InfoCons Consumer Protection informs you – VELCADE – Package Leaflet

Before anything else

Read all of this leaflet carefully before you start using this medicine because it contains important information for you .

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• If you get any side effects, talk to your doctor or pharmacist. This includes anyside effects not listed in this leaflet. See section 4.

What is i n this leaflet:

1. What VELCADE is and what it is used for 2. What you need to know b efore you use VELCADE 3. How to use VELCADE 4. Possible side effects 5. How to store V ELCADE 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 function and gro wth. By interfering with their function, bortezomib can kill cancer cells .

VELCADE is used for the treatment of multiple myeloma (a cancer of the bone marrow) in patients older than 1 8years :

• alone or together with the medicines pegylated liposomal doxoru bicin or dexamethasone , for patients whose disease is worsening (progressive) after receiving at least one prior treatment and for whom blood stem cell transplantation was not successful or is unsuitable.
• in combination with the medicines melphalan and pre dnisone, for patients whose disease has not been previously treated and are unsuitable for high -dose chemotherapy with blood stem cell transplantation.
• incombination with the medicines dexamethasone or dexamethasone together with thalidomide, for patients whose disease has not been previously treated and before receiving high-dose chemotherapy with blood stem cell transplantation (induction treatment).

VELCADE is used for the treatment of mantle cell lymphoma ( a type of cancer affecting the lymph nodes ) in patients 18 years or older in combination with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone, for patients whose disease has not been previously treated and for whom blood stem cell transplantation is unsuitable.

2. What you nee d to know before you use VELCADE

Do not use VELCADE

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

Warnings and precautions

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 78 fainting, dizziness or light -headedness in the past  kidney problems  moderate to severe 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  seizures  shingles (locali sed including around the eyes or spread across the body)  symptoms of tumo ur lysis syndrome such as muscle cramping, muscle weakness, confusion, visual loss or disturbances and shortness of breath  memory loss, trouble thinking, difficulty with walking or loss of vision. These may be signs of a serious brain infection and your doctor may suggest further testing and follow -up.

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

If you have mantle cell lymphoma and are given the m edicine rituximab with VELCADE you should tell your doctor:  if you think you have hepatitis infection now or have had it in the past. In a few cases, patients who have had hepatitis B might have a repeated attack of h epatitis, which can be fatal. I fyou have a history of hepatitis B infection you will be carefully checked by your doctor for signs of active hepatitis B.

You must read the package leaflets of all medicinal products to be taken in combination with VELCADE for information related to these medic inesbefore starting treatment with VELCADE .

When thalidomide is used ,particular attention to pregnancy testing and prevention require ments is needed (see Pregnancy and breast -feeding in this section ).

Children and adolescents

VELCADE should not be used in children and adolescents because it is not known how the medicine will affect them .

Other medicines and VELCADE

Please tell your doctor, or pharmacist if you are taking ,have recently taken or might take any other medicines.

In particular, tell you rdoctor if you are using 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, pheny toin or phenobarbital used to treat epilepsy
• St.John’s Wort (Hypericum perforatum ),used for depression or other conditions
• oral antidiabetics Pregnancy and breast -feeding You should not use VELCADE if you are pregnant, unless clearly necessary.

Wom en of childbearing potential must use effective contraception during treatment and for 8 months following completion of treatment. Talk to your doctor if you wish to freeze your eggs before starting treatment.

Men should not father a child while using V ELC ADE andshould use effective contraception during treatment and for up to 5 months after treatment has stopped. Talk to your doctor if you wish to conserve your sperm before starting treatment.

79You should not breast -feed while using VELCADE. Discuss wit h your doctor when it is safe to restart breast -feeding after finishing your treatment.

Thalidomide causes birth defects and foetal death. When VELCADE is given in combination with thalidomide you must follow the pregnancy prevention programme for thalido mide (see package leaflet for thalidomide).

Driving and using machines

VELCADE might cause tiredness, dizziness, fainting, or blurred vision. Do not drive or operate tools or machines if you experience such side effects; even if you do not, you should sti ll be cautious.

3. How to use VELCADE Your doctor will work out your dose of VELCADE according to your height and weight (body surface area). The usual starting dose of VELCADE is 1.3 mg/m2body surface area twice a week .

Your doctor may change the dose and total number of treatment cycles, depending on your response to the treatment on the occurrence of certain side effects and on your underlying conditions (e.g. liver problems) .

Progressive multiple myeloma When VELCADE is given alone, you will receiv e 4doses of VELCADE intravenously on days 1, 4, 8 and 11, followed by a 10 -day ‘rest period’ without treatment. Th is 21-dayperiod (3weeks) corresponds to one treatment cycle. You might receive up to 8 cycles (24 weeks).

You may also be given VELCADE to gether with the medicines pegylated liposomal doxorubicin or dexamethasone .

When VELCADE is given together with p egylated liposomal doxorubicin , you will receive VELCADE intravenously as a21-daytreatment cycle and p egylated liposomal doxorubicin 30mg/m2 is given on day 4 of the VELCADE 21-daytreatment cycle as an intravenous infusion after the VELCADE injection.

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

When VELCADE is given together with dexamethasone, you will receive VELCADE intravenously as a21-daytreatment cycle and dexamethasone 20 mg is given orally on days 1, 2, 4, 5, 8, 9, 11, and 12, of the VELCADE, 21-daytreatment cycle.

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

Previously untreated multiple myeloma If you have not been treated bef ore for multiple myeloma, and you are not suitable for blood stem cell transplantation you will receive VELCADE intravenously together with two other medicines; melphalan and prednisone.

In this case, the duration of a treatment cycle is 42 days (6 weeks). You will receive 9 cycles (54weeks).  In cycles 1 to 4, VELCADE is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32.  In cycles 5 to 9, VELCADE is administered once weekly on days 1, 8, 22 and 29.

Melphalan (9mg/m2) and prednisone (60mg/m2)are both given orally on days 1, 2, 3 and 4 of the first week of each cycle.

