Bortezomib Accord

Patient Information Leaflet: Information for the User

Bortezomib Accord 2.5 mg/mL Injection Solution

bortezomib
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

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 so-called "proteasome inhibitor".
Proteasomes play an important role in controlling cell functions and cell growth.
By interfering with their function, bortezomib can kill tumour cells.
Bortezomib Accord is used to treat multiple myeloma (a type of malignant neoplasm of the bone marrow) in patients aged over 18 years:

• alone or in combination with pegylated liposomal doxorubicin or dexamethasone, for patients with disease that is worsening (progressive) after having received at least one prior treatment, or in whom stem cell transplantation has not been successful or is not feasible.
• in combination with melphalan and prednisone, for patients with previously untreated disease who are not eligible for high-dose chemotherapy with stem cell transplantation.
• in combination with dexamethasone or dexamethasone together with thalidomide, for patients with previously untreated disease and prior to receiving high-dose chemotherapy with stem cell transplantation (induction treatment).

Bortezomib Accord is used for the treatment of mantle cell lymphoma (a type of malignant neoplasm affecting the lymph nodes) in patients aged 18 years or older. In this case, Bortezomib Accord is used in combination with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone, for patients with previously untreated disease for whom stem cell transplantation is not feasible.

2. What you need to know before using Bortezomib Accord

Do not use Bortezomib Accord

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

Warnings and precautions
Inform your doctor if you:

• have low levels of red blood cells or white blood cells
• have bleeding problems and/or low platelet count
• have diarrhoea, constipation, nausea, or vomiting
• have previously experienced fainting, dizziness, or a feeling of lightheadedness
• have kidney problems
• have moderate to severe liver problems
• have previously had numbness, tingling, or pain in your hands or feet (neuropathy)
• have a heart condition or blood pressure problems
• have shortness of breath or cough
• have seizures
• have herpes zoster (including localized around the eyes or spreading to other parts of the body)
• have symptoms of tumour lysis syndrome, such as muscle cramps, muscle weakness, confusion, vision disturbances, or shortness of breath
• experience memory loss, difficulty thinking, difficulty walking, or loss of vision. These may be signs of a serious brain infection, and your doctor may recommend further tests and monitoring.

You will need regular blood tests before and during treatment with Bortezomib Accord to monitor your blood cell counts continuously.
If you have mantle cell lymphoma and are receiving rituximab together with Bortezomib Accord, inform your doctor:

• if you think you have hepatitis or have had it in the past. In some cases, patients who have had hepatitis B may experience a reactivation of the disease, which can be fatal. If you have had a hepatitis B infection in the past, your doctor will need to monitor you closely for signs and symptoms of active hepatitis B.

Read the package leaflets of all the medicines you are taking in combination with Bortezomib Accord for information about these medicines before starting treatment with Bortezomib Accord.
When Bortezomib Accord is administered together with the medicine thalidomide, pay special attention to the instructions regarding pregnancy testing and the pregnancy prevention programme (see “Pregnancy and breastfeeding” in this section).

Children and adolescents
Bortezomib Accord must not be used in children and adolescents because its effects in these populations are unknown.

Other medicines and Bortezomib Accord
Inform your doctor or pharmacist if you are taking, have recently taken, or might 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 (Hypericum perforatum), used to treat depression or other conditions
• oral antidiabetic medicines.

Pregnancy and breastfeeding
You must not use Bortezomib Accord during pregnancy unless strictly necessary.
Men and women receiving treatment with Bortezomib Accord must use effective contraception during treatment and for up to 3 months after treatment ends. If pregnancy occurs despite these precautions, inform your doctor immediately.
You must not breastfeed during treatment with Bortezomib Accord. Discuss with your doctor the most appropriate time to resume breastfeeding after treatment ends.
The medicine thalidomide can cause birth defects and fetal death. When Bortezomib Accord is administered together with thalidomide, you must follow the thalidomide pregnancy prevention programme (see the thalidomide package leaflet).

Driving and using machines
Bortezomib Accord may cause fatigue, dizziness, fainting, or blurred vision.
Do not drive or operate machinery if you experience any of these symptoms.
Exercise particular caution even if these effects do not occur.

3. How to use Bortezomib Accord

Your doctor will calculate the dose of Bortezomib Accord based on your height and weight.
The standard starting dose of Bortezomib Accord is 1.3 mg/m² of 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 side effects, and your overall health status (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. This is 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 together with pegylated liposomal doxorubicin, you will
receive a 21-day treatment cycle with Bortezomib Accord administered intravenously or subcutaneously,
and 30 mg/m² of pegylated liposomal doxorubicin will be given 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 of treatment).

When Bortezomib Accord is administered together with dexamethasone, you will receive a 21-day
treatment cycle with Bortezomib Accord administered intravenously or subcutaneously, and oral
dexamethasone at a dose of 20 mg 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 of treatment).

Previously untreated multiple myeloma
If you have never been treated before for multiple myeloma and you are not eligible for blood stem
cell transplantation, you will receive Bortezomib Accord in combination with two other medicines:
melphalan and prednisone.

In this case, each treatment cycle lasts 42 days (6 weeks). You will receive 9 cycles (54 weeks).

• In cycles 1–4, Bortezomib Accord is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29, and 32.
• In cycles 5–9, 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 never been treated before for multiple myeloma and you are eligible for blood stem cell
transplantation, you will receive Bortezomib Accord intravenously or subcutaneously in combination
with dexamethasone, or with dexamethasone and thalidomide, as induction treatment.

When Bortezomib Accord is administered together with dexamethasone, you will receive a 21-day
treatment cycle with Bortezomib Accord administered intravenously or subcutaneously, and oral
dexamethasone 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 of treatment).

When Bortezomib Accord is administered together with thalidomide and dexamethasone, the treatment
cycle lasts 28 days (4 weeks).

Oral dexamethasone 40 mg is administered on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 28-day Bortezomib
Accord treatment cycle, and thalidomide is administered daily orally 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 may be
further increased up to 200 mg daily starting from the second cycle onwards.

