis, interstitial pneumonia, brain inflammation, and spinal cord inflammation. There is no specific antidote available.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Therapeutic category: Antineoplastic agent, alkylating agents, nitrosourea derivatives, ATC code: L01AD01 Mechanism of actionCarmustine is a non-specific anticancer drug that acts on the phases of the cell cycle and has a cytotoxic effect on tumors through multiple mechanisms. As an alkylating agent, it can alkylate reactive sites on nucleoproteins, disrupting DNA and RNA synthesis and repair. It is also capable of forming cross-links between DNA strands, preventing DNA replication and transcription. It is also known that carmustine can carbamylate lysine residues on proteins, causing irreversible inactivation of enzymes, including glutathione reductase. The carbamylating activity of carmustine is generally considered to be less significant than its alkylating activity in its anticancer effect, but carbamylation may inhibit DNA repair processes. Pharmacodynamic effectsThe anticancer 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 to reactive intermediate compounds that are capable of alkylation and carbamylation. It is believed that the alkylating intermediate compounds are responsible for the anticancer effect of carmustine. However, opinions are divided regarding the role of carbamylating intermediate compounds as mediators of the biological effects of nitrosourea derivatives. On the one hand, it has been observed that their carbamylating activity contributes to the cytotoxic properties of the parent drugs by inhibiting DNA repair enzymes. On the other hand, it is considered that the carbamylating compounds may mediate some of the toxic effects of carmustine. Carmustine easily crosses the blood-brain barrier due to its lipophilic nature. Children and adolescentsCarmustine Waymade should not be used in children and adolescents due to the high risk of pulmonary toxicity.

5.2. Pharmacokinetic Properties

DistributionCarmustine undergoes rapid decomposition after intravenous administration - within 15 minutes, no unchanged substance is detectable. Due to its good solubility in lipids and lack of ionization at physiological pH, carmustine easily crosses the blood-brain barrier. The level of radioactivity in cerebrospinal fluid is at least 50% higher than that measured in serum at the same time. The kinetics of carmustine in humans is characterized by a two-compartment model. After intravenous infusion lasting 1 hour, the concentration of carmustine in serum decreases in a biphasic manner. The alpha half-life is 1-4 minutes, and the beta half-life is 18-69 minutes. MetabolismIt is assumed that the metabolites of carmustine are responsible for its anticancer and toxic effects. EliminationAbout 60-70% of the total dose is excreted in the urine within 96 hours, and about 10% as CO2 through the respiratory tract. The fate of the remaining portion is unknown.

5.3. Preclinical Safety Data

Carmustine has been shown to be embryotoxic and teratogenic in rats and embryotoxic 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 has been shown to be carcinogenic in rats and mice at doses lower than the recommended dose for humans based on body surface area.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

PowderThe product does not contain excipients. SolventAnhydrous ethanol.

6.2. Incompatibilities

Compatibility/Incompatibility with containersThe intravenous solution is unstable in polyvinyl chloride containers. The carmustine solution can only be administered from glass bottles 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 vial3 years. After reconstitution and dilutionAfter reconstitution in accordance with the recommendations, Carmustine Waymade is stable for 24 hours provided it is stored in a refrigerator 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 for injection or glucose 50 mg/mL (5%) solution for injection. The resulting solution is stable for 24 hours provided it is stored in a refrigerator at 2°C - 8°C and for an additional 6 hours at room temperature, protected from light. The solution should be used immediately, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination. If the product is not used immediately, the user is responsible for the storage time and conditions. The reconstituted and diluted solution (i.e., the ready-to-use solution) must be administered intravenously in a drip infusion over a period of 1 to 2 hours, protected from light. The infusion time should not be less than one hour - otherwise, burning and pain at the injection site may occur. During administration, the infusion site should be monitored.

6.4. Special Precautions for Storage

Store in a refrigerator (2°C - 8°C). Do not freeze. The vials of powder and solvent should be stored in the outer carton to protect them from light. Storage conditions for the medicinal product after reconstitution and further dilution, see section 6.3.

