Prospecto: information for the user

Bortezomib Accord 2.5 mg injectable solution EFG

bortezomib

Read this prospect carefully before starting to use this medicine, because it contains important information for you.

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

Content of the prospect

1. What Bortezomib Accord is and for what it is used
2. What you need to know before starting to use Bortezomib Accord
3. How to use Bortezomib Accord
4. Possible adverse effects
5. Storage of Bortezomib Accord
6. Contents of the package and additional information

Bortezomib Accord contains the active ingredient bortezomib, a “proteasome inhibitor”. Proteasomes play an important role in controlling the functioning and growth of cells. Bortezomib can destroy cancer cells, interfering with their functioning

Bortezomib Accord is used in the treatment of multiple myeloma (a bone marrow cancer) in patients aged 18 years or older:

• alone or in combination with pegylated liposomal doxorubicin or dexamethasone, for patients whose disease is worsening (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 melphalan and prednisone, for patients whose disease has not been previously treated and who are not suitable to receive high doses of chemotherapy prior to a stem cell transplant.
• in combination with dexamethasone or dexamethasone with thalidomide, in patients whose disease has not been previously treated and who are receiving high doses of chemotherapy prior to a stem cell transplant (induction treatment).

Bortezomib Accord is used in the treatment of mantle cell lymphoma (a type of cancer that affects lymph nodes) in patients aged 18 years or older in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, in patients whose disease has not been previously treated and for those patients who are not considered suitable for a stem cell transplant.

No use Bortezomib Accord

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

Warnings and Precautions

Inform your doctor if you experience the following:

• 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 disorientation
• kidney problems
• mild 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 (including around the eyes or spread across the body)
• symptoms of tumor lysis syndrome, such as muscle cramps, muscle weakness, confusion, vision loss or changes, and difficulty breathing
• memory loss, thought changes, difficulty walking, or vision loss. These may be signs of a severe brain infection, and your doctor may recommend further testing and follow-up.

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

Inform your doctor if you have mantle cell lymphoma and are receiving rituximab in combination with Bortezomib Accord:

• if you think you have or have had hepatitis in the past. In a few cases, patients who have had hepatitis B may experience repeated hepatitis attacks, which can be fatal. If you have a history of hepatitis B, you will be closely monitored by your doctor to detect signs of active hepatitis B.

Before starting treatment with Bortezomib Accord, read the prospectuses of all medications you are taking in combination with Bortezomib Accord to consult the information related to these medications.

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 its effects on them are unknown.

Other Medications and Bortezomib Accord

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take other medications.

Particularly, inform your doctor if you are using medications that contain any of the following active ingredients:

• 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, used to treat depression or othersituations
• oral antidiabetic medications

Pregnancy and Lactation

You should not use Bortezomib Accord if you are pregnant, unless it is clearly necessary.

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

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

Talidomide causes birth defects and fetal death. When Bortezomib Accord is administered in combination with thalidomide, follow the thalidomide pregnancy prevention program (consult the thalidomide prospectus).

Driving and Operating 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.

Your doctor will tell you 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/m2of 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 appearance 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 (3-week) period corresponds to a treatment cycle. You may receive up to 8 cycles (24 weeks).

You may also receive Bortezomib Accord along with the medications pegylated liposomal doxorubicin or dexamethasone.

When Bortezomib Accord is given along with pegylated liposomal doxorubicin, you will receive Bortezomib Accord by intravenous or subcutaneous injection in a 21-day treatment cycle, and pegylated liposomal doxorubicin 30 mg/m2is administered on day 4 of the 21-day Bortezomib Accord treatment cycle by intravenous infusion after the injection of Bortezomib Accord.

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

When Bortezomib Accord is given along with dexamethasone, you will receive Bortezomib Accord by intravenous or subcutaneous injection 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).

Untreated multiple myeloma

If you have not been treated for multiple myeloma before andare nota candidate to receive a blood stem cell transplant, you will receive Bortezomib Accord along with two other medications; melphalan and prednisone.