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

Previously untreated mantle cell lymphoma
If you have never previously received specific treatment for mantle cell lymphoma, you will receive
Bortezomib Accord intravenously or subcutaneously in combination with 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 treatment cycle lasts 21 days (3 weeks). You may receive up to 8
treatment cycles (24 weeks).

The following medicines are administered on day 1 of each 21-day Bortezomib Accord treatment cycle
as intravenous infusions:
rituximab at 375 mg/m², cyclophosphamide at 750 mg/m², and doxorubicin at 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 will be administered by a healthcare professional experienced in the use of
cytotoxic medicines.

This medicine is for subcutaneous use (injected under the skin) and, after dilution, also for intravenous
use (injected into a vein). The intravenous injection is rapid, administered over a period of 3 to 5
seconds. The subcutaneous injection can be given either in the thigh or in the abdomen.

If you receive more Bortezomib Accord than you should
Since this medicine is administered by a doctor or nurse, it is unlikely that you will receive more than
the prescribed amount. In the unlikely event of an overdose, your doctor will monitor you for any
adverse effects.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these side effects can be serious.
If you are being treated with Bortezomib Accord for multiple myeloma or mantle cell lymphoma, inform your doctor immediately if you experience any of the following symptoms:

• Muscle cramps, muscle weakness
• Confusion, vision disturbances or loss of vision, blindness, seizures, headache
• Shortness of breath, swelling of the feet, or changes in heartbeat, high blood pressure, fatigue, fainting
• Cough and difficulty breathing or a feeling of tightness in the chest.

Treatment with Bortezomib Accord may very commonly 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 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 or bleeding without obvious injury (for example, bleeding from the intestine, stomach, mouth and gums, or brain or liver haemorrhage)
• Red blood cells, which may cause anaemia, with symptoms such as fatigue and paleness
• White blood cells, which may increase your susceptibility to infections or flu-like symptoms.

If you are being treated with Bortezomib Accord for multiple myeloma, the possible side effects are listed below.
Very common side effects (may affect more than 1 in 10 people)

• Tingling, numbness, prickling or burning sensation of the skin, or pain in the hands or feet due to nerve damage.
• Decrease in the number of red and/or white blood cells (see above).
• Fever.
• Nausea or vomiting, loss of appetite.
• Constipation with or without excess intestinal gas (may be severe).
• Diarrhoea: if this occurs, it is important that you drink much more water than usual. Your doctor may prescribe medication to control diarrhoea.
• Tiredness (fatigue), feeling of weakness.
• Muscle pain, bone pain.

Common side effects (may affect up to 1 in 10 people)

• Low blood pressure, sudden drop in blood pressure when standing up, which may lead to fainting.
• Increased blood pressure.
• Reduced kidney function.
• Headache.
• Feeling unwell, pain, dizziness, lightheadedness, feeling of weakness or loss of consciousness.
• Chills.
• Infections, including pneumonia, respiratory tract infections, bronchitis, fungal infection, cough with phlegm, flu-like illness.
• Infection with Herpes zoster (localized, including around the eyes, or disseminated throughout the body).
• Chest pain or difficulty breathing during physical activity.
• Various types of skin rash.
• Itching of the skin, skin nodules or dry skin.
• Facial flushing or small capillary ruptures.
• Skin redness.
• Dehydration.
• Indigestion, bloating, belching, gas, stomach pain, intestinal or stomach bleeding.
• Altered liver function.
• Mouth or lip irritation, dry mouth, mouth ulcers or sore throat.
• Weight loss, loss of taste.
• Muscle cramps, muscle spasms, muscle weakness, pain in arms and legs.
• Blurred vision.
• Infection of the outer layer of the eye and inner surface of the eyelids (conjunctivitis).
• Nosebleeds.
• Sleep disturbances or problems, sweating, anxiety, mood changes, depressed mood, restlessness or agitation, changes in mental state, disorientation.
• Swelling of the body, including swelling around the eyes and other parts of the body.

Uncommon side effects (may affect up to 1 in 100 people)

• 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.
• Circulatory failure.
• Inflammation of the membrane surrounding the heart or fluid accumulation around the heart.
• Infections, including urinary tract infections, influenza, herpes virus infections, ear infection and cellulitis.
• Blood in the stool, or mucosal bleeding, for example from the mouth or vagina.
• Cerebrovascular disorders.
• Paralysis, seizures, falls, movement disorders, abnormal or reduced sensation (feeling, hearing, taste, smell), attention disorders, tremor, spasms.
• Arthritis, including inflammation of the joints of the fingers of the hands, toes and jaw.
• Lung disorders impairing the body's ability to receive sufficient oxygen. Some of these include difficulty breathing, shortness of breath, laboured breathing even without physical activity, shallow or difficult breathing or need to stop, wheezing.
• Hiccups, speech disorders.
• Increased or decreased urine production (kidney damage), painful urination or presence of blood/protein in the urine, fluid retention.
• Altered levels of consciousness, confusion, memory failure or loss.
• Hypersensitivity.
• Hearing loss, deafness or ringing in the ears, ear discomfort.
• Hormonal changes that may affect the reabsorption of salts and water.
• Overactivity of the thyroid gland.
• Inability to produce enough insulin or resistance to normal insulin levels.
• Irritated or inflamed eyes, excessively watery eyes, eye pain, dry eyes, eye infections, eyelid swelling (chalazion), red and swollen eyelids, eye discharge, vision disturbances, eye bleeding.
• Enlarged lymph nodes.
• Joint or muscle stiffness, feeling of heaviness, groin pain.
• Hair loss or abnormal hair texture.
• Allergic reactions.
• Redness or pain at the injection site.
• Mouth pain.
• Infection or inflammation of the mouth, mouth ulcers, oesophagus, stomach and intestine, sometimes associated with pain or bleeding, reduced intestinal motility (including intestinal blockage), abdominal or oesophageal discomfort, difficulty swallowing, vomiting with blood.
• Skin infections.
• Bacterial and viral infections.
• Dental infections.
• Pancreatitis, obstruction of bile ducts.
• Genital pain, erectile problems.
• Weight gain.
• Feeling of thirst.
• Hepatitis.
• Injection site or catheter site reactions or disorders.
• Skin reactions or skin disorders (which may be severe and life-threatening), skin ulcerations.
• Bruising, falls and injuries.
• Inflammation or bleeding of blood vessels, which may appear as small red or purple spots (usually on the legs) that may develop into large bruises on the skin or tissues.
• Benign cysts.
• A serious and reversible brain condition including seizures, high blood pressure, headache, fatigue, confusion, blindness or other vision problems.

