CARMUSTINE WAYMADE 100 mg POWDER AND SOLVENT FOR CONCENTRATE FOR PERFUSION SOLUTION - Generic

Introduction

Package Leaflet: Information for the User

Carmustina Waymade 100 mg powder and solvent for concentrate for solution for infusion EFG

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the Package Leaflet

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

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

Carmustina Waymade is a medicine that contains carmustine as the active ingredient. Carmustine belongs to a group of anticancer medicines, known as nitrosoureas, which work by slowing down the growth of cancer cells.

Carmustine is indicated for the following malignant neoplasias in monotherapy or in combination with other antineoplastic agents and/or other therapeutic measures (radiotherapy, surgery):

• Brain tumors (glioblastoma, brainstem gliomas, medulloblastoma, astrocytoma, and ependymoma), brain metastases
• Second-line treatment in non-Hodgkin lymphoma and Hodgkin's disease
• As conditioning treatment prior to autologous hematopoietic progenitor cell transplantation (AHPCT) in malignant hematological disorders (Hodgkin's disease/non-Hodgkin lymphoma).
• Multiple myeloma (a malignant tumor that develops in the bone marrow): in combination with glucocorticoids such as prednisone.

2. What you need to know before you use Carmustina Waymade

Do not use Carmustina Waymade:

• If you are allergic to carmustine or any of the other ingredients of this medicine (listed in section 6);
• in children and adolescents;

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before you start using this medicine.

The main side effect of this medicine is delayed bone marrow suppression, which can manifest as fatigue, bleeding from the skin and mucous membranes, infections, and fever as a result of changes in the blood. Therefore, your doctor will monitor your blood counts every week for at least 6 weeks after each dose. Following the recommended dosage, cycles of this medicine will not be administered more frequently than every 6 weeks. The dosage will be confirmed with the blood count.

Before treatment, liver, lung, and kidney function will be evaluated and monitored periodically during treatment.

Since the use of this medicine can cause lung damage, a chest X-ray and lung function tests will be performed before starting treatment (see also the section "Possible side effects").

Treatment with high doses of this medicine (up to 600 mg/m2) is only performed in combination with subsequent stem cell transplantation. These high doses can increase the frequency or severity of pulmonary, renal, hepatic, cardiac, and gastrointestinal toxicities, as well as infections and changes in electrolyte balance (low levels of potassium, magnesium, and phosphate in the blood).

Abdominal pain (neutropenic enterocolitis) may occur as an adverse event related to therapy after treatment with chemotherapeutic agents.

Your doctor will inform you of the possibility of lung damage and allergic reactions and their symptoms. If these symptoms appear, you should contact your doctor immediately (see section 4).

Children and adolescents

This medicine must not be used in children and adolescents under 18 years of age.

Other medicines and Carmustina Waymade

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription.

• Phenytoin, used in epilepsy.
• Dexamethasone, used as an anti-inflammatory and immunosuppressant.
• Cimetidine, used for stomach problems such as indigestion.
• Digoxin, used if you have an abnormal heart rhythm.
• Melphalan, an anticancer medicine.

Carmustina Waymade with alcohol

The amount of alcohol present in this medicine may alter the effects of other medicines.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy and fertility

This medicine must not be used during pregnancy because it may harm the fetus. Therefore, this medicine should not be administered to pregnant women. If it is used during pregnancy, the patient should be aware of the possible risk to the fetus. Women of childbearing age are advised to use effective contraceptive methods to avoid becoming pregnant during treatment with this medicine and for at least six months after the end of treatment.

Male patients should use adequate contraceptive methods during treatment with this medicine and for at least 6 months after the end of treatment to avoid getting their partners pregnant.

Breastfeeding

Do not breastfeed while you are taking this medicine and for 7 days after treatment. The risk to newborns/infants cannot be excluded.

Driving and using machines

The influence of this medicine on the ability to drive and use machines is negligible or non-existent. You should talk to your doctor before driving or using tools or machines, as the amount of alcohol contained in this medicine may affect your ability to drive or use machines.

Carmustina Waymade contains anhydrous ethanol (alcohol)

This medicine contains 2.4 g of alcohol (ethanol) in a vial, which corresponds to 7.68 g in the maximum dose (320 mg). The amount of alcohol in the maximum dose (200 mg/m2 in patients weighing 70 kg) of this medicine corresponds to the amount contained in 192 ml of beer or 76.8 ml of wine.

