BORTEZOMIB FRESENIUS KABI 1 mg POWDER FOR INJECTION SOLUTION

Introduction

Package Leaflet: Information for the User

Bortezomib Fresenius Kabi 1 mg powder for solution for injection EFG

bortezomib

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 or pharmacist.
• If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. See section 4.

Contents of the pack:

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

1. What Bortezomib Fresenius Kabi is and what it is used for

This medicine contains the active substance bortezomib, a "proteasome inhibitor". Proteasomes play an important role in controlling cell function and growth. Bortezomib can destroy cancer cells by interfering with their function.

Bortezomib is used to treat multiple myeloma (a type of bone marrow cancer) in patients over 18 years of age:

• alone or with the medicines liposomal doxorubicin or dexamethasone, for patients whose disease is getting worse (in progression) after receiving at least one previous treatment and for those patients whose stem cell transplant did not work or is not suitable.
• in combination with the medicines melphalan and prednisone, for patients who have not been treated before and are not suitable for high-dose chemotherapy before a stem cell transplant.
• in combination with the medicines dexamethasone or dexamethasone and thalidomide, in patients who have not been treated before and are receiving high-dose chemotherapy before a stem cell transplant (induction treatment).

Bortezomib is used to treat mantle cell lymphoma (a type of cancer that affects the lymph nodes) in patients over 18 years of age in combination with the medicines rituximab, cyclophosphamide, doxorubicin, and prednisone, in patients who have not been treated before and for those patients who are not considered suitable for a stem cell transplant.

2. What you need to know before you use Bortezomib Fresenius Kabi

Do not use bortezomib

• if you are allergic to bortezomib, boron, or any of the other ingredients of this medicine (listed in section 6)
• if you have certain severe lung or heart problems.

Warnings and precautions

Tell your doctor if you have:

• low red or white blood cell count
• bleeding problems and/or low platelet count in the blood
• diarrhea, constipation, nausea, or vomiting
• a history of fainting, dizziness, or lightheadedness
• kidney problems
• moderate to severe liver problems
• numbness, tingling, or pain in the hands or feet (neuropathy) in the past
• heart problems or high blood pressure
• difficulty breathing or coughing
• seizures
• shingles (localized, including around the eyes, or widespread)
• symptoms of tumor lysis syndrome, such as muscle cramps, muscle weakness, confusion, vision loss, or difficulty breathing
• memory loss, changes in thinking, difficulty walking, or vision loss. These may be signs of a serious brain infection and your doctor may advise further tests and monitoring.

You will need to have regular blood tests before and during treatment with bortezomib to check your blood cell count regularly.

You must tell your doctor if you have mantle cell lymphoma and are given rituximab with bortezomib:

Before starting treatment with bortezomib, you should read the package leaflets of all the medicines you need to take with bortezomib to see the information about these medicines.

When using thalidomide, special attention should be paid to pregnancy testing and prevention measures (see Pregnancy and Breastfeeding in this section).

Children and adolescents

Bortezomib should not be used in children and adolescents because it is not known how it affects them.

Using bortezomib with other medicines

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

In particular, tell your doctor if you are using medicines that contain any of the following active substances:

• ketoconazole, to treat fungal infections
• ritonavir, to treat HIV infection
• rifampicin, an antibiotic to treat bacterial infections
• carbamazepine, phenytoin, or phenobarbital used to treat epilepsy
• St. John's Wort (Hypericum perforatum), used for depression or other conditions
• oral antidiabetics

Pregnancy and breastfeeding

You should not use this medicine if you are pregnant unless it is clearly necessary.

Women of childbearing age must use effective contraception during treatment and for up to 8 months after finishing treatment. Talk to your doctor if you want to freeze your eggs before starting treatment.

Men should not father a child while using bortezomib and should use effective contraception during treatment and for up to 5 months after treatment.

You should not breastfeed while using bortezomib. Ask your doctor when it is safe to restart breastfeeding after finishing your treatment.

Thalidomide causes birth defects and fetal death. When bortezomib is given with thalidomide, you should follow the thalidomide pregnancy prevention program (see the thalidomide package leaflet).

Driving and using machines

Bortezomib can cause fatigue, dizziness, fainting, or blurred vision. Do not drive or use tools or machines if you experience these side effects; even if you do not experience them, you should still be cautious.

3. How to use Bortezomib Fresenius Kabi

Your doctor will tell you the dose of bortezomib according to your height and weight (body surface area). The usual starting dose of bortezomib is 1.3 mg/m2 of body surface area twice a week.

Your doctor may change the dose and the total number of treatment cycles depending on your response to treatment, the occurrence of certain side effects, and your underlying condition (e.g., liver problems).

