Velcade

Package leaflet: Information for the user

VELCADE 1 mg powder for solution for injection

bortezomib
Please read all of this leaflet carefully before you are given 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 get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

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

1. What VELCADE is and what it is used for

VELCADE contains the active substance bortezomib, a so-called "proteasome inhibitor".
Proteasomes play an important role in regulating cell functions and cell growth.
By interfering with their function, bortezomib can kill tumour cells.
VELCADE 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 blood stem cell transplantation has failed or is not feasible.
• in combination with the medicines melphalan and prednisone for patients with previously untreated disease who cannot receive high-dose chemotherapy with blood stem cell transplantation.
• in combination with dexamethasone or with dexamethasone and thalidomide, for patients with previously untreated disease and prior to receiving high-dose chemotherapy with blood stem cell transplantation (induction treatment).

VELCADE 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, VELCADE is used in combination with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone, for patients with previously untreated disease for whom blood stem cell transplantation is not feasible.

2. What you need to know before using VELCADE

Do not use VELCADE

• 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 red blood cell or white blood cell count
• bleeding problems and/or low platelet count in the blood
• diarrhea, 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 the hands or feet (neuropathy)
• heart condition or blood pressure problems
• shortness of breath or cough
• seizures
• herpes zoster (including around the eyes or spreading to other parts of the body)
• symptoms of tumor lysis syndrome such as muscle cramps, muscle weakness, confusion, vision 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 recommend further tests and monitoring.

You will need to have regular blood tests before and during treatment with VELCADE to continuously monitor your blood cell counts.
If you have mantle cell lymphoma and are being given rituximab together with VELCADE, 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 previously had hepatitis B infection, your doctor must closely monitor you for signs and symptoms of active hepatitis B.

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

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

Other medicines and VELCADE
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 VELCADE during pregnancy unless strictly necessary.
Women of childbearing potential must use effective contraception during treatment and for 8 months after the end of treatment. Consult your doctor if you wish to freeze your eggs before starting treatment.
Men must not father a child during treatment with VELCADE and must use an effective contraceptive method during treatment and for 5 months after the end of treatment. Consult your doctor if you wish to preserve sperm before starting treatment.
You must not breastfeed during treatment with VELCADE. Discuss with your doctor the most appropriate time to resume breastfeeding after the end of therapy.
The medicine thalidomide causes birth defects and fetal death. When VELCADE is administered together with thalidomide, you must follow the thalidomide pregnancy prevention program (see the thalidomide package leaflet).

Driving and use of machines
VELCADE 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 VELCADE

Your doctor will calculate the dose of VELCADE based on your height and weight. The standard starting dose of VELCADE 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 adverse effects, and your overall health status (e.g. liver problems).

Relapsed multiple myeloma
When VELCADE is administered alone, you will receive 4 doses of VELCADE by intravenous injection 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 VELCADE in combination with pegylated liposomal doxorubicin or dexamethasone.

When VELCADE is administered together with pegylated liposomal doxorubicin, you will receive a 21-day treatment cycle with VELCADE by intravenous injection, and 30 mg/m² of pegylated liposomal doxorubicin will be administered on day 4 of the 21-day VELCADE treatment cycle as an intravenous infusion, after the VELCADE injection.

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

When VELCADE is administered together with dexamethasone, you will receive a 21-day treatment cycle with VELCADE by intravenous injection and oral dexamethasone at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the 21-day VELCADE 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 VELCADE by intravenous injection 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 1–4, VELCADE is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29, and 32.
• In cycles 5–9, VELCADE 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 VELCADE by intravenous injection in combination with dexamethasone, or with dexamethasone and thalidomide, as induction therapy.

When VELCADE is administered together with dexamethasone, you will receive a 21-day treatment cycle with VELCADE by intravenous injection and oral dexamethasone 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 21-day VELCADE treatment cycle.

You will receive 4 cycles (12 weeks of treatment).

When VELCADE is administered together with thalidomide and dexamethasone, the treatment cycle duration is 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 VELCADE treatment cycle, and thalidomide is administered daily by mouth 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 subsequently be 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 VELCADE by intravenous injection in combination with the medicines rituximab, cyclophosphamide, doxorubicin, and prednisone.