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

• Heart problems including heart attack, angina.
• Severe inflammation of nerves, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome).
• Hot flushes.
• Change in vein colour.
• Inflammation of the spinal nerve.
• Ear problems, ear bleeding.
• Reduced activity of the thyroid gland.
• Budd-Chiari syndrome (clinical signs caused by blockage of the liver veins).
• Change or abnormal intestinal function.
• Brain haemorrhage (bleeding).
• Yellowing of the eyes and skin (jaundice).
• Severe allergic reaction (anaphylactic shock), signs include difficulty breathing, chest pain or tightness, and/or dizziness/weakness, severe skin itching or skin swellings, swelling of the face, lips, tongue and/or throat which may cause difficulty swallowing, collapse.
• Breast disorders.
• Vaginal discharge.
• Swelling of the genitals.
• Inability to tolerate alcohol consumption.
• Wasting or loss of body mass.
• Increased appetite.
• Fistulas.
• Joint effusion.
• Cysts in the membrane covering the joints (synovial cysts).
• Fractures.
• Muscle fibre rupture leading to further complications.
• Enlarged liver, liver haemorrhage.
• Kidney tumour.
• Skin condition resembling psoriasis.
• Skin tumour.
• Skin pallor.
• Increased platelets or plasma cells (a type of white blood cells) in the blood.
• Blood clot in small blood vessels (thrombotic microangiopathy).
• Abnormal reaction to blood transfusion.
• Partial or complete loss of vision.
• Decreased libido.
• Loss of saliva.
• Eye protrusion.
• Photophobia (excessive sensitivity of the eye to light).
• Rapid breathing.
• Rectal pain.
• Gallstones.
• Hernia.
• Injuries.
• Brittle or weak nails.
• Abnormal deposition of proteins in vital organs.
• Coma.
• Intestinal ulcers.
• Damage to multiple organs.
• Death.

If you are being treated with Bortezomib Accord in combination with other medicines for mantle cell lymphoma, the possible side effects are listed below.
Very common side effects (may affect more than 1 in 10 people)

• Pneumonia.
• Loss of appetite.
• Tingling, numbness, prickling or burning sensation of the skin, or pain in the hands or feet due to nerve damage.
• Nausea and vomiting.
• Diarrhoea.
• Mouth ulcers.
• Intestinal constipation.
• Muscle pain, bone pain.
• Hair loss or abnormal hair texture.
• Tiredness, feeling of weakness.
• Fever.

Common side effects (may affect up to 1 in 10 people)

• Infection with Herpes zoster (localized, including around the eyes, or disseminated throughout the body).
• Infection with herpes virus.
• Bacterial and viral infections.
• Respiratory infections, bronchitis, cough with phlegm, flu-like illness.
• Fungal infections.
• Hypersensitivity (allergic reaction).
• Inability to produce enough insulin or resistance to normal insulin levels.
• Fluid retention.
• Difficulty or problems sleeping.
• Loss of consciousness.
• Altered levels of consciousness, confusion.
• Dizziness.
• Increased heart rate, high blood pressure, sweating.
• Vision disturbances, 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 up, which may lead to fainting.
• Shortness of breath during physical activity.
• Cough.
• Hiccups.
• Ringing in the ears, ear discomfort.
• Intestinal or stomach bleeding.
• Indigestion.
• Stomach pain, bloating.
• Difficulty swallowing.
• Infection or inflammation of the stomach and intestine.
• Stomach pain.
• Mouth or lip irritation, sore throat.
• Altered liver function.
• Itching of the skin.
• Skin redness.
• Rash.
• Muscle spasms.
• Urinary tract infection.
• Limb pain.
• Swelling of the body, including swelling around the eyes and other parts of the body.
• Chills.
• Redness and pain at the injection site.
• Feeling of general malaise.
• Loss of body weight.
• Increase in body weight.

Uncommon side effects (may affect up to 1 in 100 people)

• Hepatitis.
• Severe allergic reaction (anaphylactic reaction), signs of which may include difficulty breathing, chest pain or tightness, and/or dizziness/weakness, severe skin itching or skin swellings, swelling of the face, lips, tongue and/or throat which may cause difficulty swallowing, collapse.
• Movement disorders, paralysis, contractions.
• Dizziness.
• Hearing loss, deafness.
• Lung disorders impairing the body's ability to receive sufficient oxygen. Some of these include difficulty breathing, shortness of breath, laboured breathing even without physical activity, shallow, difficult or interrupted breathing, wheezing.
• Blood clots in the lungs.
• Yellowing of the eyes and skin (jaundice).
• Eyelid swelling (chalazion), red and swollen eyelids.

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

• Blood clotting in small blood vessels (thrombotic microangiopathy).
• Severe inflammation of nerves, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome).

Reporting of side effects
If you experience any side effect, if any of the side effects worsens or if you notice any side effect not listed in this leaflet, consult your doctor or pharmacist immediately. You can also report side effects directly via the national reporting system referred to in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Bortezomib Accord

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the vial and the outer carton after
"Exp.".
Store in a refrigerator (2 °C to 8 °C).
Keep the vial in the outer packaging to protect the medicine from light.

Diluted solution
Chemical and physical in-use stability of the diluted solution at a concentration of 1 mg/mL has been
demonstrated for 24 hours at 20-25 °C. From a microbiological point of view, unless the method of
opening/dilution excludes the risk of microbial contamination, the diluted solution should be used
immediately after preparation. If not used immediately, it is the responsibility of the user to ensure
appropriate storage conditions and duration of the medicine before use.
Bortezomib Accord is for single use only. Any unused product and waste materials must be disposed of
in accordance with local regulations.

6. Package contents and other information

What Bortezomib Accord contains
The active substance is bortezomib.