Progressive multiple myeloma

When bortezomib is given alone, you will receive 4 doses of bortezomib by intravenous injection on days 1, 4, 8, and 11, followed by a 10-day "rest" period without treatment. This 21-day period (3 weeks) is one treatment cycle. You may receive up to 8 cycles (24 weeks).

You may also receive bortezomib with the medicines liposomal doxorubicin or dexamethasone.

When bortezomib is given with liposomal doxorubicin, you will receive bortezomib by intravenous injection in a 21-day treatment cycle and liposomal doxorubicin 30 mg/m2 will be given on day 4 of the bortezomib 21-day treatment cycle, by intravenous infusion after the bortezomib injection.

You may receive up to 8 cycles (24 weeks).

When bortezomib is given with dexamethasone, you will receive bortezomib by intravenous injection in a 21-day treatment cycle and dexamethasone 20 mg will be given orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of the bortezomib 21-day treatment cycle.

You may receive up to 8 cycles (24 weeks).

Previously untreated multiple myeloma

If you have not been treated for multiple myeloma before and are not a candidate for a stem cell transplant, you will receive bortezomib with two other medicines; melphalan and prednisone.

In this case, the duration of one treatment cycle is 42 days (6 weeks). You will receive 9 cycles (54 weeks).

• In cycles 1 to 4, bortezomib is given twice a week on days 1, 4, 8, 11, 22, 25, 29, and 32.
• In cycles 5 to 9, bortezomib is given once a week on days 1, 8, 22, and 29.

Melphalan (9 mg/m2) and prednisone (60 mg/m2) are given orally during the first 4 days of each cycle.

If you have not received any previous treatment for multiple myeloma and area candidate for a stem cell transplant, you will receive bortezomib by intravenous injection with the medicines dexamethasone, or dexamethasone and thalidomide, as induction treatment.

When bortezomib is given with dexamethasone, you will receive bortezomib by intravenous injection in a 21-day treatment cycle and dexamethasone will be given orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib 21-day treatment cycle.

You will receive 4 cycles (12 weeks).

When bortezomib is given with thalidomide and dexamethasone, the duration of one treatment cycle is 28 days (4 weeks).

Dexamethasone 40 mg is given orally on days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib 28-day treatment cycle and thalidomide is given orally once daily at a dose of 50 mg up to day 14 of the first cycle and, if tolerated, the thalidomide dose is increased to 100 mg on days 15-28 and from the second cycle onwards, it may be increased further to 200 mg daily. You may receive up to 6 cycles (24 weeks).

Previously untreated mantle cell lymphoma

If you have not been treated for mantle cell lymphoma before, you will receive bortezomib by intravenous injection with the medicines rituximab, cyclophosphamide, doxorubicin, and prednisone.

Bortezomib is given by intravenous injection on days 1, 4, 8, and 11, followed by a "rest" period without treatment. The duration of one treatment cycle is 21 days (3 weeks). You may receive up to 8 cycles (24 weeks).

The following medicines are given by intravenous infusion on day 1 of the bortezomib 21-day treatment cycle:

Rituximab at a dose of 375 mg/m2, cyclophosphamide at a dose of 750 mg/m2, and doxorubicin at a dose of 50 mg/m2.

Prednisone is given orally at a dose of 100 mg/m2 on days 1, 2, 3, 4, and 5 of the bortezomib treatment cycle.

How bortezomib is given

This medicine is given by intravenous injection only. You will be given bortezomib by a healthcare professional who is experienced in the use of cytotoxic medicines.

The bortezomib powder must be dissolved before administration. This will be done by a healthcare professional. The reconstituted solution is then injected into a vein or under the skin. The injection into a vein is rapid, lasting between 3 and 5 seconds.

If you receive more bortezomib than you should

This medicine will be given to you by your doctor or nurse, so it is unlikely that you will receive too much. In the unlikely event of an overdose, your doctor will monitor you for side effects.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them. Some of these effects can be serious.

If you are administered bortezomib for multiple myeloma or mantle cell lymphoma, report immediately to your doctor if you observe any of the following symptoms:

• Muscle cramps, muscle weakness
• Confusion, loss or alteration of vision, blindness, convulsions, headaches
• Difficulty breathing, swelling of the feet or alterations in heart rhythm, high blood pressure, fatigue, fainting
• Cough and difficulty breathing or oppression in the chest.