VELCADE is administered by intravenous injection on days 1, 4, 8, and 11, followed by a treatment-free "rest" period. The treatment cycle duration is 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 VELCADE 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 VELCADE treatment cycle.

How VELCADE is administered
This medicine is for intravenous use only. VELCADE will be administered by a healthcare professional experienced in the use of cytotoxic medicines.

The VELCADE powder must be reconstituted before administration. This will be done by a healthcare professional. The resulting solution is then injected rapidly into a vein over a period of 3 to 5 seconds.

If you receive more VELCADE 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 given VELCADE for multiple myeloma or mantle cell lymphoma, tell your doctor immediately if you notice 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 feeling of chest tightness.

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

• Platelets, which could 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 can 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 given VELCADE for the treatment of multiple myeloma, the possible side effects are listed below:
Very common side effects (may affect more than 1 in 10 people)

• Hypersensitivity, numbness, tingling 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 of general malaise, pain, dizziness, feeling of emptiness in the head, feeling of weakness or loss of consciousness
• Chills
• Infections, including pneumonia, respiratory infections, bronchitis, fungal infection, cough with sputum, flu-like illness
• Herpes zoster infection (localized including around the eyes or disseminated over 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 ruptures of capillaries
• Skin redness
• Dehydration
• Heartburn, bloating, belching, gas, stomach pain, intestinal or stomach bleeding
• Liver function abnormalities
• 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 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 faeces, or bleeding from mucous membranes, for example mouth, vagina
• Cerebrovascular disorders
• Paralysis, seizures, falls, movement disorders, abnormal, altered or reduced sensation (feeling, hearing, tasting, smelling), attention disorders, tremor, spasms
• Arthritis, including inflammation of the joints of the fingers of the hands, toes and jaw
• Lung disorders impairing your 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 urine, fluid retention
• Altered levels of consciousness, confusion, failure or loss of memory
• Hypersensitivity
• Hearing loss, deafness or ringing in the ears, ear discomfort
• Hormonal changes that may affect salt and water reabsorption
• 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
• Swollen 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
• Skin reactions or disorders (which may be severe and life-threatening), skin ulcerations
• Bruising, falls and injuries
• Blood vessel inflammation or haemorrhage, 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 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 nerve inflammation, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome)
• Hot flushes
• Change in vein colour
• Inflammation of the spinal nerve
• Ear problems, bleeding from the ear
• Reduced activity of the thyroid gland
• Budd-Chiari syndrome (clinical signs caused by blockage of the liver veins)
• Altered or abnormal intestinal function
• Cerebral haemorrhage (bleeding in the brain)
• 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 cell) in the blood
• Blood clot in small blood vessels (thrombotic microangiopathy)
• Abnormal reaction to blood transfusion
• Partial or total 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 given VELCADE in combination with other medicines for the treatment of 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
• Hypersensitivity, numbness, tingling 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)

• Herpes zoster infection (localized including around the eyes or disseminated over the body)
• Herpes virus infection
• Bacterial and viral infections
• Respiratory infections, bronchitis, cough with sputum, 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
• Heartburn
• Stomach pain, bloating
• Difficulty swallowing
• Infection or inflammation of the stomach and intestine
• Stomach pain
• Irritation of the mouth or lips, sore throat
• Liver function abnormalities
• 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 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
• Lung disorders impairing your 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 nerve inflammation, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. 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 VELCADE

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 carton following
EXP.
Store below 30°C. Keep the vial in the outer packaging to protect the medicine from light.
The reconstituted solution should be used immediately after preparation. If the reconstituted solution is not used immediately, the conditions and duration of storage are the responsibility of the preparer. However, the reconstituted solution is stable for 8 hours at 25°C prior to administration when stored in the original vial and/or in a syringe, with a maximum storage time for the reconstituted medicine not exceeding 8 hours.
VELCADE 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 VELCADE contains

• The active substance is bortezomib. Each vial contains 1 mg of bortezomib (as mannitol boronic ester). After reconstitution, 1 ml of injectable solution contains 1 mg of bortezomib.
• The excipients are mannitol (E421) and nitrogen.