• Each vial contains 1 mL or 1.4 mL of injectable solution containing 2.5 mg per mL of bortezomib (as mannitol boronic ester).
• The other ingredients are mannitol (E421) and water for injections.

For intravenous use:
after dilution, 1 mL of intravenous injection solution contains 1 mg of bortezomib.
For subcutaneous use:
1 mL of subcutaneous injection solution contains 2.5 mg of bortezomib.

Description of the appearance of Bortezomib Accord and contents of the pack
Bortezomib Accord injectable solution is a clear, colourless solution.
Glass vial with grey rubber stopper and aluminium seal with orange flip-off cap, containing 1 mL of solution.
Glass vial with grey rubber stopper and aluminium seal with red flip-off cap, containing 1.4 mL of solution.

Packs
1 x 1 mL vial
4 x 1 mL vials
1 x 1.4 mL vial
4 x 1.4 mL vials
Not all pack sizes may be marketed.

Marketing Authorisation 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,
3526KV Utrecht
The Netherlands

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

The following information is intended exclusively for healthcare professionals

Note: Bortezomib Accord is a cytotoxic agent. Therefore, particular care must be taken during handling and preparation. It is recommended to wear gloves and other protective clothing to prevent skin contact.
Pregnant personnel should not handle this medicinal product.
IN THE ABSENCE OF ANY TYPE OF PRESERVATIVE, ASEPTIC TECHNIQUE MUST BE
OBSERVED DURING HANDLING OF BORTEZOMIB ACCORD.
Bortezomib 2.5 mg/mL injectable solution IS FOR SUBCUTANEOUS OR
INTRAVENOUS USE. Do not administer by other routes. Intrathecal administration has
resulted in death.
.

1. INTRAVENOUS INJECTION PREPARATION

1.1 Preparation of the 2.5 mg/1 mL vial: add 1.6 mL of sterile injectable sodium chloride solution 9 mg/mL (0.9%) to the vial containing Bortezomib.
Preparation of the 3.5 mg/1.4 mL vial: add 2.2 mL of sterile injectable sodium chloride solution 9 mg/mL (0.9%) to the vial containing Bortezomib.
Each vial contains an overfill of 0.1 mL. Consequently, each 1 mL and 1.4 mL vial contains 2.75 mg and 3.75 mg of bortezomib, respectively.
The concentration of the resulting solution is 1 mg/mL. The solution will be clear and colourless.
1.2 The solution should be inspected visually before administration to check for the presence of particulate matter or discoloration. If particulate matter or discoloration is observed, the solution must not be used and should be discarded.
Ensure that the correct dose is administered by intravenous route (1 mg/mL).
1.3 The diluted solution is preservative-free and should be used immediately after preparation. However, the chemical and physical in-use stability of the diluted solution has been demonstrated for 24 hours at 20–25°C. The total storage time of the diluted medicinal product before administration should not exceed 24 hours. If the diluted solution is not used immediately, it is the responsibility of the user to ensure that the storage conditions and duration comply with the requirements prior to use. It is not necessary to protect the diluted medicinal product from light.

2. INTRAVENOUS INJECTION ADMINISTRATION

2.1 After dilution, withdraw the appropriate volume of the diluted solution according to the dose calculated based on the patient's body surface area.
2.2 Confirm the dose and concentration in the syringe before use (check that the syringe is labeled for intravenous administration).
2.3 Administer the solution as an intravenous bolus by injecting over 3–5 seconds through a peripheral or central venous catheter.
2.4 Flush the intravenous catheter with 9 mg/mL (0.9%) sodium chloride injectable solution.

3. PREPARATION FOR SUBCUTANEOUS INJECTION

3.1 Bortezomib injectable solution is ready for subcutaneous administration.
The concentration of the solution is 2.5 mg/mL. The solution is clear and colorless.
3.2 The solution should be inspected visually before administration to check for the presence of particulate matter or discoloration. If particulate matter or discoloration is observed, the solution must not be used and should be discarded.
Ensure that the correct dose is administered by subcutaneous route (2.5 mg/mL).
3.3 The product does not contain preservatives and must be used immediately after withdrawing the appropriate amount of solution.
3.4 During preparation for administration and during administration itself, it is not necessary to protect the medicinal product from light.

4. SUBCUTANEOUS INJECTION ADMINISTRATION

4.1 Withdraw the appropriate volume of solution according to the dose calculated based on the patient's body surface area.
4.2 Confirm the dose and concentration in the syringe before use (check that the syringe is labeled for subcutaneous administration).
4.3 Inject the solution subcutaneously at an angle of 45–90°.
4.4 The solution is administered subcutaneously in the thighs (right or left) or in the abdomen (right or left).
4.5 With subsequent administrations, the injection site must be rotated.
4.6 If local reactions occur at the injection site following subcutaneous injection of bortezomib, a lower concentration of bortezomib solution may be administered (1 mg/mL instead of 2.5 mg/mL) or intravenous injection is recommended.

5. DISPOSAL

The vial is for single use only, and any remaining solution must be discarded.
Unused medicine and waste materials derived from this medicine must be disposed of in accordance with
applicable local regulations.

Package leaflet: information for the user

Bortezomib Accord 1 mg powder for solution for injection, 3.5 mg powder for solution for injection

bortezomib
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

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 so-called "proteasome inhibitor".
Proteasomes play an important role in controlling cell functions and cell growth.
By interfering with their function, bortezomib can kill tumour cells.
Bortezomib Accord is used in the treatment of multiple myeloma (a type of malignant neoplasm of the
bone marrow) in patients over 18 years of age:

• alone or in combination with pegylated liposomal doxorubicin or dexamethasone, for patients with progressive disease after having received at least one prior therapy, or in whom blood stem cell transplantation has failed or is not feasible.
• in combination with melphalan and prednisone for patients with previously untreated disease who are not eligible for high-dose chemotherapy with blood stem cell transplantation.
• in combination with dexamethasone or dexamethasone plus thalidomide for patients with previously untreated disease and prior to receiving high-dose chemotherapy with blood stem cell transplantation (induction treatment).