If you have not been treated before for multiple myeloma, and you are suitable for blood stem cell transplantation you will receive VELCADE intravenously together with the med icines dexamethasone, or dexamethasone and thalidomide, as induction treatment.

When VELCADE is given together with dexamethasone, you will receive VELCADE intravenously as a21-daytreatment cycle and d examethasone 40 mg is given orally on days 1, 2, 3 ,4,8, 9, 10 and 11 of the VELCADE 21-daytreatment cycle.

80You will receive 4 cycles (12 weeks).

When VELCADE is given together with thalidomide and dexamethasone ,the duration of a treatment cycle is 28 days (4 weeks).

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

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

Previously untreated mantle cell lymphoma If you have not been treated before for mantle cell lymphoma you will receive VELCADE intravenously together with the m edicines rituximab, cyclophosphamide, doxorubicin and prednisone.

VELCADE is given intravenously on days 1, 4, 8 and 11, followed by a ‘rest period’ without treatment. The duration of a treatment cycle is 21 days (3 weeks). You might receive up to 8 cycles (24weeks).

The following medicinal products are given on day 1 of each VELCADE 21-daytreatment cycle as intravenous infusions:

Rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2and doxorubicin at 50 mg/m2.

Prednisone is given orally at 100 mg/m2on days 1, 2, 3, 4 and 5 of the VELCADE treatment cycle.

How VELCADE is given This medicine is for intravenous use only. VELCADE will be administered bya health care professional experienced in the use of cytotoxic medic ines.

VELCADE powder has to be dissol ved before administration. This will be done by a healthcare professional. The resulting solution is then injected into a vein rapidly, over 3 to 5seconds.

If you are given too much VELCADE As this medicine is being given by your doctor or nurse, it is u nlikely that you will be given too much.

In the unlikely event of an overdose ,your doctor will monitor you for side effects.

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

If you are given VELCADE for multiple myeloma or mantle cell lymphoma, tell your doctor straight away if you notice any of the following symptoms :

• muscle cramping, muscle weakness
• confusion, visual loss or disturbances, blindne ss, seizures, headaches
• shortness of breath, swelling of your feet or changes in your heart beat, high blood pressure, tiredness, fainting
• coughing and breathing difficulties or tightness in the chest.

Treatment with VELCADE can very commonly cause a decr ease 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 t he 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 anae mia, with symptoms such as tiredness and paleness
• white blood cells may make you more prone to infections or flu -like symptoms .

81If you are given VELCADE for the treatment of multiple myeloma the side effects you may get are listed below:

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

 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  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  Tiredness (f atigue), feeling weak  Muscle pain, bone pain

Common side effects ( may affect up to 1 in10people )

 Low blood pressure, s udden fall of blood pressure on standing which may lead to fainting  High blood pressure  Reduced functioning of your kidneys  Headache  General ill feeling, pain, vertigo , light -headedness, a feeling of weakness or loss of consciousness  Shivering  Infections, including pneumonia, respiratory infections, bronchitis, fungal infections, coughing with phlegm, flu like illness  Shingles (locali sed including around the eyes or spread across the body)  Chest pains or shortness of breath with exercise  Different types of rash  Itching of the skin, lumps on the skin or dry skin  Facial blushing or tiny broken capillaries  Redness of the skin  Dehydration  Hear tburn, bloating, belching, wind, stomach pain, bleeding from your bowels or stomach  Alteration of liver functioning  A sore mouth or lip, dry mouth, mouth ulcers or throat pain  Weight loss, loss of taste  Muscle cramps, muscle spasms, muscle weakness, pain i n your limbs  Blurred vision  Infection of the outermost layer of the eye and the inner surface of the eyelids (conjunctivitis)  Nose bleeds  Difficulty or problems in sleeping, sweating, anxiety, mood swings, depressed mood, restlessness or agitation, changes in your mental status, disorientation  Swelling of body, to include around eyes and other parts of the body

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

 Heart failure, h eart attack, chest pain, chest discomfort , increased or reduced heart rate  Failing of your kidneys  Inflammation of a vein, blood clots in your veins and lungs  Problems with blood clotting  Insuffici ent circulation  Inflammation of the lining around your heart or fluid around your heart  Infections including urinary tract infections , the flu, herpes virus infections, ear infection and cellulitis  Bloody stools, or bleeding fr om mucosal membranes, e.g., mouth, vagina  Cerebrovascular disorders 82 Paralysis, seizures, falling, movement disorders, abnormal or change in, or reduced sensati on (feeling, hearing, tasting, smelling) , attention disturbance, trembling , twitching  Arthritis, including inflammation of the joints in the fingers, toes, and the jaw  Disorders that affect your lungs, preventing your body from getting enough oxygen. Some of these include difficulty breathing, shortness of breath, shortness of breath without exercise, breathing that becomes shallow, difficult or stops, wheezing  Hiccups, speech disorders  Increased or decreased urine production (due to kidney damage), painful pa ssing of urine or blood/proteins in the urine, fluid retention  Altered levels of consciousness, confusion , memory impairment or loss  Hypersensitivity  Hearing loss, deafness or ringing in the ears , ear discomfort  Hormone abnormality which may affect salt an d water absorption  Overactive thyroid gland  Inability to produce enough insulin or resistance to normal levels of insulin  Irritated or inflamed eyes, excessively wet eyes, painful eyes, dry eyes, eye infections ,lump in the eyelid (chalazion) , red and swol len eyelids , discharge from the eyes, abnormal vision, bleeding of the eye  Swelling of your lymph glands  Joint or muscle stiffness, sense of heaviness, pain in your groin  Hair loss and abnormal hair texture  Allergic reactions  Redness orpain at the injecti on site  Mouth pain  Infections or inflammation of the mouth, mouth ulcers, oesophagus, stomach and intestines, sometimes associated with pain or bleeding, poor movement of the intestines (including blockage), abdominal or oesophageal discomfort, difficulty swallowing, vomiting of blood  Skin infections  Bacterial and viral infections  Tooth infection  Inflammation of the pancreas, obstruction of the bile duct  Genital pain, problem having an erection  Weight increase  Thirst  Hepatitis  Injection site or injection de vice related disorders  Skin reactions and disorders (which may be severe and life threatening), skin ulcers  Bruises, falls and injuries  Inflammation or haemorrhage of the blood vessels that can appear as small red or purple dots (usually on the legs) to la rge bruise -like patches under the skin or tissue  Benign cysts  Asevere reversible brain condition which includes seizures, high blood pressure, headaches, tiredness, confusion, blindness or other vision problems.