Description of the appearance of VELCADE and package contents

VELCADE 1 mg or 3.5 mg powder for solution for injection is a white to off-white powder.

Each VELCADE 1 mg pack contains one glass vial with a green cap, packed in a transparent blister.

Marketing Authorisation Holder:
JANSSEN-CILAG INTERNATIONAL NV
Turnhoutseweg, 30
B-2340 Beerse
Belgium

Manufacturer
Janssen Pharmaceutica NV
Turnhoutseweg, 30
B-2340 Beerse
Belgium

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

België/Belgique/Belgien Lietuva
Janssen-Cilag NV UAB "JOHNSON & JOHNSON"
Tel/Tél: +32 14 64 94 11 Tel: +370 5 278 68 88
[email protected] [email protected]

България Luxembourg/Luxemburg
„Джонсън & Джонсън България” ЕООД Janssen-Cilag NV
Tel.: +359 2 489 94 00 Tél/Tel: +32 14 64 94 11
[email protected] [email protected]

Česká republika Magyarország
Janssen-Cilag s.r.o. Janssen-Cilag Kft.
Tel: +420 227 012 227 Tel.: +36 1 884 2858
[email protected]

Danmark Malta
Janssen-Cilag A/S AM MANGION LTD
Tlf.: +45 4594 8282 Tel: +356 2397 6000
[email protected]

Deutschland Nederland
Janssen-Cilag GmbH Janssen-Cilag B.V.
Tel: 0800 086 9247 /+49 2137 955 6955 Tel: +31 76 711 1111
[email protected] [email protected]

Eesti Norge
UAB "JOHNSON & JOHNSON" Eesti filiaal Janssen-Cilag AS
Tel: +372 617 7410 Tlf: +47 24 12 65 00
[email protected] [email protected]

Ελλάδα Österreich
Janssen-Cilag Φαρμακευτική Μονοπρόσωπη Janssen-Cilag Pharma GmbH
Α.Ε.Β.Ε. Tel: +43 1 610 300
Tel: +30 210 80 90 000

España Polska
Janssen-Cilag, S.A. Janssen-Cilag Polska Sp. z o.o.
Tel: +34 91 722 81 00 Tel.: +48 22 237 60 00
[email protected]

France Portugal
Janssen-Cilag Janssen-Cilag Farmacêutica, Lda.
Tél: 0 800 25 50 75 / + 33 1 55 00 40 03 Tel: +351 214 368 600
[email protected]

Hrvatska România
Johnson & Johnson S.E. d.o.o. Johnson & Johnson România SRL
Tel: +385 1 6610 700 Tel: +40 21 207 1800
[email protected]

Ireland Slovenija
Janssen Sciences Ireland UC Johnson & Johnson d.o.o.
Tel: 1 800 709 122 Tel: +386 1 401 18 00
[email protected] [email protected]

Ísland Slovenská republika
Janssen-Cilag AB Johnson & Johnson, s.r.o.
c/o Vistor hf. Tel: +421 232 408 400
Sími: +354 535 7000
[email protected]

Italia Suomi/Finland
Janssen-Cilag SpA Janssen-Cilag Oy
Tel: 800.688.777 / +39 02 2510 1 Puh/Tel: +358 207 531 300
[email protected] [email protected]

Κύπρος Sverige
Βαρνάβας Χατζηπαναγής Λτδ Janssen-Cilag AB
Τηλ: +357 22 207 700 Tfn: +46 8 626 50 00
[email protected]

Latvija United Kingdom
UAB "JOHNSON & JOHNSON" filiāle Latvijā (Northern Ireland)
Tel: +371 678 93561 Janssen Sciences Ireland UC
[email protected] Tel: +44 1 494 567 444
[email protected]

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

The following information is intended exclusively for healthcare professionals:

