Bortezomib Accord 2.5 mg/ml solution for injection

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Bortezomib Accord 2.5 mg injection solution EFG

bortezomib

Read the entire package leaflet carefully before you start using this medicine, because it contains important information for you.

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

Package leaflet contents

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

1. What Bortezomib Accord is and what it is 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 cancer of the bone marrow) in patients over 18 years of age:

• alone or in combination with pegylated liposomal doxorubicin or dexamethasone, for patients whose disease is worsening (progressing) after having received at least one prior treatment, and for those patients for whom blood stem cell transplantation has not worked or is not suitable
• in combination with melphalan and prednisone, for patients whose disease has not been previously treated and who are not suitable candidates for high-dose chemotherapy prior to blood stem cell transplantation
• in combination with dexamethasone or dexamethasone together with thalidomide, for patients whose disease has not been previously treated and who are receiving high-dose chemotherapy prior to blood stem cell transplantation (induction treatment).

Bortezomib Accord is used to treat mantle cell lymphoma (a type of cancer affecting the lymph nodes) in patients aged 18 years or older, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, for patients whose disease has not been previously treated and for whom blood stem cell transplantation is not considered appropriate.

2. What you need to know before using Bortezomib

Do not use Bortezomib Accord

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

Warnings and precautions

Inform your doctor if you have any of the following:

• low red or white blood cell counts
• bleeding problems and/or low platelet count in the blood
• diarrhoea, constipation, nausea, or vomiting
• history of fainting, dizziness, or lightheadedness
• kidney problems
• moderate to severe liver problems
• previous numbness, tingling, or pain in hands or feet (peripheral neuropathy)
• heart problems or blood pressure issues
• difficulty breathing or cough
• seizures
• shingles (localized, including around the eyes, or widespread throughout the body)
• symptoms of tumour 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 recommend further tests and monitoring.

You will need to have regular blood tests before and during treatment with Bortezomib Accord to monitor your blood cell counts regularly.

You must inform your doctor if you have mantle cell lymphoma and are being given rituximab in combination with Bortezomib Accord:

• if you think you currently have or have previously had hepatitis infection. In some cases, patients with a history of hepatitis B may experience reactivation of the infection, which can be fatal. If you have a history of hepatitis B infection, your doctor will closely monitor you for signs of active hepatitis.

Before starting treatment with Bortezomib Accord, you should read the package leaflets of all the medicines you are to take in combination with Bortezomib Accord to review the information related to these medicines.

When using thalidomide, special attention must be paid to pregnancy testing and preventive measures (see Pregnancy and Breast-feeding in this section).

Children and adolescents

Bortezomib Accord must 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 need to take any other medicines.

In particular, inform your doctor if you are taking medicines containing any of the following active substances:

• ketoconazole, used to treat fungal infections
• ritonavir, used to treat HIV infection
• rifampicin, an antibiotic used to treat bacterial infections
• carbamazepine, phenytoin, or phenobarbital, used to treat epilepsy
• St. John’s wort, used for depression or other conditions
• oral antidiabetic medicines

Pregnancy and breastfeeding

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

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

You must not breastfeed while using Bortezomib Accord. Consult your doctor to determine when it is safe to resume breastfeeding after completing your treatment.

Thalidomide causes birth defects and fetal death. When Bortezomib Accord is administered in combination with thalidomide, the thalidomide pregnancy prevention programme must be followed (refer to 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 machinery 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 determine the dose of Bortezomib Accord based on your height and weight (body surface area). The usual starting dose of Bortezomib Accord is 1.3 mg/m² body surface area, administered twice weekly. Your doctor may adjust the dose and the total number of treatment cycles depending on your response to treatment, the occurrence of certain adverse effects, and your underlying condition (e.g., liver problems).

Relapsed multiple myeloma

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

You may also receive Bortezomib Accord in combination with pegylated liposomal doxorubicin or dexamethasone.

When Bortezomib Accord is administered with pegylated liposomal doxorubicin, you will receive Bortezomib Accord intravenously or subcutaneously in a 21-day treatment cycle, and pegylated liposomal doxorubicin 30 mg/m² is administered on day 4 of the 21-day Bortezomib Accord treatment cycle, as an intravenous infusion after the Bortezomib Accord injection.