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

 Heart problems to include heart attack, angina  Serious nerve inflammation, which may cause paralysis and difficulty breathing (Guillain -Barré syndrome)  Flushing  Discolo uration of the veins  Inflammation of the spinal nerve  Problems with your ea r, bleeding from your ear  Underactivity of your thyroid gland  Budd –Chiari syndrome (the clinical symptoms caused by blockage of the hepatic veins) 83 Changes in or abnormal bowel function  Bleeding in the brain  Yellow discolouration of eyes and skin (jaundice)  Serious allergic reaction (anaphylactic shock) signs of which may include difficulty breathing, chest pain or chest tightness, and/ or feeling dizzy/faint, severe itching of the skin or raised lumps on the skin, swelling of the face, lips, tongue and /or t hroat, which may cause difficulty in swallowing ,collapse  Breast disorders  Vaginal tears  Genital swelling  Inability to tolerate alcohol consumption  Wasting, or loss of body mass  Increased appetite  Fistula  Joint effusion  Cysts in the lining of joints (synov ial cysts)  Fracture  Breakdown of muscle fibers leading to other complications  Swelling of the liver, bleeding from the liver  Cancer of the kidney  Psoriasis like skin condition  Cancer of the skin  Paleness of the skin  Increase of platelets or plasma cells (a type of white cell) in the blood  Blood clot in small blood vessels (thrombotic microangiopathy)  Abnormal reaction to blood transfusions  Partial or total loss of vision  Decreased sex drive  Drooling  Bulging eyes  Sensitivity to light  Rapid breathing  Rectal p ain  Gallstones  Hernia  Injuries  Brittle or weak nails  Abnormal protein deposits in your vital organs  Coma  Intestinal ulcers  Multi -organ failure  Death If you are given VELCADE together with other medicines for the treatment of mantle cell lymphoma the side effects you may get are listed below:

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

 Pneumonia  Loss of appetite  Sensitivity, 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 84 Constipation  Muscle pain, bone pain  Hair loss and abnormal hair texture  Tiredness, feeling weak  Fever

Common side effects ( may affect up to 1 in10people )

 Shingles (locali sed including around the eyes or spread across the body)  Herpes virus infections  Bacterial and viral infections  Respiratory infections, bronchitis, coughing with phlegm, flu like illness  Fungal infections  Hypersensitivity (allergic reaction)  Inability to produce enough insulin or resistance to normal level s of insulin  Fluid retention  Difficulty or problems in sleeping  Loss of conciousness  Altered level of consciousness, confusion  Feeling dizzy  Increased heartbeat, high blood pressure, sweating,  Abnormal vision, blurred vision  Heart failure, heart attack, ch est pain, chest discomfort, increased or reduced heart rate  High or low blood pressure  Sudden fall of blood pressure upon standing which may lead to fainting  Shortness of breath with exercise  Cough  Hiccups  Ringing in the ears, ear discomfort  Bleeding from your bowels or stomach  Heartburn  Stomach pain ,bloating  Difficulty swallowing  Infection or inflammation of the stomach and intentines  Stomach pain  Sore mouth or lip, throat pain  Alteration of liver function  Itching of skin  Redness of skin  Rash  Muscle spasm s  Infection of the urinary tract  Pain in limbs  Swelling of body, to include eyes and other parts of the body  Shivering  Redness and pain at injection site  General ill feeling  Weight loss  Weight increase

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

 Hepatitis  Severe allergic reaction (anaphylactic reaction )signs of which may include difficulty breathing, chest pain or chest tightness, and/or feeling dizzy/faint, severe itching of the skin or raised 85lumps on the skin, swelling of the face, lips, t ongue and /or throat, which may cause difficulty in swallowing, collapse  Movement disorders, paralysis, twitching  Vertigo  Hearing loss, deafness  Disorders that affect your lungs, preventing your body from getting enough oxygen. Some of these include diffic ulty breathing, shortness of breath, shortness of breath without exercise, breathing that becomes shallow, difficult or stops, wheezing  Blood clots in your lungs  Yellow discolo uration of the eyes and skin (jaundice)  Lump in the eyelid (chalazion), red and swollen eyelids

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

 Blood clot in small blood vessels (thrombotic microangiopathy )  Serious nerve inflammation, which may cause paralysis and difficulty breathing (Guillain -Barré syndrome) Reporting of si de effects If you get any side effects, talk to your doctor or pharmacist .This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting si de 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 the carton after E XP.

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

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

VELCADE is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

6. Contents of the pack and other information

What VELCADE contains

• The active substance is bortezomib. Each vial contains 1 mg of bortezomib (as a mannitol boronic ester). After reconstitution, 1ml 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

VELCAD E 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.

86Marketing Authori sation Holder JANSSEN -CILAG INTERNATIONAL NV Turnhoutseweg 30 B-2340 Beerse Belgium

Manufacturer

Janssen Pharmaceutica NV Turnhoutseweg 30 B-2340 Beerse Belgium For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

België/Belgique/Belgien Janssen -Cilag NV Tel/Tél:+32 14 64 94 11 [email protected] UAB “JOHNSON & JOHNSON ” Tel: +370 5 278 68 88 [email protected] България „Джонсън & Джонсън България” ЕООД Тел.: +359 2 489 94 00 [email protected]/Luxemburg Janssen -Cilag NV Tél/Tel: +32 14 64 94 11 [email protected] Česká republika Janssen -Cilag s.r.o.