1. RECONSTITUTION FOR INTRAVENOUS INJECTION

Note: VELCADE is a cytotoxic agent. Therefore, special 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 VELCADE.
1.1 Preparation of the 1 mg vial: carefully add 1 ml of sterile injectable sodium chloride solution 9 mg/ml (0.9%) to the vial containing the VELCADE powder, using a 1 ml syringe and without removing the vial stopper. The lyophilized powder dissolves completely in less than 2 minutes.
The concentration of the resulting solution is 1 mg/ml. The solution will be clear and colorless, with a final pH between 4 and 7. It is not necessary to check the pH of the solution.
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 must be discarded.
Confirm the concentration on the vial label to ensure that the correct dose is administered intravenously (1 mg/ml).
1.3 The reconstituted solution is preservative-free and must be used immediately after preparation, although it is chemically and physically stable for 8 hours at 25°C in the original vial and/or in a syringe, with a maximum of 8 hours in the syringe. The total storage time of the reconstituted medicinal product must not exceed 8 hours prior to administration. If the reconstituted solution is not used immediately after preparation, it is the responsibility of the user to ensure appropriate storage conditions and storage times before 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 labeled for intravenous administration).
• Inject the solution intravenously as a bolus over 3–5 seconds through a peripheral or central intravenous catheter.
• Flush the intravenous catheter with sterile injectable sodium chloride 9 mg/ml (0.9%) solution.

VELCADE 1 mg powder for injectable solution is for INTRAVENOUS USE ONLY. 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 resulting from this medicine must be disposed of in accordance with
applicable local regulations.

Patient Information Leaflet: Information for the User

VELCADE 3.5 mg powder for injectable solution

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

• Keep this leafleaflet. 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 VELCADE is and what it is used for
2. What you need to know before using VELCADE
3. How to use VELCADE
4. Possible side effects
5. How to store VELCADE
6. Contents of the pack and other information

1. What VELCADE is and what it is used for

VELCADE 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.
VELCADE is used to treat 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 disease that has worsened (progressive) after having received at least one prior treatment, or in whom blood stem cell transplantation has failed or is not feasible
• in combination with the medicines melphalan and prednisone for patients with previously untreated disease who cannot receive high-dose chemotherapy with blood 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 blood stem cell transplantation (induction treatment)

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

2. What you need to know before using VELCADE

Do not use VELCADE

• 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 red or white blood cell counts
• you have bleeding problems and/or low platelet count in the blood
• you have diarrhoea, constipation, nausea, or vomiting
• you have previously experienced fainting, dizziness, or a feeling of lightheadedness
• you have kidney problems
• you have moderate to severe liver problems
• you have previously had conditions such as numbness, tingling, or pain in the hands or feet (neuropathy)
• you have a heart condition or blood pressure problems
• you have shortness of breath or cough
• you have seizures
• you have herpes zoster (including localized around the eyes or spreading to other parts of the body)
• symptoms of tumour lysis syndrome such as, for example, 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 recommend further tests and examinations.

You will need to have regular blood tests before and during treatment with VELCADE to continuously monitor your blood cell counts.
If you have mantle cell lymphoma and are receiving rituximab together with VELCADE, 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 hepatitis, 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 VELCADE for information about these medicines before starting treatment with VELCADE.
When VELCADE 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
VELCADE must not be used in children and adolescents because its effects in these populations are unknown.
Other medicines and VELCADE
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 VELCADE during pregnancy unless absolutely necessary.
Women of childbearing potential must use effective contraception during treatment and for 8 months after the end of treatment. Consult your doctor if you wish to freeze your eggs before starting treatment.
Men must not father a child during treatment with VELCADE and must use an effective contraceptive method during treatment and for 5 months after the end of treatment. Consult your doctor if you wish to preserve sperm before starting treatment.
You must not breastfeed while taking VELCADE. Discuss with your doctor the most appropriate time to resume breastfeeding after the end of treatment.
The medicine thalidomide causes congenital malformations and fetal death. When VELCADE is administered together with thalidomide, you must follow the thalidomide pregnancy prevention programme (see the thalidomide package leaflet).
Driving and using machines
VELCADE 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 are not apparent.

