VELCADE 3.5 mg powder for solution for injection

VELCADE contains the active substance bortezomib, a so-called ?proteasome inhibitor?. Proteasomes play an important role in controlling cell function and growth. By interfering with their function, bortezomib can kill cancer cells.

VELCADE is used for the treatment multiple myeloma (a cancer of the bone marrow) in adults:

• in combination with other medicines containing melphalan and prednisone, for patients who have not been previously treated for multiple myeloma and are unsuitable for high-dose chemotherapy with bone marrow transplant.
• alone (monotherapy) for patients whose disease is worsening (progressive) after receiving at least one prior treatment and for whom. bone marrow transplantation was not successful or is unsuitable.

Do not use VELCADE

• if you are allergic (hypersensitive) to the active substance or to any of the other ingredients of VELCADE
• if you have severe liver problems
• if you have certain severe pulmonary or heart problems.

Take special care with VELCADE

You should tell your doctor if you have any of the following:

• low numbers of red or white blood cells
• bleeding problems and/or low number of platelets in your blood
• diarrhoea, constipation, nausea or vomiting
• fainting, dizziness or light-headedness in the past.
• kidney problems
• liver problems.
• numbness, tingling, or pain in the hands or feet (neuropathy) in the past.
• heart or blood pressure problems.
• shortness of breath or cough

You will have to take regular blood tests before and during your treatment with VELCADE, to check your blood cell counts regularly.

VELCADE should not be used in children and adolescents, due to limited experience.

Using other medicines

Please tell your doctor, or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
In particular, tell you doctor if you are using medicines containing any of the following active substances:

• ketoconazole, used to treat fungal infections
• rifampicin, and antibiotic used to treat bacterial infections
• oral antidiabetics

Pregnancy and breast-feeding
You should not use VELCADE if you are pregnant, unless clearly necessary.

Both men and women receiving VELCADE must use effective contraception during and for up to 3 months after treatment. If, despite these measures, pregnancy occurs, tell your doctor immediately.

You should not breast-feed while using VELCADE. Discuss with your doctor when it is safe to restart breast-feeding after finishing your treatment.

Driving and using machinesVELCADE might cause tiredness, dizziness, fainting, or blurred vision. Do not drive or operate any dangerous tools or machines if you experience such side effects; even if you do not, you should still be cautious.

Your doctor will work out your dose of VELCADE according to your height and weight (body surface

area). The usual starting dose is 1.3 mg/m 2 body surface area.
Your doctor may change the dose and total number of cycles, depending on your response to the treatment on the occurrence of certain side effects and on your underlying conditions.

MonotherapyWhen VELCADE is given alone, one cycle of treatment with VELCADE consists of a total of 4 doses. Doses are given on days 1, 4, 8 and 11, followed by a 10-day ?rest period? without treatment. Therefore, the duration of a treatment cycle is 21 days (3 weeks).

Combination therapy
If you have not been treated before for multiple myeloma, you will receive VELCADE together with two other medicines containing melphalan and prednisone.
In this case, the duration of a cycle is 6 weeks. The treatment consists of a total of 9 cycles (54 weeks). In Cycles 1-4, VELCADE is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, VELCADE is administered once weekly (days 1, 8, 22 and 29). Melphalan and prednisone are both given orally on days 1, 2, 3 and 4 of the first week of each cycle.

How VELCADE is given

You will receive VELCADE in a specialised medical unit, under the supervision of a health care professional experienced in the use of cytotoxic medicinal products.
VELCADE powder has to be dissolved before administration. This will be done by a healthcare professional. The resulting solution is then injected into a vein rapidly, over 3 to 5 seconds.

Like all medicines, VELCADE can cause side effects, although not everybody gets them. Some of these effects may be serious.

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

• platelets, which may make you be more prone to bruising, or to bleeding without obvious injury (e.g. bleeding from your bowels, stomach, mouth and gum or bleeding in the brain or bleeding from the liver).
• red blood cells, which can cause anaemia, with symptoms such as tiredness and paleness
• white blood cells may make you more prone to infections or flu-like symptoms.