Tel: +420 227 012 227Magyarország Janssen -Cilag Kft.

Tel.: +36 1 884 2858 [email protected] Danmark Janssen -Cilag A/S Tlf.: +45 4594 8282 [email protected] AM MANGION LTD Tel: +356 2397 6000 Deutschland Janssen -Cilag GmbH Tel: 0800 086 9247 / +49 2137 9556955 [email protected] Janssen -Cilag B.V.

Tel: + 31 76 711 1111 [email protected] Eesti UAB “JOHNSON & JOHNSON” Eesti filiaal Tel: +372 617 7410 [email protected] Janssen -Cilag AS Tlf: +47 24 12 65 00 [email protected] Ελλάδα Janssen -Cilag Φαρμακευτική Μονοπρόσωπη Α.Ε.Β.Ε.

Tηλ: +30 210 80 90 000Österreich Janssen -Cilag Pharma GmbH Tel:+43 1 610 300 España Janssen -Cilag , S.A.

Tel: +34 91 722 81 00 [email protected] Polska Janssen -Cilag Polska Sp. z o.o.

Tel.: +4 8 22 237 60 00 87France Janssen -Cilag Tél: 0 800 25 50 75 / +33 1 55 00 4003 [email protected] Janssen -Cilag Farmacêutica, Lda .

Tel: +351 214 368 600 Hrvatska Johnson & Joh nson S.E. d.o.o.

Tel: +385 1 6610 700 [email protected] ânia Johnson & Johnson România SRL Tel: +40 21 207 1800 Ireland Janssen Sciences Ireland UC Tel: 1 800 709 122 [email protected] Johnson & Johnson d.o.o.

Tel:+386 1 401 18 00 [email protected] Ísland Janssen -Cilag AB c/o Visto rhf.

Sími: +354 535 7000 [email protected]á republika Johnson & Johnson ,s.r.o.

Tel: +421 232 408 400 Italia Janssen -Cilag SpA Tel: 800.688.777 / +39 02 2510 1 [email protected]/Finland Janssen -Cilag Oy Puh/Tel: +358 207 531300 [email protected] Κύπρος Βαρνάβας Χατζηπαναγής Λτδ Τηλ: +357 22 207 700Sverige Janssen -Cilag AB Tfn:+46 8 626 50 00 [email protected] Latvija UAB “JOHNSON & JOHNSON” filiāle Latvijā Tel: +371 678 93561 [email protected] Kingdom (Northern Ireland) Janssen Sciences Ireland UC Tel: +44 1 494 567 444 [email protected]

This leaflet was last revised in

Detailed information on this medicine is available on the website of the European Medicines Agency https://www.ema.europa.eu .

88The following information is intende d for healthcare professionals only:

1. RECONSTITUTION FOR INTRAVENOUS INJECTION 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 i s recommended.

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

1.1 Preparation of the 1 mg vial: carefully add 1. 0mlof sterile, 9 mg/ml (0.9%) sodium chloride solution for injection to the vi al containing the VELCADE powder by using a 1 ml syringe without removing the vialstopper .Dissolution of the lyophilised powder is completed in less than 2 minutes.

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 so lution should be discarded. C onfirm concentration on vial to ensure that the correct dose is being given for the intravenous route of administration ( 1mg/ml).

1.3 The reconstituted solution is preservative free and should be used immediately after prepar ation.

However, the chemical and physical in -use stability has been demonstrated for 8hours at 25 °C stored in the original vial and/or a syringe .Thetotal storage time for the reconstituted medicinal product should not exceed 8hours prior to administrat ion. 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  Once disso lved, withdraw the appropriate amount of the reconstituted solution according to calculated dose based upon the patient´s Body Surface Area.  Confirm the dose and concentration in the syringe prior to use (check that the syringe is marked as intravenous adm inistration) .  Inject the solution as a 3 -5second 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.

VELCADE 1mg powder for solution for injection IS FOR INTRAVENOUS USE ONLY .Do not give by other routes. Intrathecal administration has resulted in death.

3. DISPOSAL A vial is for single use only and the remaining solution must be discarded.

Any unused product or waste material should be disposed of in accordance with local requirements.

89Package leaflet: Information for the user VELCADE 3. 5mg powder for solution for injection bortezomib Read all of this leaflet carefully before you start using this medicine because it contains important information for you .

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• If you get any side effects, talk to your doctor or pharmacist. This includes anyside effe cts not listed in this leaflet .See section 4.

What is i n this leaflet:

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

ℹ️ 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 function and growth. By interfering with the ir function, bortezomib can kill cancer cells .

VELCADE is used for the treatment of multiple myeloma (a cancer of the bone marrow) in patients older than 1 8years :

• alone or together with the medicines pegylated liposomal doxorubicin or dexamethasone , for patients whose disease is worsening (progressive) after receiving at least one prior treatment and for whom blood stem cell transplantation was not successful or is unsuitable.
• in combination with the medicines melphalan and prednisone, for patients whose disease has not been previously treated and are unsuitable for high -dose chemotherapy with blood stem cell transplantation.
• incombination with the medicines dexamethasone or dexamethasone together with thalidomide, for patients whose disease has not been previously treated and before receiving high-dose chemotherapy with blood stem cell transplantation (induction treatment).

VELCADE is used for the treatment of mantle cell lymphoma (a type of cancer affecting the lymph nodes ) in patients 18 years or older in combination with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone, for patients whose disease has not been previously treated and for whom blood stem cell transplantation is unsuitable.