3. How to use VELCADE

Your doctor will calculate the dose of VELCADE based on your height and weight. The standard starting dose of VELCADE 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 adverse effects, and your overall health condition (e.g. liver problems).

Relapsed multiple myeloma
When VELCADE is given alone, you will receive 4 doses of VELCADE 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 VELCADE in combination with pegylated liposomal doxorubicin or dexamethasone.

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

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

When VELCADE is administered together with dexamethasone, you will receive a 21-day treatment cycle with VELCADE 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 VELCADE 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 stem cell transplantation, you will receive VELCADE 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, VELCADE is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29, and 32.
• In cycles 5–9, VELCADE 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 stem cell transplantation, you will receive VELCADE intravenously or subcutaneously in combination with dexamethasone, or with dexamethasone and thalidomide, as induction treatment.

When VELCADE is administered together with dexamethasone, you will receive a 21-day treatment cycle with VELCADE given intravenously or subcutaneously, and oral dexamethasone 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the 21-day VELCADE treatment cycle.
You will receive 4 cycles (12 weeks of treatment).

When VELCADE is administered together with thalidomide and dexamethasone, the treatment cycle lasts 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 VELCADE 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 subsequently be increased up to 200 mg daily starting from the second cycle onward. 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 VELCADE intravenously or subcutaneously in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone.

VELCADE 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 VELCADE 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 VELCADE treatment cycle.

How VELCADE is administered
This medicine is for intravenous or subcutaneous use. VELCADE will be administered by a healthcare professional experienced in the use of cytotoxic medicines.
The VELCADE 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 administered either in the thigh or the abdomen.

If you receive more VELCADE 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 everyone gets them. Some of these effects can be serious.
If you are being given VELCADE for multiple myeloma or mantle cell lymphoma, inform your doctor immediately if you notice 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 VELCADE 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 regular blood tests before and during treatment with VELCADE 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 apparent injury (for example, bleeding from the intestine, stomach, mouth and gums, or brain or liver haemorrhage)
• Red blood cells, which can 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 given VELCADE for the treatment of multiple myeloma, the possible side effects are listed below:
Very common side effects (may affect more than 1 in 10 people)

• Tingling, numbness, pins and needles, or burning sensation of the skin, or pain in the hands or feet due to nerve damage.
• Reduction 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, which may lead to fainting.
• Increased blood pressure.
• Reduced kidney function.
• Headache.
• General feeling of discomfort, 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.
• Herpes zoster infection (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.
• Heartburn, bloating, burping, 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.
• Body swelling, 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 bleeding from mucous membranes, for example mouth, vagina.
• Cerebrovascular disorders.
• Paralysis, seizures, falls, movement disorders, abnormal or reduced sensation (feeling, hearing, tasting, smelling), attention disorders, tremor, spasms.
• Arthritis, including inflammation of the joints in fingers, toes, and jaw.
• Lung disorders, impairing your body’s ability to receive sufficient oxygen. These may 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 salt and water reabsorption.
• 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 disorders, 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, oesophageal, stomach or intestinal ulcers, 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.
• Pancreatic inflammation, obstruction of bile ducts.
• Genital pain, erectile dysfunction.
• Weight gain.
• Feeling of thirst.
• Hepatitis.
• Injection site or catheter site reactions.
• Skin reactions or disorders (which may be severe and life-threatening), skin ulceration.
• 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, 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 nerve inflammation, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome).
• Hot flushes.
• Change in the colour of veins.
• Spinal nerve inflammation.
• Ear problems, bleeding from the ear.
• Reduced activity of the thyroid gland.
• Budd-Chiari syndrome (clinical signs caused by blockage of the liver veins).
• Altered or abnormal bowel function.
• Cerebral haemorrhage (bleeding in the brain).
• 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 other 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 cell) in the blood.
• Blood clotting 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 protein deposition in vital organs.
• Coma.
• Intestinal ulcers.
• Damage to multiple organs.
• Death.