6.5. Nature and Contents of Container

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

6.6. Special Precautions for Disposal and Other Handling

AdministrationThe carmustine-containing product in the form of powder for concentrate for solution for infusion does not contain preservatives and is not intended for use in multidose vials. Reconstitution and further dilution should be performed under aseptic conditions. The dry frozen product does not contain any preservatives and is intended for single use only. The lyophilizate may have the form of dry flakes or a frozen mass. The presence of an oily layer may indicate that the medicinal product has melted. Such products are not suitable for use due to the risk of exceeding a temperature of 30°C. Such a medicinal product should not be used. In case of doubt as to whether the product has been stored under appropriate cooling conditions, all vials in the carton should be immediately checked. For verification, the vial should be placed in bright light. Reconstitution and dilution for infusionDissolve 100 mg of freeze-dried carmustine powder in 3 mL of the supplied sterile, chilled solvent (anhydrous ethanol). Carmustine should be completely dissolved in ethanol before adding sterile water for injection. Then, aseptically add 27 mL of sterile water for injection to the ethanol solution. The resulting 30 mL solution should be thoroughly mixed. Reconstitution performed in accordance with the recommendations results in a clear, colorless, or pale yellow solution. Before using vials with reconstituted substance, check for crystal formation. If crystals have formed, they can be dissolved by warming the vial to room temperature and shaking it. After reconstitution, Carmustine Waymade is stable for 24 hours provided it is stored in a refrigerator 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 for injection or glucose 50 mg/mL (5%) solution for injection. Before administration, the resulting ready-to-use solution (i.e., the reconstituted and diluted solution) should be shaken for at least 10 seconds. The ready-to-use solution should be stored at room temperature in a light-protected glass or polypropylene container and used within 4 hours. These solutions are also stable for 24 hours provided they are stored in a refrigerator at 2°C - 8°C and for an additional 6 hours at room temperature, protected from light. The reconstituted and diluted solution (i.e., the ready-to-use solution) must be administered intravenously in a drip infusion over a period of 1 to 2 hours, protected from light. The infusion should be performed using non-PCV containers made of polyethylene. For administration of the infusion, only a suitable container made of glass or polypropylene should be used. Ensure that polypropylene containers do not contain PCV 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 such a temperature (or higher) will cause it to melt and form an oily layer on the vials. This indicates degradation of the substance - in such a case, the vials should be discarded. Administration of the Carmustine Waymade infusion in a shorter time may cause severe pain and burning at the injection site. The injection site should be monitored during administration (see section 4.2). The recommendations for safe handling of anticancer drugs and their disposal should be followed. Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORIZATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

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

8. MARKETING AUTHORIZATION NUMBERS

9. DATE OF FIRST AUTHORIZATION

RENEWAL OF THE AUTHORIZATION

Date of first authorization:

10. DATE OF REVISION OF THE TEXT

CHARACTERISTICS OF THE MEDICINAL PRODUCT

Patient Information Leaflet: Information for the User

Carmustine Waymade

100 mg, powder and solvent for concentrate for solution for infusion carmustine

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

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

Contents of the pack:

• 1. What is Carmustine Waymade and what is it used for
• 2. Important information 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 is Carmustine Waymade and what is it used for

Carmustine Waymade is a medicinal product containing carmustine as the active substance. Carmustine belongs to a group of anticancer drugs called nitrosourea derivatives, which act by slowing down the growth of cancer cells. Carmustine is effective in the treatment of the following malignant tumors in monotherapy or in combination with other anticancer drugs or other therapeutic measures (radiotherapy, surgical procedure):

• Brain tumors (glioblastoma multiforme, brainstem gliomas, medulloblastoma, astrocytoma, and ependymoma) and metastases to the brain;
• Second-line therapy for non-Hodgkin's lymphoma and Hodgkin's disease;
• As conditioning treatment before autologous hematopoietic stem cell transplantation in malignant hematological diseases (Hodgkin's disease/non-Hodgkin's lymphoma);
• Multiple myeloma (a malignant tumor developing in the bone marrow) - in combination with a glucocorticoid such as prednisone.