Treatment with bortezomib can very frequently cause a decrease in the number of red and white blood cells and platelets in the blood. Therefore, you will need to have regular blood tests before and during treatment with bortezomib to regularly check your blood cell count. You may experience a reduction in the number of:

• Platelets, which can make you more prone to bruising (bruises) or bleeding without apparent injury (e.g., intestinal, stomach, mouth, and gum bleeding or brain or liver bleeding)
• Red blood cells, which can cause anemia, with symptoms such as fatigue and paleness
• White blood cells, which can make you more prone to infections or symptoms similar to those of the flu.

If you are administered bortezomib for the treatment of multiple myeloma, the adverse effects you may experience are included below:

Very Common Adverse Effects (may affect more than 1 in 10 patients)

• Sensitivity, numbness, tingling, or burning sensation in the skin or pain in hands or feet due to nerve damage
• Decrease in the number of red and/or white blood cells (see above)
• Fever
• Feeling of discomfort (nausea) or vomiting, loss of appetite
• Constipation with or without swelling (can be severe)
• Diarrhea: if it appears, it is important to drink more water than usual. Your doctor may give you another medicine to control diarrhea
• Exhaustion (fatigue), feeling of weakness
• Muscle pain, bone pain

Common Adverse Effects (may affect up to 1 in 10 patients)

• Low blood pressure, sudden drop in blood pressure when standing, which could lead to fainting
• High blood pressure
• Decreased kidney function
• Headache
• Feeling of general discomfort, pain, dizziness, drowsiness, feeling of weakness or loss of consciousness
• Chills
• Infections, including pneumonia, respiratory infections, bronchitis, fungal infections, cough with phlegm, flu-like illness
• Herpes zoster (localized, including around the eyes or spread throughout the body)
• Chest pain or difficulty breathing when exercising
• Various types of rashes
• Itching of the skin, skin bumps, or dry skin
• Facial flushing or rupture of small blood vessels
• Redness of the skin
• Dehydration
• Heartburn, bloating, belching, flatulence, stomach pain, intestinal or stomach bleeding
• Alteration of liver function
• Sores in the mouth or lip, dry mouth, mouth ulcers, or sore throat
• Weight loss, loss of taste
• Muscle cramps, muscle spasms, muscle weakness, pain in the limbs
• Blurred vision
• Infection of the outer layer of the eye and the inner surface of the eyelids (conjunctivitis)
• Nasal bleeding
• Difficulty or problems sleeping, sweating, anxiety, mood changes, depressed mood, restlessness, or agitation, changes in mental state, disorientation
• Swelling of the body, including around the eyes and in other parts of the body

Uncommon Adverse Effects (may affect up to 1 in 100 patients)

• Heart problems, including heart attack, angina pectoris
• Severe nerve inflammation, which can cause paralysis and difficulty breathing (Guillain-Barré syndrome)
• Flushing
• Discoloration of the veins
• Inflammation of the spinal nerves
• Ear problems, ear bleeding
• Underactive thyroid gland
• Budd-Chiari syndrome (clinical symptoms caused by obstruction of the hepatic veins)
• Changes or anomalies in intestinal function
• Cerebral hemorrhage
• Yellowing of the eyes and skin (jaundice)
• Severe allergic reaction (anaphylactic shock), whose signs can be difficulty breathing, pain or oppression in the chest and/or feeling of dizziness/fainting, intense itching of the skin or skin bumps, swelling of the face, lips, tongue, and/or throat, which can cause difficulty swallowing, collapse
• Breast disorders
• Vaginal tear
• Genital inflammation
• Inability to tolerate alcohol consumption
• Emaciation or loss of body mass
• Increased appetite
• Fistula
• Joint effusion
• Cysts in the joint lining (synovial cysts)
• Fracture
• Breakdown of muscle fibers that can cause other complications
• Liver swelling, liver bleeding
• Kidney cancer
• Skin disease similar to psoriasis
• Skin cancer
• Pallor of the skin
• Increased platelets or plasma cells (a type of white blood cell) in the blood
• Blood clot in small blood vessels (thrombotic microangiopathy)
• Abnormal reaction to blood transfusions
• Partial or total loss of vision
• Loss of libido
• Drooling
• Bulging eyes
• Sensitivity to light
• Rapid breathing
• Rectal pain
• Gallstones
• Hernia
• Wounds
• Weak or brittle nails
• Abnormal protein deposits in vital organs
• Coma
• Intestinal ulcers
• Multi-organ failure
• Death

Rare Adverse Effects (may affect up to 1 in 1,000 patients)