⚠️ 2. What you need to know before you use VEL CADE

Do not use VELCADE

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

Warnings and precautions

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 90 fainting, dizziness or light -headedness in the past  kidney problems  moderate to severe 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  seizures  shingles (locali sed including around the eyes or spread across the body)  symptoms of tumo ur lysis syndrome such as muscle cramping, muscle weakness, confusion, visual loss or disturbances and shortness of breath  memory loss, trouble thinking, difficulty with walking or loss of vision. These may be signs of a serious brain infection and your doctor m ay suggest further testing and follow -up.

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

If you have mantle cell lymphoma and are given the medicine rituximab with VELCA DE you should tell your doctor:  if you think you have hepatitis infection now or have had it in the past. In a few cases, patients who have had hepatitis B might have a repeated attack of hepatitis, which can be fatal. If you have a history of hepatitis B infection you will be carefully checked by your doctor for signs of active hepatitis B.

You must read the package leaflets of all medicinal products to be taken in combination with VELCADE for information related to these medicines before starting treatme nt with VELCADE .

When thalidomide is used, particular attention to pregnancy testing and prevention require ments is needed (see Pregnancy and breast -feeding in this section ).

Children and adolescents

VELCADE should not be used in children and adolescents because it is not known how the medicine will affect them .

Other medicines and VELCADE

Please tell your doctor, or pharmacist if you are taking ,have recently taken or might take any other medicines.

In particular, tell you rdoctor if you are using medici nes 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 t o treat epilepsy
• St.John’s Wort (Hypericum perforatum ),used for depression or other conditions
• oral antidiabetics Pregnancy and breast -feeding You should not use VELCADE if you are pregnant, unless clearly necessary.

Women of childbearing potential must use effective contraception during treatment and for 8 months following completion of treatment. Talk to your doctor if you wish to freeze your eggs before starting treatment.

Men should not father a child while using VELCADE and should use effective contraception during treatment and for up to 5 months after treatment has stopped. Talk to your doctor if you wish to conserve your sperm before starting treatment.

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

91Thalidomide causes birth defects and foetal death. When VELCADE is given in combination with thalidomide you must follow the pregnancy prevention programme for thalidomide (see package leaflet for thalidomide).

Driving and using machines

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

💊 3. How to u se VELCADE

Your doctor will work out your dose of VELCADE according to your height and weight (body surface area). The usual starting dose of VELCADE is 1.3 mg/m2body surface area twice a week .

Your doctor may change the dose and total number of treatmen t cycles, depending on your response to the treatment on the occurrence of certain side effects and on your underlying conditions (e.g. liver problems) .

Progressive multiple myeloma When VELCADE is given alone, you will receive 4doses of VELCADE intraven ously or subcutaneously on days 1, 4, 8 and 11, followed by a 10 -day ‘rest period’ without treatment. This 21-dayperiod (3weeks) corresponds to one treatment cycle. You might receive up to 8 cycles (24weeks).

You may also be given VELCADE together with the medicines pegylated liposomal doxorubicin or dexamethasone .

When VELCADE is given together with p egylated liposomal doxorubicin , you will receive VELCADE intravenously or subcutaneously as a21-daytreatment cycle and p egylated liposomal doxorubicin 30mg/m2 is given on day 4 of the VELCADE 21-daytreatment cycle as an intravenous infusion after the VELCADE injection.

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

When VELCADE is given together with dexamethasone, you will receive VELCADE intravenously or subcutaneously as a21-daytreatment cycle and dexamethasone 20 mg is given orally on days 1, 2, 4, 5, 8, 9, 11, and 12 , of the VELCADE, 21-daytreatment cycle.

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

Previously untreated multiple myeloma If you have not been treated before for multiple myeloma, and you are not suitable for blood stem cell transplantation you will receive VELCADE together with two other medicines; melphalan and prednisone.

In this case, the duration of a treatment cycle is 42 days (6weeks). You will receive 9 cycles (54weeks).  In cycles 1 to 4, VELCADE is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32.  In cycles 5 to 9, VELCADE is administered once weekly on days 1, 8, 22 and 29.

Melphalan (9mg/m2) and predniso ne (60mg/m2)are both given orally on days 1, 2, 3 and 4 of the first week of each cycle.

If you have not been treated before for multiple myeloma, and you are suitable for blood stem cell transplantation you will receive VELCADE intravenously or subcuta neously together with the medicines dexamethasone, or dexamethasone and thalidomide, as induction treatment.

When VELCADE is given together with dexamethasone, you will receive VELCADE intravenously or subcutaneously as a21-daytreatment cycle and d exame thasone 40 mg is given orally on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE 21-daytreatment cycle.

You will receive 4 cycles (12 weeks).

92When VELCADE is given together with thalidomide and dexamethasone ,the duration of a treatment cycle is 28 days (4weeks).

Dexamethasone 40 mg is given orally on days 1, 2, 3 , 4, 8, 9, 10 and 11 of the VELCADE 28 -day treatment cycle and thalidomide is given orally daily at 50 mg up to day 14 of the first cycle, and if tolerated the thalidomide dose is increased to 1 00mg on days 15-28 and may be further increased to 200mg daily from the second cycle onwards .

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

Previously untreated mantle cell lymphoma If you have not been treated before for mantle cell lymphoma you will receive VELCADE intravenously or subcutaneously together with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone.

VELCADE is given intravenously or subcutaneously on d ays1, 4, 8 and 11, followed by a ‘rest period’ without treatment. The duration of a treatment cycle is 21 days (3 weeks). You might receive up to 8 cycles (24 weeks).

The following medicinal products are given on day 1 of each VELCADE 21-daytreatment cyc le as intravenous infusions:

Rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2and doxorubicin at 50 mg/m2.

Prednisone is given orally at 100 mg/m2on days 1, 2, 3, 4 and 5 of the VELCADE treatment cycle.

How VELCADE is given This medicine is for intr avenous or sub cutaneous use. VELCADE will be administered by a health care professional experienced in the use of cytotoxic medici nes.

VELCADE powder has to be dissolved before administration. This will be done by a healthcare professional. The resulting s olution is then either injected into a vein or under the skin. Injection into a vein is rapid, taking 3 to 5seconds. Injection under the skin is in either the thighs or the abdomen.