2. Important information before using Carmustine Waymade

When not to use Carmustine Waymade:

• if you are allergic to carmustine or any of the other ingredients of this medicinal product (listed in section 6);
• if you have disorders of blood cell production in the bone marrow, which is manifested by a decreased platelet count, white blood cell count, or red blood cell count due to chemotherapy or for other reasons;
• if you have severe renal impairment;
• in children and adolescents;
• if you are pregnant or breastfeeding.

3. How to Use Carmustine Waymade

Carmustine Waymade will always be administered by medical personnel experienced in the use of anticancer medicines.
This medicine is for intravenous infusion.

Adults

Dosing depends on the patient's health, 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 used as monotherapy in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. The medicine can be administered as a single dose or divided into daily infusions of 75 to 100 mg/m2 over two consecutive days. Dosing is also dependent on whether Carmustine Waymade is administered with other anticancer medicines.
Doses will be increased according to the patient's response to treatment.
The recommended dose of Carmustine Waymade administered intravenously in combination with other chemotherapeutic agents before stem cell transplantation of the hematopoietic system is 300-600 mg/m2.
To avoid toxic effects on the bone marrow, blood morphology will be frequently monitored, and the dose will be adjusted if necessary.

Route of Administration

After reconstitution and dilution, Carmustine Waymade is administered intravenously by infusion over a period of one to two hours, protected from light. The duration of the infusion should not be less than one hour - otherwise, burning and pain may occur at the injection site. The injection site will be monitored during the infusion.
The duration of treatment will be determined by the doctor and may vary from patient to patient.

Overdose of Carmustine Waymade

Since the medicine will be administered by a doctor or nurse, incorrect dosing is unlikely. The patient should inform their doctor or nurse if they have any concerns about the amount of medicine they have received.
If the patient has any further questions about the use of this medicine, they should ask their doctor, pharmacist, or nurse.

4. Possible Adverse Effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The Patient Should Immediately Inform Their Doctor or Nurse if They Experience Any of the Following Symptoms:

Wheezing, breathing difficulties, swelling of the eyelids, face, or lips, rash, or itching (especially if it affects the whole body), as well as a feeling of impending fainting. These may be symptoms of a severe allergic reaction.

Carmustine Waymade May Cause the Following Adverse Effects:

Very Common(may affect more than 1 in 10 people):

• Delayed myelosuppression (reduced production of blood cells by the bone marrow), which may increase the risk of infection in case of reduced white blood cell count;
• Ataxia (lack of voluntary coordination of muscle movements);
• Dizziness;
• Headache;
• Transient eye redness, blurred vision due to retinal hemorrhage;
• Hypotension (decrease in blood pressure);
• Phlebitis associated with pain, swelling, redness, and tenderness;
• Respiratory disorders (respiratory problems) associated with difficulty breathing; This medicine may cause severe (potentially life-threatening) lung damage. Lung damage may occur many years after treatment. The patient should immediately inform their doctor if they experience any of the following symptoms: shortness of breath, persistent cough, chest pain, persistent weakness or fatigue;
• Severe nausea and vomiting;
• In case of contact with the skin: skin inflammation;
• Accidental contact with the skin may cause transient discoloration (darkening of the skin or nail area). Common(may affect up to 1 in 10 people)
• Acute leukemias and bone marrow dysplasias (abnormal development of the bone marrow). Possible symptoms include: gum bleeding, bone pain, fever, frequent infections, frequent nosebleeds or heavy bleeding, lymph node swelling in the neck or armpits, abdomen, or groin, pallor, shortness of breath, weakness, fatigue, or general energy decline;
• Anemia (reduced red blood cell count);
• 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;
• Anorexia;
• Constipation;
• Diarrhea;
• Stomatitis;
• Reversible liver toxicity in case of high-dose treatment. This disorder may lead to increased liver enzyme activity and bilirubin levels (these are 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 small veins in the liver) characterized by blockage of very small (microscopic) veins in the liver. Possible symptoms include: fluid accumulation in the abdomen, splenomegaly, severe bleeding from the esophagus, yellowing of the skin and whites of the eyes;
• Breathing difficulties due to interstitial pulmonary fibrosis (when using lower doses);
• Kidney disorders;
• Gynecomastia (breast enlargement in men).

