VELCADE 1mg powder for injection medication leaflet

VELCADE 1 mg powder for solution for injection

Each vial contains 1 mg bortezomib (as a mannitol boronic ester).

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

For the full list of excipients, see section 6.1.

Powder for solution for injection.

White to off-white cake or powder.

VELCADE as monotherapy or in combination with pegylated liposomal doxorubicin ordexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma whohave received at least 1 prior therapy and who have already undergone or are unsuitable forhaematopoietic stem cell transplantation.

VELCADE in combination with melphalan and prednisone is indicated for the treatment of adultpatients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapywith haematopoietic stem cell transplantation.

VELCADE in combination with dexamethasone, or with dexamethasone and thalidomide, is indicatedfor the induction treatment of adult patients with previously untreated multiple myeloma who areeligible for high-dose chemotherapy with haematopoietic stem cell transplantation.

VELCADE in combination with rituximab, cyclophosphamide, doxorubicin and prednisone isindicated for the treatment of adult patients with previously untreated mantle cell lymphoma who areunsuitable for haematopoietic stem cell transplantation.

VELCADE treatment must be initiated under supervision of a physician experienced in the treatmentof cancer patients, however VELCADE may be administered by a healthcare professional experiencedin use of chemotherapeutic agents. VELCADE must be reconstituted by a healthcare professional (seesection 6.6).

Posology for treatment of progressive multiple myeloma (patients who have received at least one priortherapy)

VELCADE 1 mg powder for solution for injection is administered via intravenous injection at therecommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. It is recommendedthat patients receive 2 cycles of VELCADE following a confirmation of a complete response. It is alsorecommended that responding patients who do not achieve a complete remission receive a total of8 cycles of VELCADE therapy. At least 72 hours should elapse between consecutive doses of

VELCADE.

Dose adjustments during treatment and re-initiation of treatment for monotherapy

VELCADE treatment must be withheld at the onset of any Grade 3 non-haematological or any

Grade 4 haematological toxicities, excluding neuropathy as discussed below (see also section 4.4).

Once the symptoms of the toxicity have resolved, VELCADE treatment may be re-initiated at a25% reduced dose (1.3 mg/m2 reduced to 1.0 mg/m2; 1.0 mg/m2 reduced to 0.7 mg/m2). If the toxicityis not resolved or if it recurs at the lowest dose, discontinuation of VELCADE must be consideredunless the benefit of treatment clearly outweighs the risk.

Neuropathic pain and/or peripheral neuropathy

Patients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy are to bemanaged as presented in Table 1 (see section 4.4). Patients with pre-existing severe neuropathy maybe treated with VELCADE only after careful risk/benefit assessment.

Table 1: Recommended* posology modifications for bortezomib-related neuropathy

Severity of neuropathy Posology modification

Grade 1 (asymptomatic; loss of deep tendon Nonereflexes or paresthesia) with no pain or loss offunction

Grade 1 with pain or Grade 2 (moderate Reduce VELCADE to 1.0 mg/m2symptoms; limiting instrumental Activities of or

Daily Living (ADL)**) Change VELCADE treatment schedule to1.3 mg/m2 once per week

Grade 2 with pain or Grade 3 (severe symptoms; Withhold VELCADE treatment until symptomslimiting self care ADL***) of toxicity have resolved. When toxicityresolves re-initiate VELCADE treatment andreduce dose to 0.7 mg/m2 once per week.

Grade 4 (life-threatening consequences; urgent Discontinue VELCADEintervention indicated)and/or severe autonomic neuropathy

* Based on posology modifications in Phase II and III multiple myeloma studies and post-marketing experience.

Grading based on NCI Common Toxicity Criteria CTCAE v 4.0.

** Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc;

***Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medicinal products, andnot bedridden.

Combination therapy with pegylated liposomal doxorubicin

VELCADE 1 mg powder for solution for injection is administered via intravenous injection at therecommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hoursshould elapse between consecutive doses of VELCADE.

Pegylated liposomal doxorubicin is administered at 30 mg/m² on day 4 of the VELCADE treatmentcycle as a 1 hour intravenous infusion administered after the VELCADE injection.

Up to 8 cycles of this combination therapy can be administered as long as patients have not progressedand tolerate treatment. Patients achieving a complete response can continue treatment for at least2 cycles after the first evidence of complete response, even if this requires treatment for more than8 cycles. Patients whose levels of paraprotein continue to decrease after 8 cycles can also continue foras long as treatment is tolerated and they continue to respond.

For additional information concerning pegylated liposomal doxorubicin, see the corresponding

Summary of Product Characteristics.

Combination with dexamethasone

VELCADE 1 mg powder for solution for injection is administered via intravenous injection at therecommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and11 in a 21 day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hoursshould elapse between consecutive doses of VELCADE.

Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the VELCADEtreatment cycle.

Patients achieving a response or a stable disease after 4 cycles of this combination therapy cancontinue to receive the same combination for a maximum of 4 additional cycles.