• Heart problems, including heart attack, angina pectoris
• Severe nerve inflammation, which can cause paralysis and difficulty breathing (Guillain-Barré syndrome)
• Flushing
• Discoloration of the veins
• Inflammation of the spinal nerves
• Ear problems, ear bleeding
• Underactive thyroid gland
• Budd-Chiari syndrome (clinical symptoms caused by obstruction of the hepatic veins)
• Changes or anomalies in intestinal function
• Cerebral hemorrhage
• Yellowing of the eyes and skin (jaundice)
• Severe allergic reaction (anaphylactic shock), whose signs can be difficulty breathing, pain or oppression in the chest and/or feeling of dizziness/fainting, intense itching of the skin or skin bumps, swelling of the face, lips, tongue, and/or throat, which can cause difficulty swallowing, collapse
• Breast disorders
• Vaginal tear
• Genital inflammation
• Inability to tolerate alcohol consumption
• Emaciation or loss of body mass
• Increased appetite
• Fistula
• Joint effusion
• Cysts in the joint lining (synovial cysts)
• Fracture
• Breakdown of muscle fibers that can cause other complications
• Liver swelling, liver bleeding
• Kidney cancer
• Skin disease similar to psoriasis
• Skin cancer
• Pallor of the skin
• Increased platelets or plasma cells (a type of white blood cell) in the blood
• Blood clot in small blood vessels (thrombotic microangiopathy)
• Abnormal reaction to blood transfusions
• Partial or total loss of vision
• Loss of libido
• Drooling
• Bulging eyes
• Sensitivity to light
• Rapid breathing
• Rectal pain
• Gallstones
• Hernia
• Wounds
• Weak or brittle nails
• Abnormal protein deposits in vital organs
• Coma
• Intestinal ulcers
• Multi-organ failure
• Death

If you are administered bortezomib along with other medicines for the treatment of mantle cell lymphoma, the adverse effects you may experience are included below:

Very Common Adverse Effects (may affect more than 1 in 10 patients)

• Pneumonia
• Loss of appetite
• Sensitivity, numbness, tingling, or burning sensation in the skin or pain in hands or feet due to nerve damage
• Nausea or vomiting
• Diarrhea
• Sores in the mouth
• Constipation
• Muscle pain, bone pain
• Hair loss and abnormal hair texture
• Exhaustion, feeling of weakness
• Fever

Common Adverse Effects (may affect up to 1 in 10 patients)

• Herpes zoster (localized, including around the eyes or spread throughout the body)
• Herpes virus infection
• Bacterial and viral infections
• Respiratory infections, bronchitis, cough with phlegm, flu-like illness
• Fungal infections
• Hypersensitivity (allergic reaction)
• Inability to produce sufficient insulin or resistance to normal insulin levels
• Fluid retention
• Difficulty or problems sleeping
• Loss of consciousness
• Alteration of consciousness level, confusion
• Feeling of dizziness
• Increased heart rate, high blood pressure, sweating
• Abnormal vision, blurred vision
• Heart failure, heart attack, chest pain, chest discomfort, increased or decreased heart rate
• High or low blood pressure
• Sudden drop in blood pressure when standing, which could lead to fainting
• Difficulty breathing when exercising
• Cough
• Hiccup
• Ringing in the ears, ear discomfort
• Intestinal or stomach bleeding
• Heartburn
• Stomach pain, bloating
• Difficulty swallowing
• Infection or inflammation of the stomach and intestine
• Stomach pain
• Sores in the mouth or lip, sore throat
• Alteration of liver function
• Itching of the skin
• Redness of the skin
• Rash
• Muscle spasms
• Urinary tract infection
• Pain in the limbs
• Swelling of the body, including around the eyes and in other parts of the body
• Chills
• Redness and pain at the injection site
• Feeling of general discomfort
• Weight loss
• Weight gain

Uncommon Adverse Effects (may affect up to 1 in 100 patients)

• Hepatitis
• Severe allergic reaction (anaphylactic reaction), whose signs can be difficulty breathing, pain or oppression in the chest and/or feeling of dizziness/fainting, intense itching of the skin or skin bumps, swelling of the face, lips, tongue, and/or throat, which can cause difficulty swallowing, collapse
• Movement disorders, paralysis, tremors
• Dizziness
• Hearing loss, deafness
• Disorders affecting the lungs, preventing the body from receiving sufficient oxygen. Some of these are difficulty breathing, shortness of breath, shortness of breath without exercise, breathing that can become shallow, difficult, or stop, rapid breathing
• Blood clots in the lungs
• Yellowing of the eyes and skin (jaundice)
• Cyst in the eyelid (chalazion), eyelids reddened and swollen

Rare Adverse Effects (may affect up to 1 in 1,000 patients)

• Blood clot in small blood vessels (thrombotic microangiopathy)
• Severe nerve inflammation, which can cause paralysis and difficulty breathing (Guillain-Barré syndrome)

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Bortezomib Fresenius Kabi

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

Do not use this medicine after the expiration date that appears on the vial and packaging after CAD.