If you are given too much VELCADE As this medicine is being given by you r doctor or nurse, it is unlikely that you will be given too much.

In the unlikely event of an overdose, your doctor will monitor you for side effects.

❗ 4. Possible side effects

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

If you are given VELCADE for multiple myeloma or mantle cell lymphoma, tell your doctor straight away if you notice any of the following symptoms :

• muscle cramping, muscle weakness
• confusion, visual los s or disturbances, blindness, seizures, headaches
• shortness of breath, swelling of your feet or changes in your heart beat, high blood pressure, tiredness, fainting
• coughing and breathing difficulties or tightness in the chest.

Treatment with VELCADE can very commonly cause a decrease in the numbers of red and white blood cells and platelets in your blood. Therefore, y ou 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 c ells, 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 .

93If you are given VELCADE for the treatment of multiple myeloma the side effects you may get are listed below:

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

 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  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 cont rol diarrhoea  Tiredness (fatigue), feeling weak  Muscle pain, bone pain

Common side effects ( may affect up to 1 in10people )

 Low blood pressure, s udden fall of blood pressure on standing which may lead to fainting  High blood pressure  Reduced functioning o f your kidneys  Headache  General ill feeling, pain, vertigo , light -headedness, a feeling of weakness or loss of consciousness  Shivering  Infections, including pneumonia, respiratory infections, bronchitis, fungal infections, coughing with phlegm, flu like il lness  Shingles (locali sed including around the eyes or spread across the body)  Chest pains or shortness of breath with exercise  Different types of rash  Itching of the skin, lumps on the skin or dry skin  Facial blushing or tiny broken capillaries  Redness of the skin  Dehydration  Heartburn, bloating, belching, wind, stomach pain, bleeding from your bowels or stomach  Alteration of liver functioning  A sore mouth or lip, dry mouth, mouth ulcers or throat pain  Weight loss, loss of taste  Muscle cramps, muscle spasm s, muscle weakness, pain in your limbs  Blurred vision  Infection of the outermost layer of the eye and the inner surface of the eyelids (conjunctivitis)  Nose bleeds  Difficulty or problems in sleeping, sweating, anxiety, mood swings, depressed mood, restless ness or agitation, changes in your mental status, disorientation  Swelling of body, to include around eyes and other parts of the body

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

 Heart failure, h eart attack, chest pain, chest discomfort , incre ased or reduced heart rate  Failing of your kidneys  Inflammation of a vein, blood clots in your veins and lungs  Problems with blood clotting  Insufficient circulation  Inflammation of the lining around your heart or fluid around your heart  Infections includin g urinary tract infections, the flu, herpes virus infections, ear infection and cellulitis  Bloody stools, or bleeding fr om mucosal membranes, e.g., mouth, vagina  Cerebrovascular disorders 94 Paralysis, seizures, falling, movement disorders, abnormal or change in, or reduced sensati on (feeling, hearing, tasting, smelling) , attention disturbance, trembling , twitching  Arthritis, including inflammation of the joints in the fingers, toes, and the jaw  Disorders that affect your lungs, preventing your body from getti ng enough oxygen. Some of these include difficulty breathing, shortness of breath, shortness of breath without exercise, breathing that becomes shallow, difficult or stops, wheezing  Hiccups, speech disorders  Increased or decreased urine production (due to kidney damage), painful passing of urine or blood/proteins in the urine, fluid retention  Altered levels of consciousness, confusion , memory impairment or loss  Hypersensitivity  Hearing loss, deafness or ringing in the ears , ear discomfort  Hormone abnormalit ywhich may affect salt and water absorption  Overactive thyroid gland  Inability to produce enough insulin or resistance to normal levels of insulin  Irritated or inflamed eyes, excessively wet eyes, painful eyes, dry eyes, eye infections ,lump in the eyelid (chalazion) , red and swollen eyelids , discharge from the eyes, abnormal vision, bleeding of the eye  Swelling of your lymph glands  Joint or muscle stiffness, sense of heaviness, pain in your groin  Hair loss and abnormal hair texture  Allergic reactions  Redness or pain at the injection site  Mouth pain  Infections or inflammation of the mouth, mouth ulcers, oesophagus, stomach and intestines, sometimes associated with pain or bleeding, poor movement of the intestines (including blockage), abdominal or oesophage al discomfort, difficulty swallowing, vomiting of blood  Skin infections  Bacterial and viral infections  Tooth infection  Inflammation of the pancreas, obstruction of the bile duct  Genital pain, problem having an erection  Weight increase  Thirst  Hepatitis  Injection site or injection device related disorders  Skin reactions and disorders (which may be severe and life threatening), skin ulcers  Bruises, falls and injuries  Inflammation or haemorrhage of the blood vessels that can appear as small red or purple dots (usually on the legs) to large bruise -like patches under the skin or tissue  Benign cysts  Asevere reversible brain condition which includes seizures, high blood pressure, headaches, tiredness, confusion, blindness or other vision problems.