Frequency Not Known(frequency cannot be estimated from the available data)

• Muscle pain;
• Seizures (convulsions), including status epilepticus;
• Tissue damage due to leakage at the injection site;
• Infertility;
• It has been shown that carmustine has an adverse effect on the development of unborn children;
• Electrolyte disorders (and electrolyte imbalance (low levels of potassium, magnesium, and phosphorus in the blood)).

Reporting Adverse Effects

If the patient experiences any side effects, including any not listed in this leaflet, they should tell their doctor or nurse. Adverse effects can be reported directly to the Department of Adverse Reaction Monitoring 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 effects can help gather more information on the safety of this medicine.
Adverse effects can also be reported to the marketing authorization holder.

5. How to Store Carmustine Waymade

The medicine will be stored by a doctor or other medical personnel.
The medicine should be stored out of sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after the words "EXP". The expiry date refers to the last day of the month stated.
Store in a refrigerator (2°C - 8°C). Do not freeze.
Both vials (with active substance and solvent) should be stored in the outer carton to protect the contents from light.
After reconstitution and dilution
Reconstituted 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 be further 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 provided they are stored at 2°C - 8°C and for an additional 6 hours at room temperature provided they are protected from light.
Given the risk of contamination of the product by microorganisms, it should be used immediately, unless the method of opening/reconstitution/dilution rules out this risk. If the product is not used immediately, the user is responsible for the storage time and conditions.
Do not dispose of any medicines via wastewater or household waste. The patient should ask their pharmacist or doctor how to dispose of medicines with the aim of protecting 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 does not contain excipients.
• Solvent: Anhydrous ethanol.

What Carmustine Waymade Looks Like and Contents of the Pack

Powder and solvent for solution for infusion
1 vial of 100 mg powder
code: 08720865197173
1 vial of 3 mL solvent
code: 08720865197173

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Waymade B.V.
Herikerbergweg 88,
1101CM Amsterdam,
Netherlands
medinfo@Waymade.co.uk