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

• In cycles 1 to 4, Bortezomib Accord is administered twice a week on days 1, 4, 8, 11, 22, 25, 29, and 32.
• In cycles 5 to 9, Bortezomib Accord is administered once a week on days 1, 8, 22, and 29. Melphalan (9 mg/m2) and prednisone (60 mg/m2) are administered orally during days 1, 2, 3, and 4 of the first weekof each cycle.

If you have not received any previous treatment for multiple myeloma andarea candidate to receive a blood stem cell transplant, you will receive Bortezomib Accord by intravenous or subcutaneous injection along with the medications dexamethasone, or dexamethasone and thalidomide, as induction treatment.

When Bortezomib Accord is given along with dexamethasone, you will receive Bortezomib Accord by intravenous or subcutaneous injection in a 21-day treatment cycle, and dexamethasone is administered orally in doses 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 along 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 a day in doses of 50 mg until 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 and onwards, it may be increased further to 200 mg daily.

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

Untreated mantle cell lymphoma

If you have not been treated before for mantle cell lymphoma, you will receive Bortezomib Accord by intravenous or subcutaneous injection along with the medications rituximab, cyclophosphamide, doxorubicin, and prednisone.

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

The following medications are administered by intravenous infusion on day 1 of the 21-day Bortezomib Accord treatment cycle:

Rituximab in doses of 375 mg/m2, cyclophosphamide in doses of 750 mg/m2, and doxorubicin in doses of 50 mg/m2.

Prednisone is administered orally in doses of 100 mg/m2on days 1, 2, 3, 4, and 5 of the 21-day Bortezomib Accord treatment cycle.

How Bortezomib Accord is administered

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

This medication is for subcutaneous (injection under the skin) use, and after dilution, also for intravenous (injection into a vein) use. 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 medication will be administered by your doctor or nurse, so it is unlikely that you will receive an excessive amount. In the unlikely event of an overdose, your doctor will monitor you for any adverse effects.

Like all medicines, this medicine can cause side effects, although not everyone will experience them. Some of these side effects can be serious.

If you are given Bortezomib Accord for multiple myeloma or mantle cell lymphoma, tell your doctor right away 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
• Coughs and difficulty breathing or chest tightness.

Treatment with Bortezomib Accord can cause very frequently a decrease in the number of red and white blood cells and platelets in the blood. Therefore, regular blood tests will be performed 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 may make you more prone to the appearance of bruises (bruises), or bleeding without visible injury (for example, 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 may make you more prone to infections or symptoms similar to the flu.

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

Very common side effects (can affect more than 1 in 10 patients)

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

Common side effects (can 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
• General feeling of being unwell, pain, dizziness, feeling weak or loss of consciousness
• Chills
• Infections, including pneumonia, respiratory infections, bronchitis, fungal infections, coughs with phlegm, flu-like illness
• Herpes zoster (localized including around the eyes or extended over the body)
• Chest pain or difficulty breathing while exercising
• Different types of rashes
• Itching skin, skin lumps or dry skin
• Facial flushing or small blood vessel rupture
• Redness of the skin
• Dehydration
• Heartburn, swelling, belching, flatulence, stomach pain, intestinal or stomach bleeding
• Alteration of liver function
• Mouth or lip sores, dry mouth, mouth ulcers or throat pain
• Weight loss, loss of taste
• Conjunctivitis (infection of the outer layer of the eye and the inner surface of the eyelids)
• 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