Rare side effect s (may affect up to 1 in 1,000 people )  Heart problems to include heart attack, angina  Serious nerve inflammation, which may cause paralysis and difficulty breathing (Guillain -Barré syndrome)  Flushing  Discolo uration of the veins  Inflammation of the spinal n erve  Problems with your ear, bleeding from your ear  Underactivity of your thyroid gland  Budd –Chiari syndrome (the clinical symptoms caused by blockage of the hepatic veins) 95 Changes in or abnormal bowel function  Bleeding in the brain  Yellow discolouration o f eyes and skin (jaundice)  Serious allergic reaction (anaphylactic shock) signs of which may include difficulty breathing, chest pain or chest tightness, and/ or feeling dizzy/faint, severe itching of the skin or raised lumps on the skin, swelling of the fa ce, lips, tongue and /or throat, which may cause difficulty in swallowing ,collapse  Breast disorders  Vaginal tears  Genital swelling  Inability to tolerate alcohol consumption  Wasting, or loss of body mass  Increased appetite  Fistula  Joint effusion  Cysts in t he lining of joints (synovial cysts)  Fracture  Breakdown of muscle fibers leading to other complications  Swelling of the liver, bleeding from the liver  Cancer of the kidney  Psoriasis like skin condition  Cancer of the skin  Paleness of the skin  Increase of pl atelets or plasma cells (a type of white cell) in the blood  Blood clot in small blood vessels (thrombotic microangiopathy )  Abnormal reaction to blood transfusions  Partial or total loss of vision  Decreased sex drive  Drooling  Bulging eyes  Sensitivity to ligh t  Rapid breathing  Rectal pain  Gallstones  Hernia  Injuries  Brittle or weak nails  Abnormal protein deposits in your vital organs  Coma  Intestinal ulcers  Multi -organ failure  Death If you are given VELCADE together with other medicines for the treatment of mant le cell lymphoma the side effects you may get are listed below:

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

 Pneumonia  Loss of appetite  Sensitivity, 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 96 Constipation  Muscle pain, bone pain  Hair loss and abnormal hair texture  Tiredness, feeling weak  Fever

Common side effects ( may affect up to 1 in10people )

 Shingles (locali sed including around the eyes or spread across the body)  Herpes virus infections  Bacterial and viral infections  Respiratory infections, bronchitis, coughing with phlegm, flu like illness  Fungal infections  Hypersensitivity (allergic reaction)  Inability to produce enough insulin or resistance to normal levels of insulin  Fluid retention  Difficulty or problems in sleeping  Loss of conciousness  Altered level of consciousness, confusion  Feeling dizzy  Increased heartbeat, high blood pressure, sweating,  Abnormal vision , blurred vision  Heart failure, heart attack, chest pain, chest discomfort, increased or reduced heart rate  High or low blood pressure  Sudden fall of blood pressure upon standing which may lead to fainting  Shortness of breath with exercise  Cough  Hiccups  Ringing in the ears, ear discomfort  Bleeding from your bowels or stomach  Heartburn  Stomach pain, bloating  Difficulty swallowing  Infection or inflammation of the stomach and intentines  Stomach pain  Sore mouth or lip, throat pain  Alteration of liver function  Itching of skin  Redness of skin  Rash  Muscle spasms  Infection of the urinary tract  Pain in limbs  Swelling of body, to include eyes and other parts of the body  Shivering  Redness and pain at injection site  General ill feeling  Weight loss  Weight increase

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 chest tightness, and/or feeling dizzy/faint, severe itching of the skin or raised 97lumps on the skin, swe lling of the face, lips, tongue and /or throat, which may cause difficulty in swallowing, collapse  Movement disorders, paralysis, twitching  Vertigo  Hearing loss, deafness  Disorders that affect your lungs, preventing your body from getting enough oxygen. S ome of these include difficulty breathing, shortness of breath, shortness of breath without exercise, breathing that becomes shallow, difficult or stops, wheezing  Blood clots in your lungs  Yellow discolo uration of the eyes and skin (jaundice)  Lump in the e yelid (chalazion), red and swollen eyelids

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

 Blood clot in small blood vessels (thrombotic microangiopathy)  Serious nerve inflammation, which may cause paralysis and difficulty breathing (Guillain -Barré syndrome)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix 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 the carton after EXP.

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

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 solut ion is stable for 8hours at 25 °C stored in the original vial and/or a syringe, with a total storage time for the reconstituted medicine not ex ceeding 8hours prior to administration .

VELCADE is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

📦 6. Contents of the pack and other information

What VELCADE contains

• The active su bstance is bortezomib. Each vial contains 3.5 mg of bortezomib (as a mannitol boronic ester).
• The other ingredients are mannitol (E421) and nitrogen.

Intravenous reconstitution:

After reconstitution, 1ml of solution for intravenous injection contains 1 mg bortezomib.

Subcutaneous reconstitution:

After reconstitution, 1ml of solution for subcutaneous injection contains 2.5 mg bortezomib.

98What VELCADE looks like and contents of the pack VELCADE powder for solution for injection is a white to off -white ca ke or powder.

Each carton of VELCADE 3.5 mg powder for solution for injection contains a glass 10mlvial with a royal blue cap, in a transparent blister pack.

Marketing Authori sation Holder JANSSEN -CILAG INTERNATIONAL NV Turnhoutseweg 30 B-2340 Beerse Belgium

Manufacturer

Janssen Pharmaceutica NV Turnhoutseweg 30 B-2340 Beerse Belgium For any information about this medicine , please contact the local representative of the Marketing Authorisation Holder.

België/Belgique/Belgien Janssen -Cilag NV Tel/Tél :+3214 64 94 11 [email protected] UAB “JOHNSON & JOHNSON ” Tel: +370 5 278 68 88 [email protected] България „Джонсън & Джонсън България” ЕООД Тел.: +359 2 489 94 00 [email protected]/Luxemburg Janssen -Cilag NV Tél/Tel: +32 14 64 94 11 [email protected] Česká republika Janssen -Cilag s.r.o.

Tel: +420 227 012 227Magyarország Janssen -Cilag Kft.

Tel.: +36 1 884 2858 [email protected] Danmark Janssen -Cilag A/S Tlf.: +45 4594 8282 [email protected] AM MANGION L TD Tel: +356 2397 6000 Deutschland Janssen -Cilag GmbH Tel: 0800 086 9247 / +49 2137 955 6955 [email protected] Janssen -Cilag B.V.

Tel: + 31 76 711 1111 [email protected] Eesti UAB “JOHNSON & JOHNSON” Eesti filiaal Tel: +372 617 7410 [email protected] Janssen -Cilag AS Tlf: +47 24 12 65 00 [email protected] Ελλάδα Janssen -Cilag Φαρμακευτική Μονοπρόσωπη Α.Ε.Β.Ε.