This medicine does not require special storage conditions regarding temperature. Store the vial in the outer packaging to protect it from light.

The chemical and physical stability of the reconstituted solution has been demonstrated at concentrations of 1 mg/ml for 96 hours at 25°C and 8 days at 2-8°C, when stored in the original syringe and/or vial.

From a microbiological point of view, the product must be used immediately after preparation. If not used immediately, the storage times and conditions prior to use will be the responsibility of the user. The total storage time of the reconstituted medicine should not exceed 96 hours (if stored at 25°C) and 8 days (if stored at 2-8°C) before administration.

Bortezomib is exclusively for single use. The disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.

6. Container Contents and Additional Information

Composition of Bortezomib Fresenius Kabi

• The active ingredient is bortezomib. Each vial contains 1 mg of bortezomib (as boronic acid mannitol ester). After reconstitution, 1 ml of injectable solution contains 1 mg of bortezomib.
• The other components are mannitol (E421).

Appearance of the Product and Container Contents

Bortezomib powder for injectable solution is a lyophilized powder or paste of white or off-white color.

Each container of Bortezomib Fresenius Kabi 1 mg powder for injectable solution contains a 5 ml transparent glass vial with a gray rubber stopper and a green aluminum flip-off cap, containing 1 mg of bortezomib.

The vial is presented wrapped in a retractable sleeve (without tray) or in a tray with a lid. Each box contains 1 single-use vial.

Marketing Authorization Holder

Fresenius Kabi Deutschland GmbH

Else-Kröner-Straße 1,

61352 Bad Homburg v.d.Höhe

Germany

Manufacturer

Fresenius Kabi Deutschland GmbH

Pfingstweide 53

61169 Friedberg,

Germany

Or

Fresenius Kabi Polska Sp. z.o.o.,

ul. Sienkiewicza 25, Kutno,

99-300, Poland

Further information on this medicinal product can be obtained from the marketing authorization holder.

Date of Last Revision of this Leaflet:

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu.

This information is intended solely for healthcare professionals:

1. RECONSTITUTION FOR INTRAVENOUS INJECTION

Note: Bortezomib is a cytotoxic agent. Therefore, caution should be exercised during handling and preparation. The use of gloves and other protective clothing is recommended to prevent skin contact.

BORTEZOMIB DOES NOT CONTAIN PRESERVATIVES AND THEREFORE IT IS ADVISED TO STRICTLY FOLLOW ASEPTIC TECHNIQUE DURING ITS HANDLING.

1.1. Preparation of a 1 mg vial: carefully add1 ml of sterile sodium chloride injection solution 9 mg/ml (0.9%) to the vial containing the bortezomib powder using a suitable sized syringe without removing the vial stopper. The dissolution of the lyophilized powder is complete in less than 2 minutes.

The concentration of the resulting solution will be 1 mg/ml. The solution should be colorless and clear, with a final pH of 4 to 7. It is not necessary to check the pH of the solution.

1.2. Before administration, visually inspect the solution to rule out the presence of particles and discoloration. If any discoloration or particles are observed, the solution should be discarded. Check that the correct dose is being used for intravenous administration (1 mg/ml).

1.3. The chemical and physical stability of the reconstituted solution has been demonstrated at concentrations of 1 mg/ml for 96 hours at 25°C and 8 days at 2-8°C, stored in the original vial and/or syringe.

From a microbiological point of view, the reconstituted product should be used immediately after preparation. If not used immediately, the storage times and conditions prior to use will be the responsibility of the user. The total storage time of the reconstituted medicinal product should not exceed 96 hours (if stored at 25°C) and 8 days (if stored at 2-8°C) before administration.

It is not necessary to protect the reconstituted product from light.

1. ADMINISTRATION

• Once dissolved, withdraw the appropriate amount of the reconstituted solution based on the calculated dose according to the patient's Body Surface Area.
• Confirm the dose and concentration contained in the syringe before use (check that the syringe is marked for intravenous administration).
• Inject the solution through a peripheral or central intravenous catheter in a vein as a bolus over 3-5 seconds.
• Flush the peripheral or intravenous catheter with sterile sodium chloride solution 9 mg/ml (0.9%).

Bortezomib Fresenius Kabi 1 mg SHOULD ONLY BE ADMINISTERED INTRAVENOUSLY. Do not administer by other routes. Intrathecal administration has resulted in fatal cases.

1. DISPOSAL

A vial is for single use and any remaining solution should be discarded.

Disposal of unused medicinal products and all materials that have come into contact with them should be carried out in accordance with local regulations.