Side effects may occur with certain frequencies, which are defined as follows:

• very common: affects more than 1 user in 10
• common: affects 1 to 10 users in 100
• uncommon: affects 1 to 10 users in 1,000
• rare: affects 1 to 10 users in 10,000
• very rare: affects less than 1 user in 10,000
• not known: frequency cannot be estimated from the available data

Very common side effects

• Sensitivity, numbness, tingling or burning sensation of the skin, or pain in the hands or feet, due to nerve damage.
• Reduction in the number of red blood cells and or white blood cells (see above)
• Fever, shivering fits
• Shortness of breath without exercise
• Feeling sick (nausea) or vomiting, loss of appetite
• Constipation with or without bloating (can be severe),
• Diarrhoea: if this happens, it is important that you drink more water than usual. Your doctor may give you another medicine to control diarrhoea .
• Muscle pain
• Tiredness
• Headache
• Herpes zoster infection (including disseminated)

Common side effects

• Sudden fall of blood pressure on standing which may lead to fainting
• Depression which may be severe, confusion
• Swelling around the eyes or face (which may rarely be due to a serious allergic reaction), or swelling in the ankles, wrists, arms or legs.
• General ill feeling, dizziness, light-headedness, or a feeling of weakness
• Changes in potassium in your blood, too much sugar in your blood
• Chest pains or coughing with phlegm, shortness of breath with exercise
• Different types of rash and/or itching, lumps on the skin or dry skin
• Redness of the skin or redness and pain at the injection site
• Dehydration
• Heartburn, bloating, belching, wind or stomach pain
• A sore mouth or lip, dry mouth, mouth ulcers or throat pain
• Weight loss, loss of taste
• Muscle cramps, bone pain, pain in your limbs or back
• Blurred vision
• Nose bleeds
• Difficulty in sleeping, sweating, anxiety
• Overtiredness (fatigue)

Uncommon side effects

• Palpitations (sensation of rapid or irregular heart beat), changes in heart beat, heart failure, heart attack, chest pain, chest discomfort or decreased ability of the heart to work
• Bleeding from your bowels or stomach, bloody stools, bleeding in the brain, bleeding from the liver or bleeding from mucosal membranes e.g. mouth
• Paralysis, seizures
• Breathing becomes shallow, difficult or stops, wheezing, difficulty in breathing, cough that produces frothy sputum that may be tinged with blood or coughing blood
• Increased or decreased urine production (due to kidney damage), painful passing of urine or blood/proteins in the urine
• Yellow discolouration of eyes and skin (jaundice)
• Loss of attention, restlessness or agitation, changes in your mental status, mood swings
• Facial blushing or tiny broken capillaries
• Hearing loss, deafness or ringing in the ears
• Changes in calcium, sodium, magnesium, and phosphates in your blood, too little sugar in your blood
• Hormone abnormality affecting salt and water absorption
• Irritated eyes, excessively wet or dry eyes, discharge from the eyes, abnormal vision, eye infections (including herpes zoster), bleeding of the eye or sensitivity to light
• Swelling of your lymph nodes
• Joint or muscle stiffness, muscle spasms or twitching, pain in your bottom
• Hair loss
• Allergic reactions
• Mouth pain, retching
• Abdominal pain
• Weight increase
• Severe skin reactions, which may have blisters and involve the mouth, throat, eyes and genitals, that can be life-threatening (Stevens Johnson Syndrome and toxic epidermal necrolysis).
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a severe reversible brain condition which includes seizures, high blood pressure, headaches, tiredness, confusion, blindness or other vision problems.

Rare

• Inflammation of the lining around your heart
• Inflammation of the blood vessels that can appear as small red or purple dots (usually on the legs) to bruise-like patches on the skin.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist immediately.

Keep out of the reach and sight of children.

Do not store above 30°C. Keep the vial in the outer carton in order to protect from light.

Do not use after the expiry date stated on the vial and the carton after EXP.

The reconstituted solution should be used immediately after preparation. If the reconstituted solution is not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. However, the reconstituted solution is stable for 8 hours at 25 °C in the original vial and/or a syringe prior to administration, with a maximum of 8 hours in the syringe.

What VELCADE contains

• The active substance is bortezomib. Each vial contains 1 mg or 3.5 mg of bortezomib (as a mannitol boronic ester). After reconstitution, 1 ml of solution for injection contains 1 mg bortezomib.
• The other ingredients are mannitol (E421) and nitrogen.

What VELCADE looks like and contents of the pack

VELCADE powder for solution for injection is a white to off-white cake or powder.

Each carton of VELCADE 1 mg powder for solution for injection contains a glass vial with a green cap, in a transparent blister pack.

Each carton of VELCADE 3.5 mg powder for solution for injection contains a glass vial with a royal blue cap, in a transparent blister pack.