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

When Bortezomib Accord is administered with dexamethasone, you will receive Bortezomib Accord intravenously or subcutaneously in a 21-day treatment cycle, and dexamethasone 20 mg is administered 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 previously been treated for multiple myeloma and are not a candidate for blood stem cell transplantation, you will receive Bortezomib Accord in combination 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 administered twice weekly on days 1, 4, 8, 11, 22, 25, 29, and 32.
• In cycles 5 to 9, Bortezomib Accord is administered once weekly on days 1, 8, 22, and 29. Melphalan (9 mg/m²) and prednisone (60 mg/m²) are administered orally on days 1, 2, 3, and 4 of the first week of each cycle.

If you have not previously received treatment for multiple myeloma and are a candidate for blood stem cell transplantation, you will receive Bortezomib Accord intravenously or subcutaneously in combination with dexamethasone, or with dexamethasone and thalidomide, as induction therapy.

When Bortezomib Accord is administered with dexamethasone, you will receive Bortezomib Accord intravenously or subcutaneously in a 21-day treatment cycle, and dexamethasone is administered 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 administered with thalidomide and dexamethasone, the duration of a treatment cycle is 28 days (4 weeks).

Dexamethasone 40 mg is administered orally on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 28-day Bortezomib Accord treatment cycle, and thalidomide is administered orally once daily at a dose of 50 mg up to day 14 of the first cycle; if tolerated, the thalidomide dose is increased to 100 mg on days 15–28, and from the second cycle onwards may be further increased to 200 mg daily.

You may receive up to 6 cycles (24 weeks).

Previously untreated mantle cell lymphoma

If you have not previously been treated for mantle cell lymphoma, you will receive Bortezomib Accord intravenously or subcutaneously in combination with the medicines rituximab, cyclophosphamide, doxorubicin, and prednisone.

Bortezomib Accord is administered intravenously or subcutaneously 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 administered 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 administered 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 administered

Bortezomib Accord must be administered by a healthcare professional experienced in the use of cytotoxic medicinal products.

This medicine is for subcutaneous use (injection under the skin), and after dilution, also for intravenous use (injection into a vein). The intravenous injection is rapid and lasts between 3 and 5 seconds. The subcutaneous injection is administered in the thighs or abdomen.

If you receive more Bortezomib Accord than you should

This medicine will be administered by your doctor or nurse, so it is unlikely that you will receive an excessive amount. In the unlikely event that an overdose occurs, your doctor will monitor you for any adverse effects.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone gets them. Some of these effects may be serious.

If you are given Bortezomib Accord for multiple myeloma or mantle cell lymphoma, inform your doctor immediately if you notice any of the following symptoms:

• muscle cramps, muscle weakness
• confusion, loss or changes in vision, blindness, seizures, headaches
• difficulty breathing, swelling of the feet or changes in heart rhythm, high blood pressure, fatigue, fainting
• cough and difficulty breathing or chest tightness.

Treatment with Bortezomib Accord may very commonly cause a decrease in the number of red blood cells, white blood cells, and platelets in the blood. Therefore, you will need to have regular blood tests before and during treatment with Bortezomib Accord to monitor your blood cell counts regularly. You may experience a reduction in the number of:

• platelets, which may make you more prone to bruising (contusions) or bleeding without obvious injury (for example, bleeding in the intestine, stomach, mouth and gums, or bleeding in the brain or liver)
• red blood cells, which may cause anaemia, with symptoms such as fatigue and paleness
• white blood cells, which may make you more susceptible to infections or flu-like symptoms.

If you are given Bortezomib Accord for the treatment of multiple myeloma, the adverse effects you may experience are listed below:

Very common adverse effects (may affect more than 1 in 10 patients)

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

Frequent adverse effects (may affect up to 1 in 10 patients)

• Low blood pressure, sudden drop in blood pressure upon standing, which could lead to fainting
• High blood pressure
• Decreased kidney function
• Headache
• General malaise, pain, dizziness, lightheadedness, weakness, or loss of consciousness
• Chills
• Infections, including pneumonia, respiratory infections, bronchitis, fungal infections, productive cough, flu-like illness
• Shingles (localized, including around the eyes, or widespread throughout the body)
• Chest pain or difficulty breathing during exercise
• Various types of rashes
• Itchy skin, skin lumps, or dry skin
• Facial flushing or small capillary rupture
• Redness of the skin
• Dehydration
• Stomach burning, bloating, belching, flatulence, stomach pain, intestinal or stomach bleeding
• Impaired liver function
• Mouth or lip sores, dry mouth, mouth ulcers, or sore throat
• Weight loss, loss of taste
• Infection of the outer layer of the eye and 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 other body parts