Bortezomib Accord is used for the treatment of mantle cell lymphoma (a type of malignant neoplasm
affecting the lymph nodes) in patients aged 18 years or older. In this case, Bortezomib Accord is
used in combination with rituximab, cyclophosphamide, doxorubicin and prednisone, for patients with
previously untreated disease for whom blood stem cell transplantation is not feasible.

2. What you should know before using Bortezomib Accord

Do not use Bortezomib Accord

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

Warnings and precautions
Inform your doctor if you have:

• low red blood cell or white blood cell count
• bleeding problems and/or low platelet count in the blood
• diarrhoea, constipation, nausea or vomiting
• previous episodes of fainting, dizziness or lightheadedness
• kidney problems
• moderate to severe liver problems
• previous history of numbness, tingling or pain in hands or feet (neuropathy)
• heart or blood pressure disorders
• shortness of breath or cough
• seizures
• herpes zoster (shingles), including localized around the eyes or spreading to other parts of the body
• symptoms of tumour lysis syndrome such as muscle cramps, muscle weakness, confusion, visual disturbances or loss of vision, and shortness of breath
• memory loss, difficulty thinking, difficulty walking or loss of vision. These may be signs of a serious brain infection, and your doctor may perform further tests and examinations.

You will need regular blood tests before and during treatment with Bortezomib Accord to monitor your blood cell counts continuously.
If you have mantle cell lymphoma and are being treated with rituximab in combination with Bortezomib Accord, inform your doctor:

• if you think you have hepatitis or have had it in the past. In some cases, patients who have had hepatitis B may experience reactivation of the infection, which can be fatal. If you have previously had hepatitis B infection, your doctor will need to monitor you closely for signs and symptoms of active hepatitis B.

Read the package leaflets of all medicines you are taking in combination with Bortezomib Accord for information about those medicines before starting treatment with Bortezomib Accord.
When Bortezomib Accord is administered together with the medicine thalidomide, pay special attention to the instructions regarding pregnancy testing and the pregnancy prevention programme (see "Pregnancy and breastfeeding" in this section).

Children and adolescents
Bortezomib Accord must not be used in children and adolescents because it is not known how the medicine works in these populations.

Other medicines and Bortezomib Accord
Inform your doctor or pharmacist if you are taking, have recently taken, or might 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 (Hypericum perforatum), used to treat depression or other conditions
• oral antidiabetic medicines.

Pregnancy and breastfeeding
You must not use Bortezomib Accord during pregnancy unless strictly necessary.
Men and women receiving treatment with Bortezomib Accord must use effective contraception during treatment and for up to 3 months after treatment ends. If pregnancy occurs despite these precautions, inform your doctor immediately.
You must not breast-feed while receiving Bortezomib Accord. Discuss with your doctor the most appropriate time to resume breastfeeding after treatment ends.
The medicine thalidomide causes birth defects and fetal death. When Bortezomib Accord is administered together with thalidomide, you must follow the thalidomide pregnancy prevention programme (see the thalidomide package leaflet).

Driving and using machines
Bortezomib Accord may cause fatigue, dizziness, fainting or blurred vision.
Do not drive or operate machinery if you experience any of these symptoms.
Exercise particular caution even if these effects do not occur.

3. How to use Bortezomib Accord

Your doctor will calculate the dose of Bortezomib Accord based on your height and weight. The
standard starting dose of Bortezomib Accord is 1.3 mg/m² of body surface area 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 overall health status (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. This is 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 together with pegylated liposomal doxorubicin, you will
receive a 21-day treatment cycle with Bortezomib Accord given intravenously or subcutaneously, and
30 mg/m² of pegylated liposomal doxorubicin will be 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 of treatment).

When Bortezomib Accord is administered together with dexamethasone, you will receive a 21-day
treatment cycle with Bortezomib Accord given intravenously or subcutaneously, and oral dexamethasone
at a dose of 20 mg 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 of treatment).

Previously untreated multiple myeloma
If you have never been treated before for multiple myeloma and you are not eligible for blood stem
cell transplantation, you will receive Bortezomib Accord in combination with two other medicines:
melphalan and prednisone.

In this case, each treatment cycle lasts 42 days (6 weeks). You will receive 9 cycles (54 weeks).

• In cycles 1–4, Bortezomib Accord is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29, and 32.
• In cycles 5–9, 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 never been treated before for multiple myeloma and you are eligible for blood stem cell
transplantation, you will receive Bortezomib Accord intravenously or subcutaneously in combination
with dexamethasone, or with dexamethasone and thalidomide, as induction treatment.

When Bortezomib Accord is administered together with dexamethasone, you will receive a 21-day
treatment cycle with Bortezomib Accord given intravenously or subcutaneously, and oral dexamethasone
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 of treatment).

When Bortezomib Accord is administered together with thalidomide and dexamethasone, the treatment
cycle lasts 28 days (4 weeks).

Oral dexamethasone 40 mg is administered on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 28-day Bortezomib
Accord treatment cycle, and thalidomide is administered daily orally 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 may be
further increased up to 200 mg daily starting from the second cycle onwards. You may receive up to 6
cycles (24 weeks of treatment).

Previously untreated mantle cell lymphoma
If you have never previously received specific treatment for mantle cell lymphoma, you will receive
Bortezomib Accord intravenously or subcutaneously in combination with 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. Each treatment cycle lasts 21 days (3 weeks). You may receive up to 8
treatment cycles (24 weeks).

The following medicines are administered on day 1 of each 21-day Bortezomib Accord treatment cycle
as intravenous infusions: rituximab at 375 mg/m², cyclophosphamide at 750 mg/m², and doxorubicin at
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
This medicine is for intravenous or subcutaneous use. Bortezomib Accord will be administered by a
healthcare professional experienced in the use of cytotoxic medicines.

The Bortezomib Accord powder must be reconstituted before administration. This will be done by a
healthcare professional. The resulting solution is then injected rapidly into a vein or under the skin.
The intravenous injection is rapid, taking 3 to 5 seconds. The subcutaneous injection can be given in
either the thigh or the abdomen.