Tηλ: +30 210 80 90 000Österreich Janssen -Cilag Pharma GmbH Tel:+43 1 610 300 99España Janssen -Cilag , S.A.

Tel: +34 91 722 81 00 [email protected] Polska Janssen -Cilag Polska Sp. z o.o.

Tel.: +4 8 22 237 60 00 France Janssen -Cilag Tél: 0 800 25 50 75 / +33 1 55 00 4 003 [email protected] Janssen -Cilag Farmacêutica, Lda .

Tel: +351 214 368 600 Hrvatska Johnson & Johnson S.E. d.o.o.

Tel: +385 1 6610 700 [email protected] ânia Johnson & Johnson România SRL Tel: +40 21 207 1800 Ireland Janssen Sciences Ireland UC Tel: 1 800 709 122 [email protected] Johnson & Johnson d.o.o.

Tel:+386 1 401 18 00 [email protected] Ísland Janssen -Cilag AB c/o Visto rhf.

Sími: +354 535 7000 [email protected] sSlovenská republika Johnson & Johnson ,s.r.o.

Tel: +421 232 408 400 Italia Janssen -Cilag SpA Tel:800.688.777 / +39 02 2510 1 [email protected]/Finland Janssen -Cilag Oy Puh/Tel: +358 207 531300 [email protected] Κύπρος Βαρνάβας Χατζηπαναγής Λτδ Τηλ: +357 22 207 700Sverige Janssen -Cilag AB Tfn:+468 626 50 00 [email protected] Latvija UAB “JOHNSON & JOHNSON” filiāle Latvijā Tel: +371 678 93561 [email protected] Kingdom (Northern Ireland) Janssen Sciences Ireland UC Tel: +44 1 494 567 444 [email protected]

This leaflet was last revised in

Detailed information on this medicine is available on the website of the European Medicines Agency https://www.ema.europa.eu .

100The following information is intende d for healthcare professionals only:

1. RECONSTITUTION FOR INTRAVENOUS INJECTION 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 i s recommended.

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

1.1 Preparation of the 3.5 mg vial: carefully add 3. 5mlof sterile, 9 mg/ml (0.9%) sodium chloride solution for injection to the vial containing the VELCADE powder by using a syringe of the appropriate size without removing the vial stopper .Dissolution of the lyophilised powder is completed in less than 2 minutes.

The concentration of the resulting solution will be 1 mg/ml. The so lution 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 matte r is observed, the solution should be discarded. Be sure that the correct dose is being given for the intravenous route of administration ( 1mg/ml).

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

Howe ver, the chemical and physical in -use stability has been demonstrated for 8hours at 25 °C stored in the original vial and/or a syringe . The total storage time for the reconstituted medicinal product should not exceed 8hours prior to administration . 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  Once dissolved, withd raw the appropriate amount of the reconstituted solution according to calculated dose based upon the patient´s Body Surface Area.  Confirm the dose and concentration in the syringe prior to use (check that the syringe is marked as intravenous administration ).  Inject the solution as a 3 -5second 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.

VELCADE 3.5 mg powder for solution for injection IS FOR SUBCUTANEOUS OR INTRAVENOUS USE . Do not give by other routes. Intrathecal administration has resulted in death.

3. DISPOSAL A vial is for single use only and the remaining solution must be discarded.

Any unused product or waste material should be disposed of in accordance with local requirements.

🩺 Information intended for healthcare professionals only

Only the 3.5mg vial can be administered subcutaneously , as described below.

1. RECONSTITUTION FOR S UBCUTANEOUS INJECTION 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 T HROUGHOUT HANDLING OF VELCADE SINCE NO PRESERVATIVE IS PRESENT.

1.1 Preparation of the 3.5 mg vial: carefully add 1. 4mlof sterile, 9 mg/ml (0.9%) sodium chloride solution for injection to the vial containing the VELCADE powder by using a syringe of the appropriate size without removing the vial stopper .Dissolution of the lyophilised powder is completed in less than 2 minutes.

The concentration of the resulting solution will be 2.5 mg/ml. The solution will be clear and colourless, with a final pH of 4 t o 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 solution should be discarded. Be sure that the correct dose is being given for the subcutaneous route of administration (2.5 mg/ml).

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 8hours at 25°C stored in the original vial and/or a syringe . The total storage time for the reconstituted medicinal product should not exceed 8hours prior to administration . If the reconstituted solution is not used immediately, in -use s torage 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  Once dissolved, withdraw the appropriate amount of the reconstituted solution according to calculated dose based upon the patient´s Body Surface Area.  Confirm the dose and concentration in the syringe prior to use. (check that the syringe is marked as subcutaneous administration) .  Inject the solution subcutaneously, under a 45-90°angle.  The reconstituted solution is administered subcutaneously through the thighs (right or left) or abdomen (right or left).  Injection sites should be rotated for successive injections.  If local injection site reactions occur following VELCADE injection subcutaneously, either a less concentrated VELCADE solution (1 mg/ml instead of 2.5 mg/ml) may be administered subcutaneously or a switch to intravenous injection is recommended.

VELCADE 3.5 mg powder for solution for injection IS FOR SUBCUTANEOUS OR INTRAVENOUS USE . Do not give by other routes. Intrathecal administration has resulted in death.

3. DISPOSAL A vial is for single use only and the remaining solution must be discarded.

102Any unused product or waste material should be disposed of in accordance with local requirements.

📄 Package Leaflet – official source

This article reproduces the information in the official package leaflet, as authorised in the European Union. You can consult the original document here: Product information VELCADE (PDF, ec.europa.eu).

You can check this medicine at any time in the Union Register of medicinal products (EU number EU/1/04/274).

⚠️ Important: This article is for information purposes only and does not replace medical advice or the package leaflet inside the medicine box. Read the leaflet carefully before use. For any questions about your treatment, talk to your doctor or pharmacist. If you experience side effects, tell your doctor or pharmacist and report them through your national reporting system.