Manufacturer

Drehm Pharma GmbH
Grünbergstraße 15/3/3,
Vienna, 1120, Austria

Date of Last Revision of the Leaflet: October 2023

Information intended for healthcare professionals only:
A brief description of the method of preparation and/or administration, incompatibilities, dosing, overdose, or actions required for monitoring, as well as laboratory tests, based on the current Summary of Product Characteristics.
The 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 should be carried out under aseptic conditions.
By following the recommended storage conditions, degradation of the substances contained in the unopened vial can be avoided until the expiry date stated on the packaging.
The lyophilized product does not contain any preservatives and is intended for single use only. The lyophilizate may have the form of dry flakes or a dry solid mass.
The presence of an oily layer may indicate that the medicinal product has melted. Such products are not suitable for use due to the risk of exceeding 30°C. Such a medicinal product should not be used. In case of doubt as to whether the product has been stored under appropriate cooling conditions, all vials in the carton should be immediately checked. For verification, the vial should be placed 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 supplied sterile cold solvent (anhydrous ethanol).
Carmustine must be completely dissolved in anhydrous ethanol before sterile water for injections can be added. Then, 27 mL of sterile water for injections should be aseptically added to the ethanol solution. The 30 mL base solution should be thoroughly mixed.
Reconstitution carried out according to the recommendations results in a clear solution (colorless or light yellow).
Before using the vials with the reconstituted substance, the patient should check if crystals have formed in them. If so, they can be dissolved by warming the vial to room temperature and 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 be further diluted using 500 mL of sodium chloride 9 mg/mL (0.9%) or dextrose 50 mg/mL (5%) solution. The reconstituted and diluted solution (i.e., the solution ready for use) should be shaken for at least 10 seconds before administration. The ready-to-use solution should be stored at room temperature in a light-protected glass or polypropylene container and used within 4 hours. These solutions are also stable for 24 hours provided they are stored at 2°C - 8°C and for an additional 6 hours at room temperature provided they are protected from light.
pH and osmolality of the ready-to-use infusion solutions:
The pH of the ready-to-use infusion solutions is between 4.0 and 6.8.
Method of administration
The reconstituted and diluted solution (i.e., the solution ready for use) must be administered intravenously by infusion over a period of 1 to 2 hours using containers that do not contain PVC. The infusion should only be administered using a glass or polypropylene container. The patient should 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 medicine to such a temperature (or higher) will cause it to melt and form an oily layer on the vials. This indicates degradation of the substance - in such a case, the vials should be discarded.
Administering the Carmustine Waymade product in a shorter time may cause severe pain and burning at the injection site. During administration of the product, the intravenous infusion site should be monitored.
The patient should follow the recommendations for the safe handling and disposal of anticancer medicines.
Dosing and laboratory tests
Initial doses
The recommended dose of Carmustine Waymade used as monotherapy in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. The medicine can be administered as a single dose or divided into daily infusions of 75 to 100 mg/m2 over two consecutive days.
When Carmustine Waymade is used in combination with other medicines that have a myelosuppressive effect or in patients with reduced bone marrow reserve, the dose should be adjusted according to the patient's hematologic profile, as presented below.
Monitoring and subsequent doses
A subsequent course of treatment with Carmustine Waymade can only be administered when the blood morphology parameters have returned to an acceptable level (platelet count above 100,000/mm3, leukocytes above 4,000/mm3), which usually occurs within six weeks.
Blood morphology should be frequently monitored, and a subsequent course of treatment should not be administered before six weeks have elapsed due to the possibility of delayed hematologic toxicity.
After the initial dose, subsequent doses should be adjusted according to the patient's hematologic response to the previous dose, both in monotherapy and in combination therapy with other medicines that have a myelosuppressive effect. The following dose adjustment scheme is suggested:

In cases where the lowest value after the initial dose is not in the same row for leukocytes and platelets (e.g., leukocyte count >4000 and platelet count <25,000), the value corresponding to the lowest percentage of the previous dose should be used (e.g., platelet count <25,000 - a maximum of 50% of the previous dose should be used).
There are no restrictions on the duration of treatment with carmustine. If the tumor remains incurable or severe or intolerable adverse effects occur, treatment with carmustine should be discontinued.
Conditioning treatment before 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 hematologic disease before hematopoietic stem cell transplantation.
Special populations
Children and Adolescents
Carmustine should not be used in children under 18 years of age due to safety concerns.
Elderly
Generally, in elderly patients, doses should be selected cautiously, and it is recommended to start with the lower end of the dose range, considering concomitant diseases and other medicines being taken. Since elderly patients are more likely to have impaired liver, kidney, or heart function, the dose should be adjusted accordingly, and the glomerular filtration rate should be monitored.
Renal Impairment
In patients with renal impairment, the dose of Carmustine Waymade should be reduced in case of decreased glomerular filtration rate.
Compatibility or incompatibility with containers
The intravenous solution is unstable in containers made of polyvinyl chloride. Containers made of PVC should not be used. The carmustine solution can only be administered from a glass or polypropylene container. The patient should ensure that polypropylene containers do not contain PVC or DEHP.

INFORMATION TO BE INCLUDED ON THE OUTER AND IMMEDIATE PACKAGING

BOX

1. NAME OF THE MEDICINAL PRODUCT

Carmustine Waymade, 100 mg, powder and solvent for solution for infusion
carmustine

2. CONTENTS OF ACTIVE SUBSTANCE

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

Contains anhydrous ethanol
Each vial of solvent contains 3 mL of anhydrous ethanol (corresponding to 2.37 g).
For more information, see the leaflet enclosed with the packaging.