If you use more Bortezomib Accord than you should
Since this medicine is administered by a doctor or nurse, it is unlikely that you will receive more than the
correct amount. In the unlikely event of an overdose, your doctor will monitor you for any adverse effects.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them. Some of these side effects may be serious.
If you are being administered Bortezomib Accord for multiple myeloma or mantle cell lymphoma, inform your doctor immediately if you experience any of the following symptoms:

• Muscle cramps, muscle weakness
• Confusion, vision disturbances or loss of vision, blindness, seizures, headache
• Shortness of breath, swelling of the feet or changes in heartbeat, 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 and white blood cells and platelets in the blood. Therefore, you will need regular blood tests before and during treatment with Bortezomib Accord to monitor your blood cell counts. You may experience a reduction in the number of:

• Platelets, which may make you more prone to bruising or bleeding without apparent injury (for example, bleeding from the intestine, stomach, mouth and gums, or brain or liver haemorrhage)
• Red blood cells, which may cause anaemia, with symptoms such as fatigue and paleness
• White blood cells, which may increase your susceptibility to infections or flu-like symptoms.

If you are being administered Bortezomib Accord for the treatment of multiple myeloma, the side effects that may occur are listed below.
Very common side effects (may affect more than 1 in 10 people)

• Hypersensitivity, numbness, tingling, burning sensation of the skin, or pain in the hands or feet due to nerve damage.
• Decrease in the number of red and/or white blood cells (see above).
• Fever.
• Nausea or vomiting, loss of appetite.
• Constipation with or without excessive intestinal gas (can be severe).
• Diarrhoea: if this occurs, it is important that you drink much more water than usual. Your doctor may prescribe medication to control diarrhoea.
• Tiredness (fatigue), feeling of weakness.
• Muscle pain, bone pain.

Common side effects (may affect up to 1 in 10 people)

• Low blood pressure, sudden drop in blood pressure upon standing which may lead to fainting.
• Increased blood pressure.
• Reduced kidney function.
• Headache.
• General feeling of malaise, pain, dizziness, feeling of emptiness in the head, weakness or loss of consciousness.
• Chills.
• Infections, including pneumonia, respiratory infections, bronchitis, fungal infection, cough with phlegm, flu-like illness.
• Infection with Herpes zoster (localized, including around the eyes, or disseminated on the body).
• Chest pain or difficulty breathing during physical activity.
• Various types of skin rash.
• Itching of the skin, skin nodules or dry skin.
• Facial redness or small capillary ruptures.
• Skin redness.
• Dehydration.
• Heartburn, bloating, belching, gas, stomach pain, intestinal or stomach bleeding.
• Altered liver function.
• Irritation of the mouth or lips, dry mouth, oral ulcers or sore throat.
• Weight loss, loss of taste.
• Muscle cramps, muscle spasms, muscle weakness, pain in arms and legs.
• Blurred vision.
• Infection of the outer layer of the eye and inner surface of the eyelids (conjunctivitis).
• Nosebleeds.
• Sleep disturbances or problems, sweating, anxiety, mood changes, depressed mood, restlessness or agitation, changes in mental state, disorientation.
• Swelling of the body, including swelling around the eyes and in other parts of the body.

Uncommon side effects (may affect up to 1 in 100 people)

• 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.
• Circulatory failure.
• Inflammation of the membrane surrounding the heart or fluid accumulation around the heart.
• Infections, including urinary tract infections, influenza, herpes virus infections, ear infection and cellulitis.
• Blood in stools, or mucosal bleeding, for example from mouth or vagina.
• Cerebrovascular disorders.
• Paralysis, seizures, falls, movement disorders, abnormal or reduced sensation (touch, hearing, taste, smell), attention disorders, tremor, spasms.
• Arthritis, including inflammation of the joints of fingers, toes and jaw.
• Disorders affecting the lungs, preventing your body from receiving sufficient oxygen. Some of these include difficulty breathing, shortness of breath, laboured breathing even without physical activity, shallow or difficult breathing or need to pause breathing, wheezing.
• Hiccups, speech disorders.
• Increased or decreased urine production (kidney damage), painful urination or presence of blood/protein in urine, fluid retention.
• Altered levels of consciousness, confusion, memory impairment or loss.
• Hypersensitivity.
• Hearing loss, deafness or ringing in the ears, ear discomfort.
• Hormonal changes that may affect the reabsorption of salts and water.
• Overactivity of the thyroid gland.
• Inability to produce enough insulin or resistance to normal insulin levels.
• Irritated or inflamed eyes, excessively watery eyes, eye pain, dry eyes, eye infections, eyelid swelling (chalazion), red and swollen eyelids, eye discharge, vision disturbances, eye bleeding.
• Enlargement of lymph nodes.
• Joint or muscle stiffness, feeling of heaviness, groin pain.
• Hair loss or abnormal hair texture.
• Allergic reactions.
• Redness or pain at the injection site.
• Mouth pain.
• Infection or inflammation of the mouth, mouth ulcers, oesophagus, stomach and intestine, sometimes associated with pain or bleeding, reduced intestinal motility (including intestinal blockage), abdominal or oesophageal discomfort, difficulty swallowing, vomiting with blood.
• Skin infections.
• Bacterial and viral infections.
• Dental infections.
• Pancreatitis, obstruction of bile ducts.
• Genital pain, erectile dysfunction.
• Weight gain.
• Feeling of thirst.
• Hepatitis.
• Reactions at the injection site or catheter site.
• Skin reactions or disorders (which may be severe and life-threatening), skin ulcerations.
• Bruising, falls and injuries.
• Inflammation or bleeding of blood vessels, which may present as small red or purple spots (usually on the legs) that may develop into large bruises on the skin or tissues.
• Benign cysts.
• A serious but reversible brain condition including seizures, high blood pressure, headache, fatigue, confusion, blindness or other vision problems.