If you are being given VELCADE in combination with other medicines for the treatment of 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, pins and needles, 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)

• Herpes zoster infection (localized, including around the eyes, or disseminated throughout the body).
• Herpes virus infection.
• Bacterial and viral infections.
• Respiratory infections, bronchitis, cough with phlegm, flu-like illness.
• Fungal infections.
• Hypersensitivity (allergic reaction).
• Inability to produce 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, 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.
• Body swelling, including swelling around the eyes and in other parts of the body.
• Chills.
• Redness and pain at the injection site.
• General feeling of discomfort.
• 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 your body’s ability to receive sufficient oxygen. These may include difficulty breathing, shortness of breath, laboured breathing even without physical activity, breathing becoming shallow, difficult or interrupted, 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 nerve inflammation, which may cause paralysis and breathing difficulties (Guillain-Barré syndrome).

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

5. How to store VELCADE

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 carton after EXP.
Store below 30°C. Keep the vial in the outer packaging to protect the medicine from light.
The reconstituted solution must be used immediately after preparation. If the reconstituted solution is not used immediately, the conditions and duration of storage are the responsibility of the preparer. However, the reconstituted solution is stable for 8 hours at 25°C prior to administration when stored in the original vial and/or in a syringe, with a maximum storage time for the reconstituted medicine not exceeding 8 hours.
VELCADE 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 VELCADE contains

• The active substance is bortezomib. Each vial contains 3.5 mg of bortezomib (as mannitol boronic ester). After reconstitution, 1 ml of injectable solution contains 1 mg of bortezomib.
• The excipients are mannitol (E421) and nitrogen.

Reconstitution for intravenous use: after reconstitution, 1 ml of intravenous injection solution contains 1 mg of bortezomib.
Reconstitution for subcutaneous use: after reconstitution, 1 ml of subcutaneous injection solution contains 2.5 mg of bortezomib.

Description of the appearance of VELCADE and contents of the pack
VELCADE powder for injectable solution is white to off-white in colour.
Each pack of VELCADE 3.5 mg contains one 10 ml glass vial with a blue closure cap, packed in a transparent blister.

Marketing Authorisation Holder:
JANSSEN-CILAG INTERNATIONAL NV
Turnhoutseweg, 30
B-2340 Beerse
Belgium

Manufacturer
Janssen Pharmaceutica NV
Turnhoutseweg, 30
B-2340 Beerse
Belgium

For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

België/Belgique/Belgien Lietuva
Janssen-Cilag NV UAB "JOHNSON & JOHNSON"
Tel/Tél: +32 14 64 94 11 Tel: +370 5 278 68 88
[email protected] [email protected]

България Luxembourg/Luxemburg
„Джонсън & Джонсън България” ЕООД Janssen-Cilag NV
Тел.: +359 2 489 94 00 Tél/Tel: +32 14 64 94 11
[email protected] [email protected]

Česká republika Magyarország
Janssen-Cilag s.r.o. Janssen-Cilag Kft.
Tel: +420 227 012 227 Tel.: +36 1 884 2858
[email protected]

Danmark Malta
Janssen-Cilag A/S AM MANGION LTD
Tlf.: +45 4594 8282 Tel: +356 2397 6000
[email protected]

Deutschland Nederland
Janssen-Cilag GmbH Janssen-Cilag B.V.
Tel: 0800 086 9247 / +49 2137 955 6955 Tel: +31 76 711 1111
[email protected] [email protected]

Eesti Norge
UAB "JOHNSON & JOHNSON" Eesti filiaal Janssen-Cilag AS
Tel: +372 617 7410 Tlf: +47 24 12 65 00
[email protected] [email protected]

Ελλάδα Österreich
Janssen-Cilag Φαρμακευτική Μονοπρόσωπη Janssen-Cilag Pharma GmbH
Α.Ε.Β.Ε. Tel: +43 1 610 300
Tηλ: +30 210 80 90 000

España Polska
Janssen-Cilag, S.A. Janssen-Cilag Polska Sp. z o.o.
Tel: +34 91 722 81 00 Tel.: +48 22 237 60 00
[email protected]

France Portugal
Janssen-Cilag Janssen-Cilag Farmacêutica, Lda.
Tél: 0 800 25 50 75 / +33 1 55 00 40 03 Tel: +351 214 368 600
[email protected]