Rare side effects (can 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
• Poor circulation
• Pericarditis (inflammation of the heart lining) or fluid around the heart
• Infections, including urinary tract infections, flu, herpes virus infection, ear infection, and cellulitis
• Mucous membrane bleeding or hemorrhages, for example, in the mouth or vagina
• Cerebrovascular disorders
• Paralysis, seizures, falls, movement disorders, changes or decreases in sensation (touch, hearing, taste, smell), attention disorders, tremors, shakiness
• Arthritis, including inflammation of the joints of the fingers of the hands and feet and jaw
• Respiratory disorders, preventing the body from receiving a sufficient amount of oxygen. Some of them are difficulty breathing, shortness of breath, shortness of breath without exercise, shallow, difficult or stopping breathing, rapid breathing
• Hiccup, speech disorders
• Increased or decreased urine production (due to kidney damage), pain when urinating or blood/protein in the urine, fluid retention
• Alteration of level of consciousness, confusion, alteration or loss of memory
• Hypersensitivity
• Loss of hearing, deafness or ringing in the ears, ear discomfort
• Alterations in hormone levels that may affect salt and water absorption
• Hyperactivity of the thyroid gland
• Inability to produce sufficient insulin or resistance to normal insulin levels
• Irritation or inflammation of the eyes, too moist eyes, eye pain, dry eyes, eye infections, chalazion (cyst on the eyelid), red and swollen eyelids, watery eyes (lacrimation), abnormal vision, eye hemorrhage
• Swollen lymph nodes
• Joint or muscle stiffness, feeling heavy, pain in the groin
• Loss of hair and abnormal hair texture
• Allergic reactions
• Redness or pain at the injection site
• Mouth pain
• Mouth or lip sores, dry mouth, mouth ulcers or throat pain
• Infections or inflammation of the mouth, ulcers in the mouth, esophagus, stomach and intestine, sometimes associated with pain or bleeding, slow movement of the intestine (including obstruction), abdominal or esophageal discomfort, difficulty swallowing, vomiting blood
• Skin infections
• Bacterial and viral infections
• Dental infection
• Pancreatitis, bile duct obstruction
• Genital pain, erectile dysfunction
• Weight gain
• Thirst
• Hepatitis
• Problems at the injection site or related to the injection device
• Severe skin reactions (life-threatening), skin ulcers
• Bruises, falls, and wounds
• Small blood vessel inflammation or hemorrhage that may appear as small red or purple spots (usually on the legs) to large patches similar to bruises under the skin or tissue.
• Benign cysts
• A severe and reversible brain disorder that includes seizures, high blood pressure, headaches, fatigue, confusion, blindness or other vision problems.

Rare side effects (can affect up to 1 in 1,000 patients)

• Heart problems, including heart attack, angina
• Severe nerve inflammation, which can cause paralysis and difficulty breathing (Guillain-Barré syndrome)
• Flushing
• Vein discoloration
• Spinal nerve inflammation
• Ear problems, ear hemorrhage
• Thyroid gland hypofunction
• Budd-Chiari syndrome (clinical symptoms caused by obstruction of the hepatic veins)
• Changes or abnormalities in intestinal function
• Brain hemorrhage
• Yellow discoloration of the eyes and skin (jaundice)
• Severe allergic reaction (anaphylactic shock), whose signs may be difficulty breathing, chest pain or tightness and/or dizziness/fainting, intense itching skin or skin lumps, facial swelling, lip, tongue, and/or throat swelling, which may cause difficulty swallowing, collapse
• Mastitis
• Vaginal rupture
• Genital inflammation
• Inability to tolerate alcohol consumption
• Emaciation or loss of body mass
• Increased appetite
• Fistula
• Joint effusion
• Benign synovial cysts
• Fracture
• Disintegration of muscle fibers that causes other complications
• Swelling of the liver, liver hemorrhage
• Kidney cancer
• Skin condition similar to psoriasis
• Skin cancer
• Pale skin
• Increased platelets or plasma cells (a type of white blood cell) in the blood
• Blood clot in small blood vessels (microangiopathy)
• Abnormal reaction to blood transfusions
• Partial or complete loss of vision
• Loss of libido
• Halitosis
• Protruding eyes
• Light sensitivity
• Accelerated breathing
• Rectal pain
• Bile stones
• Hernia
• Wounds
• Weak or brittle nails
• Anomalous protein deposits in vital organs
• Coma
• Intestinal ulcers
• Multi-organ failure
• Death

If you are given Bortezomib Accord along with other medicines for the treatment of mantle cell lymphoma, the side effects you may experience are listed below:

Very common side effects (can affect more than 1 in 10 patients)

• Pneumonia
• Loss of appetite
• Sensitivity, numbness, tingling or burning sensation in the skin or pain in the hands or feet due to nerve damage

of hands or feet due to nerve damage

• Nausea or vomiting
• Diarrhea
• Mouth ulcers
• Constipation
• Muscle pain, bone pain
• Loss of hair and abnormal hair texture
• Exhaustion, feeling weak
• Fever

Common side effects (can affect up to 1 in 10 patients)

• Herpes zoster (localized including around the eyes or extended over the body)
• Herpes virus infection
• Bacterial and viral infections
• Respiratory infections, bronchitis, coughs 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 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 when standing, which could lead to fainting
• Difficulty breathing with exercise
• Coughs
• Hiccup
• Ringing in the ears, ear discomfort
• Intestinal or stomach bleeding
• Heartburn
• Abdominal or esophageal discomfort
• Difficulty swallowing
• Infection or inflammation of the stomach and intestine
• Abdominal pain
• Lip or mouth sores, throat pain
• Alteration of liver function
• Itching skin
• Redness of the skin
• Rash
• Muscle spasms
• Urinary tract infections
• Arm or leg pain
• Swelling of the body, including around the eyes and in other parts of the body
• Chills
• Redness and pain at the injection site
• General feeling of being unwell
• Weight loss
• Weight gain

Rare side effects (can affect up to 1 in 100 patients)

• Hepatitis
• Severe allergic reaction (anaphylactic reaction), whose signs may be difficulty breathing, chest pain or tightness and/or dizziness/fainting, intense itching skin or skin lumps, facial swelling, lip, tongue, and/or throat swelling, which may cause difficulty swallowing, collapse
• Movement disorders, paralysis, shakiness
• Dizziness
• Loss of hearing, deafness
• Respiratory disorders, preventing the body from receiving a sufficient amount of oxygen. Some of them are difficulty breathing, shortness of breath, shortness of breath without exercise, shallow, difficult or stopping breathing, rapid breathing
• Blood clots in the lungs
• Yellow discoloration of the eyes and skin (jaundice)
• Chalazion (cyst on the eyelid), red and swollen eyelids

Rare side effects (can affect up to 1 in 1,000 patients)

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

Reporting side effects

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

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

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

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

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

Diluted Solution

It has been proven that the chemical and physical stability of the diluted solution at a concentration of 1mg/ml is stable for 24 hours at 20°C - 25°C. From a microbiological point of view, unless the opening/dilution method eliminates the risk of microbial contamination, the diluted solution should be used immediately after preparation. If not used immediately, the storage times and conditions before use are the responsibility of the user.

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

Composition of Bortezomib Accord

• The active ingredient is bortezomib. Each vial of 1 ml or 1.4 ml of injectable solution contains 2.5 mg/ml of bortezomib (as boric acid ester of mannitol.
• The other components are mannitol (E421) and water for injection.

Route of administration: intravenous:

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

Route of administration: subcutaneous:

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

Appearance of Bortezomib Accord and contents of the container

Bortezomib Accord powder for injectable solution is a transparent colorless solution.

Transparent Type 1 glass vial with grey rubber stopper, aluminium seal and orange closure cap, containing 1 ml of injectable solution.

Transparent Type 1 glass vial with grey bromobutyl rubber stopper, aluminium seal and red closure cap, containing 1.4 ml of injectable solution.

Container sizes

1 vial x 1 ml

4 vials x 1 ml

1 vial x 1.4 ml

4 vials x 1.4 ml

Only some container sizes may be commercially available.

Marketing Authorization Holder

Accord Healthcare S.L.U.

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

08039 Barcelona,

Spain

Responsible Person for Manufacturing

Accord Healthcare Polska Sp.z o.o., ul. Lutomierska 50, 95-200 Pabianice, Poland

Accord Healthcare B.V.,Winthontlaan 200, 3526 KV Utrecht,Netherlands

Revision date 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