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

• Heart problems including heart attack, angina.
• Severe inflammation of nerves, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome).
• Hot flushes.
• Change in the colour of veins.
• Inflammation of the spinal nerve.
• Ear problems, ear bleeding.
• Reduced activity of the thyroid gland.
• Budd-Chiari syndrome (clinical signs caused by blockage of the liver veins).
• Change or abnormal intestinal function.
• Cerebral haemorrhage (brain bleeding).
• Yellowing of the eyes and skin (jaundice).
• Severe allergic reaction (anaphylactic shock), signs include difficulty breathing, chest pain or tightness, and/or dizziness/weakness, severe skin itching or appearance of swellings on the skin, swelling of the face, lips, tongue and/or throat which may cause difficulty swallowing, collapse.
• Breast disorders.
• Vaginal discharge.
• Swelling of the genitals.
• Inability to tolerate alcohol consumption.
• Wasting or loss of body mass.
• Increased appetite.
• Fistulas.
• Joint effusion.
• Cysts in the membrane covering the joints (synovial cysts).
• Fractures.
• Muscle fibre rupture leading to further complications.
• Enlarged liver, liver haemorrhage.
• Kidney tumour.
• Skin condition similar to psoriasis.
• Skin tumour.
• Paleness of the skin.
• Increased platelets or plasma cells (a type of white blood cells) in the blood.
• Blood clot in small blood vessels (thrombotic microangiopathy).
• Abnormal reaction to blood transfusion.
• Partial or complete loss of vision.
• Decreased libido.
• Loss of saliva.
• Protruding eyes.
• Photophobia (excessive sensitivity of the eye to light).
• Rapid breathing.
• Rectal pain.
• Gallstones.
• Hernia.
• Injuries.
• Brittle or weak nails.
• Abnormal deposition of proteins in vital organs.
• Coma.
• Intestinal ulcers.
• Damage to multiple organs.
• Death.

If you are being administered Bortezomib Accord in combination with other medicines for the treatment of mantle cell lymphoma, the side effects that may occur are listed below.
Very common side effects (may affect more than 1 in 10 people)

• Pneumonia.
• Loss of appetite.
• Hypersensitivity, numbness, tingling, burning sensation of the skin, or pain in the hands or feet due to nerve damage.
• Nausea and vomiting.
• Diarrhoea.
• Mouth ulcers.
• Intestinal constipation.
• Muscle pain, bone pain.
• Hair loss or abnormal hair texture.
• Tiredness, feeling of weakness.
• Fever.

Common side effects (may affect up to 1 in 10 people)

• Infection with Herpes zoster (localized, including around the eyes, or disseminated on the body).
• Infection with herpes virus.
• Bacterial and viral infections.
• Respiratory infections, bronchitis, cough with phlegm, flu-like illness.
• Fungal infections.
• Hypersensitivity (allergic reaction).
• Inability to produce enough insulin or resistance to normal insulin levels.
• Fluid retention.
• Difficulty or problems sleeping.
• Loss of consciousness.
• Altered levels of consciousness, confusion.
• Dizziness.
• Increased heart rate, high blood pressure, sweating.
• Vision disturbances, 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 physical activity.
• Cough.
• Hiccups.
• 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.
• Irritation of the mouth or lips, sore throat.
• Altered liver function.
• Itching of the skin.
• Skin redness.
• Rash.
• Muscle spasms.
• Urinary tract infection.
• Limb pain.
• Swelling of the body, including swelling around the eyes and in other parts of the body.
• Chills.
• Redness and pain at the injection site.
• General feeling of malaise.
• Loss of body weight.
• Increase in body weight.

Uncommon side effects (may affect up to 1 in 100 people)

• Hepatitis.
• Severe allergic reaction (anaphylactic reaction), signs of which may include difficulty breathing, chest pain or tightness, and/or dizziness/weakness, severe skin itching or appearance of swellings on the skin, swelling of the face, lips, tongue and/or throat which may cause difficulty swallowing, collapse.
• Movement disorders, paralysis, contractions.
• Dizziness.
• Hearing loss, deafness.
• Disorders affecting the lungs, preventing your body from receiving sufficient oxygen. Some of these include difficulty breathing, shortness of breath, laboured breathing even without physical activity, shallow, difficult or interrupted breathing, wheezing.
• Blood clots in the lungs.
• Yellowing of the eyes and skin (jaundice).
• Eyelid swelling (chalazion), red and swollen eyelids.

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

• Blood clotting in small blood vessels (thrombotic microangiopathy).
• Severe inflammation of nerves, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome).

Reporting of side effects
If you experience any side effect, if any of the side effects worsens or if you notice any side effect not listed in this leaflet, consult your doctor or pharmacist immediately. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store 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 the outer carton after EXP.
This medicine does not require any special storage temperature. Store the vial in the outer packaging to protect the medicine from light.

Intravenous administration
The reconstituted solution is stable for 3 days at 20–25°C when stored in the original vial and/or in a syringe. From a microbiological point of view, unless the method of opening/reconstitution excludes the risk of microbial contamination, the reconstituted solution should be used immediately after preparation. If not used immediately, it is the responsibility of the user to ensure appropriate storage conditions and duration prior to use.

Subcutaneous administration
The reconstituted solution is stable for 8 hours at 20–25°C when stored in the original vial and/or in a syringe. From a microbiological point of view, unless the method of opening/reconstitution excludes the risk of microbial contamination, the reconstituted solution should be used immediately after preparation. If not used immediately, it is the responsibility of the user to ensure appropriate storage conditions and duration prior to use.

Bortezomib Accord is for single use only. Any unused product and waste material must be disposed of in accordance with local regulations.

6. Package contents and other information

What Bortezomib Accord contains
The active substance is bortezomib.
Bortezomib Accord 1 mg powder for solution for injection
Each vial contains 1 mg of bortezomib (as mannitol boronic ester).
Bortezomib Accord 3.5 mg powder for solution for injection
Each vial contains 3.5 mg of bortezomib (as mannitol boronic ester).
Reconstitution for intravenous use:
After reconstitution, 1 ml of solution for intravenous injection contains 1 mg of bortezomib.
Reconstitution for subcutaneous use:
After reconstitution, 1 ml of solution for subcutaneous injection contains 2.5 mg of bortezomib.
The excipient is mannitol (E421).