4. PHARMACEUTICAL FORM AND CONTENTS OF THE PACKAGING

Powder and solvent for solution for infusion
1 vial of powder
code: 08720865197173
1 vial of solvent
code: 08720865197173

5. METHOD AND ROUTE OF ADMINISTRATION

For single use only.
For intravenous administration after reconstitution and dilution.
The patient should read the leaflet enclosed with the packaging before using the medicine.

6. SPECIAL WARNING FOR STORAGE OF THE MEDICINAL PRODUCT

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 care during administration.
Avoid contact between the concentrate for solution for infusion and the skin.
May cause birth defects.

8. MANUFACTURE AND EXPIRY DATE

Expiry date (EXP)
After reconstitution/dilution: Shelf life of the product after reconstitution - see the leaflet enclosed with the packaging.

9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS, IF APPROPRIATE

FOR DISPOSAL

Follow the recommendations for the safe disposal of anticancer medicines.

11. NAME AND ADDRESS OF THE MARKETING AUTHORIZATION HOLDER

12. MARKETING AUTHORIZATION NUMBER

13. BATCH NUMBER

Lot

14. GENERAL CATEGORY OF AVAILABILITY

Rpz - Prescription-only medicine

15. INSTRUCTIONS FOR USE

16. INFORMATION PROVIDED IN BRAILLE

Justification for the absence of Braille information has been accepted.

17. UNIQUE IDENTIFIER - 2D CODE

Includes a 2D code that is a carrier of a unique identifier.

18. UNIQUE IDENTIFIER - HUMAN-READABLE DATA

PC
SN
NN

INFORMATION TO BE INCLUDED ON THE OUTER AND IMMEDIATE PACKAGING

POWDER VIAL

1. NAME OF THE MEDICINAL PRODUCT

Carmustine Waymade, 100 mg powder for solution for infusion
carmustine

2. CONTENTS OF ACTIVE SUBSTANCE

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 PACKAGING

Powder for solution for infusion
100 mg

5. METHOD AND ROUTE OF ADMINISTRATION

For single use only.
For intravenous administration after reconstitution and dilution.
The patient should read the leaflet enclosed with the packaging before using the medicine.

6. SPECIAL WARNING FOR STORAGE OF THE MEDICINAL PRODUCT

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 care during administration.
Avoid contact between the concentrate for solution for infusion and the skin.
May cause birth defects.

8. MANUFACTURE AND EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS, IF APPROPRIATE

FOR DISPOSAL

Follow the recommendations for the safe disposal of anticancer medicines.

11. NAME AND ADDRESS OF THE MARKETING AUTHORIZATION HOLDER

12. MARKETING AUTHORIZATION NUMBER

13. BATCH NUMBER

Lot

14. GENERAL CATEGORY OF AVAILABILITY

Rpz - Prescription-only medicine

15. INSTRUCTIONS FOR USE

16. INFORMATION PROVIDED IN BRAILLE

Justification for the 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 INCLUDED ON THE OUTER AND IMMEDIATE PACKAGING

SOLVENT VIAL

1. NAME OF THE MEDICINAL PRODUCT

Solvent for Carmustine Waymade
anhydrous ethanol
iv.

2. CONTENTS OF ACTIVE SUBSTANCE

Each vial of solvent contains 3 mL of anhydrous ethanol (corresponding to 2.37 g).

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. METHOD AND ROUTE OF ADMINISTRATION

For dissolution only.
The patient should read the enclosed patient leaflet for instructions on use.

6. SPECIAL WARNING FOR STORAGE OF THE MEDICINAL PRODUCT

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.
Store the vial in the outer packaging to protect it from light.

9. NAME AND ADDRESS OF THE MARKETING AUTHORIZATION HOLDER

10. OTHER