Hrvatska România
Johnson & Johnson S.E. d.o.o. Johnson & Johnson România SRL
Tel: +385 1 6610 700 Tel: +40 21 207 1800
[email protected]

Ireland Slovenija
Janssen Sciences Ireland UC Johnson & Johnson d.o.o.
Tel: 1 800 709 122 Tel: +386 1 401 18 00
[email protected] [email protected]

Ísland Slovenská republika
Janssen-Cilag AB Johnson & Johnson, s.r.o.
c/o Vistor hf. Tel: +421 232 408 400
Sími: +354 535 7000
[email protected]

Italia Suomi/Finland
Janssen-Cilag SpA Janssen-Cilag Oy
Tel:800.688.777 / +39 02 2510 1 Puh/Tel: +358 207 531 300
[email protected] [email protected]

Κύπρος Sverige
Βαρνάβας Χατζηπαναγής Λτδ Janssen-Cilag AB
Τηλ: +357 22 207 700 Tfn: +46 8 626 50 00
[email protected]

Latvija United Kingdom
UAB "JOHNSON & JOHNSON" filiāle Latvijā (Northern Ireland)
Tel: +371 678 93561 Janssen Sciences Ireland UC
[email protected] Tel: +44 1 494 567 444
[email protected]

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

The following information is intended for healthcare professionals only.

1. RECONSTITUTION FOR INTRAVENOUS INJECTION

Note: VELCADE is a cytotoxic agent. Therefore, special 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 FOLLOWED DURING THE HANDLING OF VELCADE.
1.1 Preparation of the 3.5 mg vial: carefully add 3.5 ml of sterile sodium chloride 9 mg/ml (0.9%) injection solution to the vial containing the VELCADE 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 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 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 must be discarded.
Confirm the concentration on the vial label to ensure that the correct dose is administered by intravenous route (1 mg/ml).
1.3 The reconstituted solution contains no preservatives and must be used immediately after preparation, although it is chemically and physically stable for up to 8 hours at 25°C in the original vial and/or in a syringe, with a maximum of 8 hours in a syringe. The total storage time of the reconstituted medicinal product must not exceed 8 hours before administration. If the reconstituted solution is not used immediately after preparation, it is the responsibility of the user to ensure that the storage conditions and duration comply with the product requirements 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 labeled for intravenous administration).
• Inject the solution intravenously as a bolus over 3–5 seconds through a peripheral or central intravenous catheter.
• Flush the intravenous catheter with sterile injectable 9 mg/ml (0.9%) sodium chloride solution.

VELCADE 3.5 mg powder for injectable solution is for SUBCUTANEOUS or
INTRAVENOUS use ONLY. 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 material from this medicine must be disposed of in accordance with
local regulations.
The following information is intended for healthcare professionals only:
Only the 3.5 mg vial can be administered by subcutaneous route as described below.

1. RECONSTITUTION FOR SUBCUTANEOUS INJECTION

Note: VELCADE is a cytotoxic agent. Therefore, special 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 FOLLOWED DURING HANDLING OF VELCADE.

1.1 Preparation of the 3.5 mg vial: carefully add 1.4 ml of sterile injectable sodium chloride solution 9 mg/ml (0.9%) to the vial containing the VELCADE 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 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.
Confirm the concentration on the vial label to ensure that the correct dose is administered by subcutaneous route (2.5 mg/ml).

1.3 The reconstituted solution contains no preservatives and must be used immediately after preparation, although it is chemically and physically stable for up to 8 hours at 25°C in the original vial and/or in a syringe, with a maximum of 8 hours in a syringe. The total storage time of the reconstituted medicinal product must not exceed 8 hours prior to administration. If the reconstituted solution is not used immediately after preparation, it is the responsibility of the user to ensure appropriate storage conditions and storage times before 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 labeled 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, rotate the injection site.
• If local reactions at the injection site occur after subcutaneous injection of VELCADE, a lower concentration of VELCADE 3.5 mg solution may be administered (1 mg/ml instead of 2.5 mg/ml), or switching to intravenous administration is recommended.

VELCADE 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
local regulations.