Description of the appearance of Bortezomib Accord and contents of the pack
Bortezomib Accord powder for solution for injection is white to off-white in colour.
Bortezomib Accord 1 mg powder for solution for injection
Each pack of Bortezomib Accord 1 mg contains one 6 ml glass vial with a grey chlorobutyl rubber stopper and an aluminium seal with a blue flip-off cap, containing 1 mg of bortezomib.
Bortezomib Accord 3.5 mg powder for solution for injection
Each pack of Bortezomib Accord 3.5 mg contains one 10 ml glass vial with a grey chlorobutyl rubber stopper and an aluminium seal with a red flip-off cap.

Marketing Authorisation 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,
The Netherlands

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
The following information is intended for healthcare professionals only.

1. RECONSTITUTION FOR INTRAVENOUS INJECTION

Note: Bortezomib Accord is a cytotoxic agent. Therefore, particular care must be taken during handling and preparation. It is recommended to wear gloves and other protective clothing to prevent skin contact.
DUE TO THE ABSENCE OF ANY TYPE OF PRESERVATIVE, ASEPTIC TECHNIQUES MUST BE OBSERVED DURING THE HANDLING OF BORTEZOMIB ACCORD.
1.1 Reconstitution of the 1 mg vial: carefully add 1.0 ml of sterile injectable sodium chloride solution 9 mg/ml (0.9%) to the vial containing Bortezomib Accord powder, using an appropriate syringe and without removing the vial stopper. The lyophilized powder dissolves completely within less than 2 minutes.
Reconstitution of the 3.5 mg vial: carefully add 3.5 ml of sterile injectable sodium chloride solution 9 mg/ml (0.9%) to the vial containing Bortezomib Accord powder, using an appropriate syringe and without removing the vial stopper. The lyophilized powder dissolves completely within less than 2 minutes.
The concentration of the resulting solution is 1 mg/ml. The solution will be clear and colourless with a final pH between 4 and 7. There is no need to check the pH of the solution.
1.2 The solution must be visually inspected prior to administration to check for the presence of particulate matter or discoloration. If particulate matter or discoloration is observed, the solution must not be used and must be discarded.
Ensure that the correct dose is administered by intravenous route (1 mg/ml).
1.3 The reconstituted solution contains no preservatives and should be used immediately after preparation, although it is chemically and physically stable for 3 days at 20–25°C in the original vial and/or in a syringe. From a microbiological standpoint, unless the method of opening/reconstitution excludes the risk of microbial contamination, the reconstituted solution should be used immediately after preparation. If not used immediately, it is the responsibility of the user to ensure appropriate storage conditions and duration prior to use.
It is not necessary to protect the reconstituted medicinal product from light.

2. ADMINISTRATION

• After reconstitution, withdraw the appropriate volume of the reconstituted solution according to the dose calculated based on the patient's body surface area.
• Confirm the dose and concentration in the syringe before use (check that the syringe is labelled for intravenous administration).
• Inject the solution intravenously as a bolus injection over 3–5 seconds through a peripheral or central intravenous catheter.
• Flush the intravenous catheter with sterile sodium chloride injection 9 mg/ml (0.9%).

Bortezomib Accord 1 mg powder for injectable solution is FOR INTRAVENOUS USE ONLY,
while Bortezomib Accord 3.5 mg powder for injectable solution is FOR SUBCUTANEOUS OR
INTRAVENOUS USE. Do not administer by other routes. Intrathecal administration has resulted in deaths.

3. DISPOSAL

The vial is for single use and any remaining solution must be discarded.
Unused medicine and waste material derived from this medicine must be disposed of in accordance with
applicable local regulations.
Only the 3.5 mg vial can be administered by subcutaneous route as described below.

1. RECONSTITUTION FOR SUBCUTANEOUS INJECTION

Note: Bortezomib Accord is a cytotoxic agent. Therefore, particular care must be taken during handling and preparation. It is recommended to wear gloves and other protective clothing to prevent skin contact.
DUE TO THE ABSENCE OF ANY TYPE OF PRESERVATIVE, ASEPTIC TECHNIQUE MUST BE OBSERVED DURING THE HANDLING OF BORTEZOMIB ACCORD.
1.1 Preparation of the 3.5 mg vial: carefully add 1.4 ml of sterile injectable sodium chloride 9 mg/ml (0.9%) solution to the vial containing Bortezomib Accord lyophilized powder, using an appropriate syringe and without removing the vial stopper. The lyophilized powder dissolves completely within less than 2 minutes.
The concentration of the resulting solution is 2.5 mg/ml. The solution will be clear and colourless, with a final pH between 4 and 7. There is no need to check the pH of the solution.
1.2 The solution should be inspected visually prior to administration to check for the presence of particulate matter or discoloration. If particulate matter or discoloration is observed, the solution must not be used and should be discarded.
Ensure that the correct dose is administered by subcutaneous route (2.5 mg/ml).
1.3 The reconstituted solution contains no preservatives and should be used immediately after preparation, although it is chemically and physically stable for 8 hours at 20–25°C in the original vial and/or in a syringe. From a microbiological standpoint, unless the method of opening/reconstitution excludes the risk of microbial contamination, the reconstituted solution should be used immediately after preparation. If not used immediately, it is the responsibility of the user to ensure appropriate storage conditions and duration prior to use.
It is not necessary to protect the reconstituted medicinal product from light.

2. ADMINISTRATION

• After reconstitution, withdraw the appropriate volume of the reconstituted solution according to the dose calculated based on the patient's body surface area.
• Confirm the dose and concentration in the syringe before use (check that the syringe is labelled for subcutaneous administration).
• Inject the solution subcutaneously at an angle of 45–90°.
• The reconstituted solution is administered subcutaneously in the thighs (right or left) or abdomen (right or left).
• For subsequent administrations, the injection site must be rotated.
• If local reactions occur at the injection site after subcutaneous administration of Bortezomib Accord, a lower concentration of Bortezomib Accord 3.5 mg solution may be administered (1 mg/ml instead of 2.5 mg/ml), or switching to intravenous injection is recommended. Bortezomib Accord 3.5 mg powder for injectable solution is for SUBCUTANEOUS or INTRAVENOUS use. Do not administer by other routes. Intrathecal administration has resulted in deaths.

3. DISPOSAL

The vial is for single use only and any remaining solution must be discarded.
Unused medicine and waste materials resulting from this medicine must be disposed of in accordance with
applicable local regulations.