Marketing Authorization Holder

JANSSEN-CILAG INTERNATIONAL N.V.
Turnhoutseweg, 30
B-2340 Beerse
Belgium

Manufacturer

Janssen Pharmaceutica N.V.
Turnhoutseweg 30
B-2340 Beerse
Belgium

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

BelgiëBelgiqueBelgien JANSSEN-CILAG NVSA Antwerpseweg 15-17 B-2340 Beerse TélTel 32 14 64 94 11 LuxembourgLuxemburg JANSSEN-CILAG NVSA Antwerpseweg 15-17 B-2340 Beerse BelgiqueBelgien Tél 32 14 64 94 11

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JANSSEN-CILAG .... 56 GR-151 21 T 30 210 80 90 000 Polska JANSSENCILAG POLSKA SP. Z O.O., WINIOWY BUSINESS PARK BUILDING F UL. IECKA 24 02-135 WARSAW POLAND Tel. 48 22 237 60 00

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Slovenija Johnson Johnson d.o.o. martinska cesta 53 SI-1000, Ljubljana Tel. 386 1 401 18 30 Ireland JANSSEN-CILAG Ltd. 50-100 Holmers Farm Way High Wycombe Buckinghamshire HP12 4EG United Kingdom Tel 44 1 494 567 567

Slovenská republika Johnson Johnson s.r.o. Plynárenska 7B SK- 824 78 Bratislava 26 Tel 421 233 552 600 Ísland JANSSEN-CILAG co Vistor Hörgatún 2 IS-210 Garðabær Sími 354 535 7000

Italia JANSSEN-CILAG SpA Via M.Buonarroti, 23 I-20093 Cologno Monzese MI Tel 39 022510.1 SuomiFinland JANSSEN-CILAG OY VaisalantieVaisalavägen 2 FIN-02130 EspooEsbo PuhTel 358 20 753 1300

7 CY-1060 T 357 22 755 214 Sverige JANSSEN-CILAG AB Box 7073 S-192 07 Sollentuna Tel 46 8 626 50 00

Latvija United Kingdom

JANSSEN-CILAG Polska Sp. z o.o. fili-le Latvij- JANSSEN-CILAG Ltd.
Matro-u iela 15, LV-1048, R-ga 50-100 Holmers Farm Way T-lr. +371 678 93561 High Wycombe
Buckinghamshire HP12 4EG - UK Tel: +44 1 494 567 567

Lietuva

UAB ?Johnson & Johnson?
Gele-inio Vilko g. 18A
LT-08104 Vilnius
Tel: +370 5 278 68 88

This leaflet was last approved in

This medicinal product has been authorised under ?Exceptional Circumstances?. This means that for scientific reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMA) will review any new information which may become available every year and this leaflet will be updated as necessary.

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INFORMATION FOR MEDICAL OR HEALTHCARE PROFESSIONALS ONLY:

1. RECONSTITUTION

Note: VELCADE is a cytotoxic agent. Therefore, caution should be used during handling and preparation. Use of gloves and other protective clothing to prevent skin contact is recommended.

ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF VELCADE SINCE NO PRESERVATIVE IS PRESENT.

1.1. a) Preparation of the 1 mg vial: add 1.0 ml of sterile, 9 mg/ml (0.9%) sodium chloride

solution for injection to the vial containing the VELCADE powder.

b) Preparation of the 3.5 mg vial: add 3.5 ml of sterile, 9 mg/ml (0.9%) sodium chloride solution for injection to the vial containing the VELCADE powder.

The concentration of the resulting solution will be 1 mg/ml. The solution will be clear and colourless, with a final pH of 4 to 7. You do not need to check the pH of the solution.

1.2. Before administration, visually inspect the solution for particulate matter and discolouration. If

any discolouration or particulate matter is observed, the reconstituted product should be discarded.

1.3. The reconstituted product is preservative free and should be used immediately after preparation.

However, the chemical and physical in-use stability has been demonstrated for 8 hours at 25 °C stored in the original vial and/or a syringe prior to administration, with a maximum of 8 hours in the syringe. If the reconstituted solution is not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

It is not necessary to protect the reconstituted medicinal product from light.

2. ADMINISTRATION

• Check the dose in the syringe.
• Inject the solution as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter into a vein.
• Flush the peripheral or intravenous catheter with sterile, 9 mg/ml (0.9%) sodium chloride solution.

3. DISPOSAL

A vial is for single use only and remaining solution must be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.