For additional information concerning dexamethasone, see the corresponding Summary of Product

Characteristics.

Dose adjustments for combination therapy for patients with progressive multiple myeloma

For VELCADE dosage adjustments for combination therapy follow dose modification guidelinesdescribed under monotherapy above.

Posology for previously untreated multiple myeloma patients not eligible for haematopoietic stem celltransplantation

Combination therapy with melphalan and prednisone

VELCADE 1 mg powder for solution for injection is administered via intravenous injection incombination with oral melphalan and oral prednisone as shown in Table 2. A 6-week period isconsidered a treatment cycle. 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.

At least 72 hours should elapse between consecutive doses of VELCADE.

Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each

VELCADE treatment cycle.

Nine treatment cycles of this combination therapy are administered.

Table 2: Recommended posology for VELCADE in combination with melphalan and prednisone

Twice weekly VELCADE (cycles 1-4)

Week 1 2 3 4 5 6

Vc Day -- -- Day Day Day rest Day Day Day Day rest(1.3 mg/m2) 1 4 8 11 period 22 25 29 32 period

M (9 mg/m2) Day Day Day Day -- -- rest -- -- -- -- rest

P (60 mg/m2) 1 2 3 4 period period

Once weekly VELCADE (cycles 5-9)

Week 1 2 3 4 5 6

Vc Day -- -- -- Day 8 rest Day 22 Day 29 rest(1.3 mg/m2) 1 period period

M (9 mg/m2) Day Day Day Day -- rest -- rest

P (60 mg/m2) 1 2 3 4 period period

Vc=VELCADE; M=melphalan, P=prednisone

Dose adjustments during treatment and re-initiation of treatment for combination therapy withmelphalan and prednisone

Prior to initiating a new cycle of therapy:

- Platelet counts should be ≥ 70 x 109/l and the absolute neutrophils count should be ≥ 1.0 x 109/l

- Non-haematological toxicities should have resolved to Grade 1 or baseline

Table 3: Posology modifications during subsequent cycles of VELCADE therapy in combinationwith melphalan and prednisone

Toxicity Posology modification or delay

Haematological toxicity during a cycle

- If prolonged Grade 4 neutropenia or Consider reduction of the melphalan dose bythrombocytopenia, or thrombocytopenia 25% in the next cycle.with bleeding is observed in the previouscycle

- If platelet counts ≤ 30 x 109/l or ANC VELCADE therapy should be withheld≤ 0.75 x 109/l on a VELCADE dosing day(other than day 1)

- If several VELCADE doses in a cycle are VELCADE dose should be reduced by 1 dosewithheld (≥ 3 doses during twice weekly level (from 1.3 mg/m2 to 1 mg/m2, or fromadministration or ≥ 2 doses during weekly 1 mg/m2 to 0.7 mg/m2)administration)

Grade ≥ 3 non-haematological toxicities VELCADE therapy should be withheld untilsymptoms of the toxicity have resolved to

Grade 1 or baseline. Then, VELCADE may bereinitiated with one dose level reduction (from1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to0.7 mg/m2). For VELCADE-related neuropathicpain and/or peripheral neuropathy, hold and/ormodify VELCADE as outlined in Table 1.

For additional information concerning melphalan and prednisone, see the corresponding Summary of

Product Characteristics.

Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem celltransplantation (induction therapy)

Combination therapy with dexamethasone

VELCADE 1 mg powder for solution for injection is administered via intravenous injection at therecommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hoursshould elapse between consecutive doses of VELCADE.

Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADEtreatment cycle.

Four treatment cycles of this combination therapy are administered.

Combination therapy with dexamethasone and thalidomide

VELCADE 1 mg powder for solution for injection is administered via intravenous injection at therecommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and11 in a 28 day treatment cycle. This 4-week period is considered a treatment cycle. At least 72 hoursshould elapse between consecutive doses of VELCADE.

Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADEtreatment cycle.

Thalidomide is administered orally at 50 mg daily on days 1-14 and if tolerated the dose is increasedto 100 mg on days 15-28, and thereafter may be further increased to 200 mg daily from cycle 2 (see

Table 4).

Four treatment cycles of this combination are administered. It is recommended that patients with atleast partial response receive 2 additional cycles.