Since this medicine is usually administered slowly over 6 hours, the effects of the alcohol may be reduced.

The amount of alcohol in this medicine may affect your ability to drive or use machinery, as it may affect your judgment and reaction speed.

If you have epilepsy or liver problems, talk to your doctor or pharmacist before taking this medicine.

The amount of alcohol in this medicine may alter the effects of other medicines. Talk to your doctor or pharmacist if you are taking other medicines.

If you are pregnant, talk to your doctor or pharmacist before taking this medicine.

If you have a history of alcoholism, talk to your doctor or pharmacist before taking this medicine.

3. How to use Carmustina Waymade

This medicine will always be administered by a healthcare professional with experience in the use of anticancer medicines.

This medicine is for intravenous infusion.

Adults

The dosage depends on the disease, body size, and response to treatment. It is usually administered at least every 6 weeks. The recommended dose of carmustine in monotherapy in patients not previously treated is 150 to 200 mg/m2 by intravenous infusion every 6 weeks. This amount can be administered in a single dose or divided into daily infusions of 75 to 100 mg/m2 over two consecutive days. The dosage will also depend on whether this medicine is administered with other anticancer medicines.

The doses will be adjusted according to your response to treatment.

The recommended dose of carmustine administered in combination with other chemotherapeutic agents before hematopoietic progenitor cell transplantation is 300-600 mg/m2 by intravenous infusion.

Blood counts will be monitored frequently to avoid bone marrow toxicity and the dose will be adjusted if necessary.

Method of administration

After reconstitution and dilution, Carmustina Waymade is administered intravenously by drip (intravenously), protected from light, over a period of one to two hours. The infusion duration should not be less than one hour to avoid burning and pain at the injection site. The injection site will be monitored during administration.

The duration of treatment will be determined by your doctor and may vary for each patient.

If you use more Carmustina Waymade than you should

Since it will be your doctor or nurse who administers this medicine to you, it is unlikely that you will receive an incorrect dose. Tell your doctor or nurse if you have any doubts about the amount of medicine you have received.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicological Poisoning Service. Phone 91 562 04 20, indicating the medicine and the amount ingested.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

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

Tell your doctor or nurse immediately if you experience any of the following side effects:

Sudden wheezing, difficulty breathing, swelling of the eyelids, face, or lips, rash, or itching (especially if it affects the whole body) and feeling of fainting. These may be signs of a severe allergic reaction.

Carmustina Waymade may cause the following side effects:

Very common(may affect more than 1 in 10 people)

• Delayed bone marrow suppression (decrease in blood cells in the bone marrow) which can increase the risk of infections if white blood cells decrease
• Ataxia (lack of voluntary muscle coordination)
• Dizziness
• Headaches
• Transient eye redness, blurred vision due to retinal hemorrhage
• Hypotension (low blood pressure)
• Phlebitis (inflammation of the veins) associated with pain, swelling, redness, sensitivity
• Respiratory disorders (related to the lungs) with respiratory problems
• This medicine may cause severe lung damage (possibly fatal). Lung damage may appear years after treatment. Tell your doctor immediately if you experience any of the following symptoms: difficulty breathing, persistent cough, chest pain, persistent weakness/fatigue
• Severe nausea and vomiting
• When used on the skin, skin inflammation (dermatitis)
• Accidental contact with the skin can cause transient hyperpigmentation (darkening of a 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) after prolonged use. Some of the symptoms are gum bleeding, bone pain, fever, frequent infections, frequent or severe nosebleeds, swelling of the lymph nodes in and around the neck, armpits, abdomen, or groin, pallor, difficulty breathing, weakness, fatigue, or general decrease in energy;

• Anemia (decrease in the number of red blood cells in the blood)
• Encephalopathy (brain disorder). It can include symptoms of muscle weakness in one area, decreased ability to make decisions or concentrate, involuntary contractions, tremors, difficulty speaking or swallowing, seizures;
• Anorexia
• Constipation
• Diarrhea
• Mouth and lip inflammation
• Reversible liver toxicity with high-dose treatment. This can cause an increase in liver enzymes and bilirubin (detected by blood tests)
• Alopecia (hair loss)
• Redness of the skin
• Reactions at the injection site