Uncommon adverse effects (may affect up to 1 in 100 patients)

• Heart failure, heart attack, chest pain, chest discomfort, increased or decreased heart rate
• Kidney failure
• Vein inflammation, blood clots in veins and lungs
• Blood clotting problems
• Inadequate circulation
• Inflammation of the heart lining or fluid around the heart
• Infections, including urinary tract infections, influenza, herpes virus infection, ear infection, and cellulitis
• Bloody stools or bleeding from mucous membranes (e.g., mouth or vagina)
• Cerebrovascular disorders
• Paralysis, seizures, falls, movement disorders, altered or changed sensation (touch, hearing, taste, smell), or decreased sensitivity, attention disorders, tremors, jerking movements
• Arthritis, including inflammation of the joints in fingers, toes, and jaw
• Disorders affecting the lungs, impairing the body's ability to receive sufficient oxygen. These may include shortness of breath, breathlessness, breathlessness without exertion, shallow, difficult, or stopped breathing, or gasping respiration
• Hiccups, speech disorders
• Increased or decreased urine production (due to kidney injury), painful urination, blood/protein in urine, fluid retention
• Altered level of consciousness, confusion, memory changes or loss
• Hypersensitivity
• Hearing loss, deafness, or ringing in the ears (tinnitus), ear discomfort
• Hormonal disorders that may affect salt and water absorption
• Overactivity of the thyroid gland
• Inability to produce sufficient insulin or resistance to normal insulin levels
• Eye irritation or inflammation, excessively watery eyes, eye pain, dry eyes, eye infections, eyelid cyst (chalazion), red and swollen eyelids, watery eyes (lacrimation), abnormal vision, eye hemorrhage
• Swollen lymph nodes
• Joint or muscle stiffness, heaviness sensation, groin pain
• Hair loss and abnormal hair texture
• Allergic reactions
• Redness or pain at the injection site
• Mouth pain
• Infections or inflammation of the mouth, esophagus, stomach, and intestine, sometimes associated with pain or bleeding, reduced intestinal movement (including obstruction), abdominal or esophageal discomfort, difficulty swallowing, vomiting blood
• Skin infections
• Bacterial and viral infections
• Dental infection
• Pancreatitis, obstruction of the bile ducts
• Genital pain, difficulty achieving erection
• Weight gain
• Thirst
• Hepatitis
• Injection site disorders or issues related to the injection device
• Skin reactions and skin disorders (which may be severe and life-threatening), skin ulcers
• Bruising, falls, and injuries
• Inflammation or bleeding of blood vessels appearing as small red or purple spots (usually on the legs) up to large bruise-like areas under the skin or tissue
• Benign cysts
• A serious and reversible brain disorder including seizures, high blood pressure, headaches, fatigue, confusion, blindness, or other vision problems.

Rare adverse effects (may affect up to 1 in 1,000 patients)

• Heart problems, including heart attack, angina
• Severe nerve inflammation, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome)
• Flushing
• Discoloration of the veins
• Inflammation of the spinal nerves
• Ear problems, ear bleeding
• Underactivity of the thyroid gland
• Budd–Chiari syndrome (clinical symptoms caused by obstruction of the hepatic veins)
• Changes or abnormalities in intestinal function
• Cerebral hemorrhage
• Yellowing of the eyes and skin (jaundice)
• Severe allergic reaction (anaphylactic shock), signs of which may include difficulty breathing, chest pain or tightness and/or dizziness/fainting, intense skin itching or skin lumps, swelling of the face, lips, tongue and/or throat, which may cause difficulty swallowing, collapse
• Breast disorders
• Vaginal laceration
• Genital swelling
• Inability to tolerate alcohol consumption
• Wasting or loss of body mass
• Increased appetite
• Fistula
• Joint effusion
• Cysts in the joint lining (synovial cysts)
• Fracture
• Breakdown of muscle fibers leading to other complications
• Liver swelling, liver bleeding
• Kidney cancer
• Skin disease resembling psoriasis
• Skin cancer
• Pallor of the skin
• Increase in 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
• Protruding eyes
• Light sensitivity
• 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 Bortezomib Accord is administered together with other medicines for the treatment of mantle cell lymphoma, the adverse effects you may experience include the following:

