BORTEZOMIB ACCORD 3.5 mg POWDER FOR INJECTABLE SOLUTION

Introduction

Package Leaflet: Information for the User

Bortezomib Accord 1 mg powder for solution for injection EFG

Bortezomib Accord 3.5 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 is Bortezomib Accord and what is it used for
2. What you need to know before you use Bortezomib Accord
3. How to use Bortezomib Accord
4. Possible side effects
5. Storage of Bortezomib Accord
6. Contents of the pack and other information

1. What is Bortezomib Accord and what is it used for

Bortezomib Accord 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 Accord 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 Accord 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 Accord

Do not use Bortezomib Accord

• 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
• 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 changes, and 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 Accord to check your blood cell count regularly.

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

Before starting treatment with Bortezomib Accord, you should read the package leaflets of all the medicines you have to take with Bortezomib Accord 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 Accord should not be used in children and adolescents because it is not known how the medicine will affect them.

Other medicines and Bortezomib Accord

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

Do not use Bortezomib Accord if you are pregnant unless clearly necessary.

Both men and women using Bortezomib Accord must use effective contraception during and up to 3 months after treatment. If, despite these measures, you become pregnant, inform your doctor immediately.

Do not breastfeed while using Bortezomib Accord. Ask your doctor when it is safe to restart breastfeeding after finishing your treatment.

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

Driving and using machines

Bortezomib Accord may 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 Accord

Your doctor will tell you the dose of Bortezomib Accord according to your height and weight (body surface area). The usual starting dose of Bortezomib Accord 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 Accord is given alone, you will receive 4 doses of Bortezomib Accord by intravenous or subcutaneous 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 Accord with the medicines liposomal doxorubicin or dexamethasone.

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

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

When Bortezomib Accord is given with dexamethasone, you will receive Bortezomib Accord by intravenous or subcutaneous 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 21-day Bortezomib Accord 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 nota candidate to receive a stem cell transplant, you will receive Bortezomib Accord 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 Accord is given twice a week on days 1, 4, 8, 11, 22, 25, 29, and 32.
• In cycles 5 to 9, Bortezomib Accord 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 to receive a stem cell transplant, you will receive Bortezomib Accord by intravenous or subcutaneous injection with the medicines dexamethasone, or dexamethasone and thalidomide, as induction treatment.

When Bortezomib Accord is given with dexamethasone, you will receive Bortezomib Accord by intravenous or subcutaneous 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 21-day Bortezomib Accord treatment cycle.

You will receive 4 cycles (12 weeks).

When Bortezomib Accord 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 28-day Bortezomib Accord 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 Accord by intravenous or subcutaneous injection with the medicines rituximab, cyclophosphamide, doxorubicin, and prednisone.

Bortezomib Accord is given by intravenous or subcutaneous 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 21-day Bortezomib Accord 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 Accord treatment cycle.

How Bortezomib Accord is given

This medicine is given by intravenous or subcutaneous injection. You will be given Bortezomib Accord by a healthcare professional who is experienced in the use of cytotoxic medicines.

The powder of Bortezomib Accord 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. The injection under the skin is given into the thighs or abdomen.

If you receive more Bortezomib Accord 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 Accord 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 Accord may very frequently cause a decrease in the number of red and white blood cells and platelets in the blood. Therefore, you will need to undergo regular blood tests before and during treatment with Bortezomib Accord 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 bleeding in the 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 Accord 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 that you 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 breaking 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)
• Nosebleeds
• 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 breathing difficulties (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 bumps on the skin, 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 lining of the joints (synovial cysts)
• Fracture
• Breakdown of muscle fibers that causes other complications
• Swelling of the liver, 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
• Bile stones
• 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 breathing difficulties (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 bumps on the skin, 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 lining of the joints (synovial cysts)
• Fracture
• Breakdown of muscle fibers that causes other complications
• Swelling of the liver, 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
• Bile stones
• Hernia
• Wounds
• Weak or brittle nails
• Abnormal protein deposits in vital organs
• Coma
• Intestinal ulcers
• Multi-organ failure
• Death

If you are administered Bortezomib Accord 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
• Ulcers in the mouth
• Constipation
• Muscle pain, bone pain
• Loss of hair 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
• 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 bumps on the skin, swelling of the face, lips, tongue, and/or throat, which can cause difficulty swallowing, collapse
• Movement disorders, paralysis, tremors
• Dizziness
• Hearing loss, deafness
• Disorders that affect 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, gasping breathing
• Blood clots in the lungs
• Yellowing of the eyes and skin (jaundice)
• Cyst on the eyelid (chalazion), red and swollen eyelids

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 breathing difficulties (Guillain-Barré syndrome)

Reporting of 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 leaflet. 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 Accord

Keep this medicine out of sight and reach of children.

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

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

The reconstituted solution should be used immediately after preparation. If the reconstituted solution is not used immediately, the storage times after reconstitution and conditions before use are the responsibility of the user.

Intravenous administration:

The reconstituted solution is stable for 3 days at 20°C - 25°C stored in the original vial and/or a syringe. From a microbiological point of view, unless the opening/reconstitution/dilution method discards the risk of microbial contamination, the reconstituted solution should be used immediately after preparation. If not used immediately, the storage times after reconstitution and conditions before use are the responsibility of the user.

Subcutaneous administration:

The reconstituted solution is stable for 8 hours at 20°C-25°C stored in the original vial and/or a syringe. From a microbiological point of view, unless the opening/reconstitution/dilution method discards the risk of microbial contamination, the reconstituted solution should be used immediately after preparation. If not used immediately, the storage times after reconstitution and conditions before use are the responsibility of the user.

Bortezomib Accord is for single use only. 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. Package Contents and Additional Information

Composition of Bortezomib Accord

The active ingredient is bortezomib.

Bortezomib Accord 1 mg powder for injectable solution

Each vial contains 1 milligram of bortezomib (as boric ester of mannitol).

Bortezomib Accord 3.5 mg powder for injectable solution

Each vial contains 3.5 milligrams of bortezomib (as boric ester of mannitol).

Reconstitution for intravenous administration:

After reconstitution, 1 ml of the solution for intravenous injection contains 1 mg of bortezomib.

Reconstitution for subcutaneous administration:

After reconstitution, 1 ml of the solution for subcutaneous injection contains 2.5 mg of bortezomib

The other component is mannitol (E421).

Appearance of Bortezomib Accord and Package Contents

Bortezomib Accord powder for injectable solution is a white or off-white paste or powder.

Bortezomib Accord 1 mg powder for injectable solution

Each package of Bortezomib Accord 1 mg powder for injectable solution contains a 6 ml glass vial with a gray chlorobutyl rubber stopper and an aluminum seal, with a blue closure cap, which contains 1 mg of bortezomib.

Bortezomib Accord 3.5 mg powder for injectable solution

Each package of Bortezomib Accord 3.5 mg powder for injectable solution contains a 10 ml glass vial with a gray chlorobutyl rubber stopper and an aluminum seal, with a red closure cap.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta, 08039 Barcelona,

Spain

Manufacturer

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50, 95-200 Pabianice,

Poland

Accord Healthcare B.V.,

Winthontlaan 200,

3526 KV Utrecht,

Netherlands

Date of Revision of this Leaflet:

Other Sources of Information

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