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

• Veno-occlusive disease (progressive blockage of small veins) in the liver, which can include symptoms of: fluid accumulation in the abdomen, enlargement of the spleen, severe bleeding from the esophagus, yellowing of the skin and the whites of the eyes.
• • Respiratory problems caused by interstitial fibrosis (with lower doses)
  • Kidney problems
  • Gynecomastia (breast growth in males)

Frequency not known(cannot be estimated from the available data)

• Muscle pain
• Seizures (crises), including status epilepticus
• Tissue damage due to leakage at the injection site
• Infertility
• Carmustine has been shown to have a negative effect on fetal development.
• Electrolyte abnormalities (and changes in electrolyte balance (low levels of potassium, magnesium, and phosphate in the blood))

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Carmustina Waymade

This medicine will be stored by your doctor or healthcare professional.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date is the last day of the month stated.

Store in a refrigerator (between 2°C and 8°C). Do not freeze.

Store both vials (active and solvent) in the outer packaging to protect them from direct light.

After reconstitution and dilution

After reconstitution, Carmustina Waymade is stable for 24 hours in the refrigerator (2°C - 8°C), stored in a glass container and protected from direct light.

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

From a microbiological point of view, unless the opening/reconstitution/dilution method excludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the in-use storage times and conditions are the responsibility of the user.

Medicines should not be disposed of via wastewater or household waste. Ask your doctor or pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Container Contents and Additional Information

Composition of Carmustina Waymade

The active ingredient is carmustine.

Each vial of powder for concentrate for solution for infusion contains 100 mg of carmustine.

After reconstitution and dilution, one ml of solution contains 3.3 mg of carmustine.

• Excipients:
• Powder: does not contain excipients.
• Solvent: anhydrous ethanol.

Appearance of the Product and Container Contents

Carmustina Waymade is a powder and solvent for concentrate for solution for infusion. A container contains a vial with 100 mg of carmustine powder and a vial of 3 ml of anhydrous ethanol solvent.

The powder is pale yellow lyophilized flakes or a frozen mass supplied in an amber glass vial.

The solvent is a clear, colorless liquid supplied in a clear glass vial.

Lyophilized flakes or frozen mass for reconstitution.

Appearance of the solution: The reconstituted solution is a clear, colorless to slightly yellowish solution.

Powder: Amber glass type I vial (30 ml) with a 20 mm gray bromobutyl rubber stopper with an easy-to-open blue matte seal.

Solvent: Type I glass vial (5 ml) with a 13 mm gray chlorobutyl rubber stopper with an easy-to-open blue matte seal.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Waymade B.V.

Herikerbergweg 88,

1101CM Amsterdam,

Netherlands

Manufacturer

Drehm Pharma GmbH

Grünbergstraße 15/3/3,

Wien, 1120, Austria

Waymade B.V.

Herikerbergweg 88,

1101CM Amsterdam,

Netherlands

Date of Last Revision of this Leaflet: October 2021.

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This information is intended solely for healthcare professionals:

This information is a brief description of preparation and/or handling, incompatibilities, dosage of the medication, overdose or monitoring measures and laboratory tests based on the current technical data sheet.

The powder of Carmustina Waymade for concentrate for solution for infusion does not contain preservatives and is not designed as a multiple-dose vial. Reconstitution and subsequent dilutions should be performed under aseptic conditions.

Following the recommended storage conditions, it is possible to avoid decomposition of the unopened vial until the expiration date indicated on the container.

The lyophilized product does not contain preservatives and is only suitable for single use. The lyophilized product may appear as dry flakes or a solidified dry mass. The presence of an oily film may be an indication of the melting of the medication. These products are not valid for use due to the risk of temperature deviations above 30 °C. This medication should no longer be used. When there are doubts about whether the product is properly refrigerated, each vial in the box should be inspected immediately. For verification, hold the vial in intense light.