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

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

Frequent adverse effects (may affect up to 1 in 10 patients)

• Herpes zoster (localized, including around the eyes, or widespread throughout the body)
• Herpes virus infection
• Bacterial and viral infections
• Respiratory infections, bronchitis, productive cough, influenza-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
• Altered level of consciousness, 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 upon standing, which may lead to fainting
• Shortness of breath during exercise
• Cough
• Hiccups
• Ringing in the ears, ear discomfort
• Gastrointestinal or stomach bleeding
• Heartburn
• Stomach pain, bloating
• Difficulty swallowing
• Infection or inflammation of the stomach and intestine
• Stomach pain
• Mouth or lip sores, sore throat
• Impaired liver function
• Skin itching
• Skin redness
• Rash
• Muscle spasms
• Urinary tract infection
• Limb pain
• Body swelling, including around the eyes and other body parts
• Chills
• Redness and pain at the injection site
• Feeling of general malaise
• Weight loss
• Weight gain

Uncommon adverse effects (may affect up to 1 in 100 patients)

• Hepatitis
• Severe allergic reaction (anaphylactic reaction), the signs of which may include difficulty breathing, pain or tightness in the chest and/or dizziness/fainting, intense itching of the skin or skin lumps, swelling of the face, lips, tongue and/or throat, which may cause difficulty swallowing, collapse
• Movement disorders, paralysis, twitching
• Dizziness
• Hearing loss, deafness
• Lung disorders affecting the lungs, preventing the body from receiving enough oxygen. Some of these include difficulty breathing, shortness of breath, breathlessness without exertion, breathing that may become shallow, difficult or stop, labored breathing
• Blood clots in the lungs
• Yellowing of the eyes and skin (jaundice)
• Cyst in 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 inflammation of the nerves, which may cause paralysis and breathing difficulty (Guillain-Barré syndrome)

Reporting of adverse reactions

If you experience any type of adverse reaction, consult your doctor or pharmacist, even if it is a possible adverse reaction not listed in this leaflet. You may also report them directly through the national reporting system detailed in Appendix V. By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. Storage of Bortezomib Accord

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

Do not use this medicine after the expiry date stated on the vial and outer packaging following EXP.

Store in a refrigerator (between 2°C and 8°C).

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

Reconstituted solution

Chemical and physical in-use stability has been demonstrated for the reconstituted solution at a concentration of 1 mg/ml for 24 hours at 20°C - 25°C. From a microbiological standpoint, unless the reconstitution method excludes the risk of microbial contamination, the reconstituted solution should be used immediately after preparation. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user.

Bortezomib Accord is for single use only. Any unused medicine and materials that have come into contact with it must be disposed of in accordance with local regulations.

6. Contents of the container and other information

Composition of Bortezomib Accord

• the active substance is bortezomib. Each vial of 1 ml or 1.4 ml of injectable solution contains 2.5 mg/ml of bortezomib (as mannitol boronic ester).
• the other components are mannitol (E421) and water for injections.

Intravenous route:

after dilution, 1 ml of the intravenous injection solution contains 1 mg of bortezomib.

Subcutaneous route:

1 ml of the subcutaneous injection solution contains 2.5 mg of bortezomib.

Appearance of Bortezomib Accord and contents of the pack

Bortezomib Accord for injection is a clear, colourless solution.

Clear Type I glass vial with grey bromobutyl rubber stopper, aluminium seal and orange flip-off cap containing 1 ml of injectable solution.

Clear Type I glass vial with grey bromobutyl rubber stopper, aluminium seal and red flip-off cap containing 1.4 ml of injectable solution.

Pack sizes

1 vial x 1 ml
4 vials x 1 ml
1 vial x 1.4 ml
4 vials x 1.4 ml

Some pack sizes may not be marketed.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n, Edifici Est, 6th floor,

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, The Netherlands

Date of 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