Reconstitution and dilution of the powder for concentrate for solution for infusion:

Dissolve the 100 mg Carmustina Waymade infusion powder with 3 ml of the supplied anhydrous ethanol solvent, which is refrigerated and sterile. Carmustine must be completely dissolved in anhydrous ethanol before adding sterile water for injections. Then, aseptically add 27 ml of sterile water for injectable preparations to the alcohol solution. The 30 ml parent solution should be well mixed. The recommended reconstitution results in a clear, colorless to yellowish solution.

Examine the reconstituted vials for crystal formation before use. If crystals are observed, they can be redissolved by warming the vial to room temperature, shaking. After reconstitution, Carmustina Waymade is stable for 24 hours, refrigerated (2°C - 8°C), stored in a glass container and protected from direct light.

The reconstituted solution should be further diluted with either 500 ml of 9 mg/ml (0.9%) sodium chloride solution or 500 ml of 50 mg/ml (5%) dextrose solution. The reconstituted and diluted solution (i.e., the ready-to-use solution) should be mixed for at least 10 seconds before administration. The ready-to-use solution should be stored at room temperature in a glass or polypropylene container, protected from light, and used within 4 hours. These solutions are also stable when refrigerated for 24 hours (2°C - 8°C) and an additional 6 hours at room temperature, protected from direct light.

pH and osmolarity of the ready-to-use infusion solutions:

The pH of the ready-to-use infusion solutions is 4.0 to 6.8.

Mode of Administration

The reconstituted and diluted solution (i.e., the ready-to-use solution) should be administered intravenously and by intravenous drip over a period of one to two hours. The administration of the infusion should be performed with a PE infusion equipment or containers without PVC. During medication administration, the container should be suitable and only made of glass or polypropylene. Ensure that the polypropylene containers used 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 this medication to this temperature or higher will cause the medication to melt and appear as an oil film in the vials. This is a sign of decomposition, and the vials should be discarded.

Infusion of Carmustina Waymade over shorter periods may produce intense pain and burning at the injection site. The injection site should be monitored during administration.

Proper handling and disposal of antineoplastics should be followed.

Dosage and Laboratory Tests

Initial Doses

The recommended dose of Carmustina Waymade as monotherapy in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. This amount can be administered in a single dose or divided into daily infusions of 75 to 100 mg/m2 over two consecutive days.

When Carmustina Waymade is used in combination with other myelosuppressive medications or in patients with depleted bone marrow reserve, the doses should be adjusted based on the patient's hematologic profile, as shown below.

Monitoring and Subsequent Doses

A new cycle of Carmustina Waymade should not be administered until the circulating blood elements have recovered to acceptable levels (platelets above 100,000/mm3, white blood cells above 4,000/mm3), which usually occurs in six weeks. Blood counts should be monitored frequently, and repeat cycles should not be administered before six weeks due to delayed hematologic toxicity.

Subsequent doses after the initial dose should be adjusted based on the patient's hematologic response to the previous dose, both as monotherapy and in combination with other myelosuppressive medications. The following scheme is suggested as a guide for dose adjustment:

In cases where the nadir of white blood cells and platelets after the initial dose is not in the same row (e.g., white blood cells > 4,000 and platelets < 25,000), the value corresponding to the lower percentage of the previous dose should be used (e.g., if the platelet value is < 25,000, a maximum of 50% of the previous dose should be administered).

There are no limits to the treatment period with carmustine. If the tumor remains incurable or severe or intolerable adverse reactions occur, treatment with carmustine should be discontinued.

Pre-TCHP Conditioning Treatment

In patients with malignant hematological disorders, before TCHP, carmustine is administered in combination with other chemotherapeutic agents at a dose of 300-600 mg/m2 intravenously.

Special Populations

Pediatric Population

Carmustine should not be used in children under 18 years of age for safety reasons.

Elderly Patients

In general, the dose for an elderly patient should be selected with caution, usually starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other medication use. Since elderly patients are more likely to have decreased renal function, the dose should be selected with caution, and glomerular filtration should be monitored, and the dose reduced accordingly.

Renal Impairment

In patients with renal impairment, the dose of Carmustina Waymade should be reduced if glomerular filtration is decreased.

Compatibility/Incompatibility with Containers

The intravenous solution is unstable in polyvinyl chloride containers. Do not use PVC containers. The carmustine solution can only be administered in glass or polypropylene containers. Ensure that the polypropylene containers used do not contain PVC or DEHP.