Table 4: Posology for VELCADE combination therapy for patients with previously untreatedmultiple myeloma eligible for haematopoietic stem cell transplantation

Vc+ Dx Cycles 1 to 4

Week 1 2 3

Vc (1.3 mg/m2) Day 1, 4 Day 8, 11 Rest Period

Dx 40 mg Day 1, 2, 3, 4 Day 8, 9, 10, 11 -

Vc+Dx+T Cycle 1

Week 1 2 3 4

Vc (1.3 mg/m2) Day 1, 4 Day 8, 11 Rest Period Rest Period

T 50 mg Daily Daily - -

T 100 mga - - Daily Daily

Dx 40 mg Day 1, 2, 3, 4 Day 8, 9, 10, 11 - -

Cycles 2 to 4b

Vc (1.3 mg/m2) Day 1, 4 Day 8, 11 Rest Period Rest Period

T 200 mga Daily Daily Daily Daily

Dx 40 mg Day 1, 2, 3, 4 Day 8, 9, 10, 11 - -

Vc=VELCADE; Dx=dexamethasone; T=thalidomidea Thalidomide dose is increased to 100 mg from week 3 of Cycle 1 only if 50 mg is tolerated and to 200 mg fromcycle 2 onwards if 100 mg is tolerated.b Up to 6 cycles may be given to patients who achieve at least a partial response after 4 cycles

Dosage adjustments for transplant eligible patients

For VELCADE dosage adjustments, dose modification guidelines described for monotherapy shouldbe followed.

In addition, when VELCADE is given in combination with other chemotherapeutic medicinalproducts, appropriate dose reductions for these products should be considered in the event of toxicitiesaccording to the recommendations in the Summary of Product Characteristics.

Posology for patients with previously untreated mantle cell lymphoma (MCL)

Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP)

VELCADE 1 mg powder for solution for injection is administered via intravenous injection at therecommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and11, followed by a 10-day rest period on days 12-21. This 3-week period is considered a treatmentcycle. Six VELCADE cycles are recommended, although for patients with a response firstdocumented at cycle 6, two additional VELCADE cycles may be given. At least 72 hours shouldelapse between consecutive doses of VELCADE.

The following medicinal products are administered on day 1 of each VELCADE 3 week treatmentcycle as intravenous infusions: rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2 anddoxorubicin at 50 mg/m2.

Prednisone is administered orally at 100 mg/m2 on days 1, 2, 3, 4 and 5 of each VELCADE treatmentcycle.

Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma

Prior to initiating a new cycle of therapy:

- Platelet counts should be ≥ 100,000 cells/μL and the absolute neutrophils count (ANC) shouldbe ≥ 1,500 cells/μL

- Platelet counts should be ≥ 75,000 cells/μL in patients with bone marrow infiltration or splenicsequestration

- Haemoglobin ≥ 8 g/dL

- Non-haematological toxicities should have resolved to Grade 1 or baseline.

VELCADE treatment must be withheld at the onset of any ≥ Grade 3 VELCADE-relatednon-haematological toxicities (excluding neuropathy) or ≥ Grade 3 haematological toxicities (see alsosection 4.4). For dose adjustments, see Table 5 below.

Granulocyte colony stimulating factors may be administered for haematologic toxicity according tolocal standard practice. Prophylactic use of granulocyte colony stimulating factors should beconsidered in case of repeated delays in cycle administration. Platelet transfusion for the treatment ofthrombocytopenia should be considered when clinically appropriate.

Table 5: Dose adjustments during treatment for patients with previously untreated mantle celllymphoma

Toxicity Posology modification or delay

- ≥ Grade 3 neutropenia with fever, Grade 4 VELCADE therapy should be withheld for up toneutropenia lasting more than 7 days, a 2 weeks until the patient has an ANCplatelet count < 10,000 cells/μL ≥ 750 cells/μL and a platelet count≥ 25,000 cells/μL.

- If, after VELCADE has been held, thetoxicity does not resolve, as defined above,then VELCADE must be discontinued.

- If toxicity resolves i.e. patient has an ANC≥ 750 cells/μL and a platelet count≥ 25,000 cells/μL, VELCADE may bereinitiated at a dose reduced by one doselevel (from 1.3 mg/m2 to 1 mg/m2, or from1 mg/m2 to 0.7 mg/m2).

- If platelet counts < 25,000 cells/μL. or ANC VELCADE therapy should be withheld< 750 cells/μL on a VELCADE dosing day(other than Day 1 of each cycle)

Grade ≥ 3 non-haematological toxicities VELCADE therapy should be withheld untilconsidered to be related to VELCADE symptoms of the toxicity have resolved to

Grade 2 or better. Then, VELCADE may bereinitiated at a dose reduced by one dose level(from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to0.7 mg/m2). For VELCADE-related neuropathicpain and/or peripheral neuropathy, hold and/ormodify VELCADE as outlined in Table 1.

In addition, when VELCADE is given in combination with other chemotherapeutic medicinalproducts, appropriate dose reductions for these medicinal products should be considered in the eventof toxicities, according to the recommendations in the respective Summary of Product Characteristics.

There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of agewith multiple myeloma or with mantle cell lymphoma.

There are no studies on the use of VELCADE in elderly patients with previously untreated multiplemyeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.

Therefore no dose recommendations can be made in this population.

In a study in previously untreated mantle cell lymphoma patients, 42.9% and 10.4% of patientsexposed to VELCADE were in the range 65-74 years and ≥ 75 years of age, respectively. In patientsaged ≥ 75 years, both regimens, VcR-CAP as well as R-CHOP, were less tolerated (see section 4.8).

Patients with mild hepatic impairment do not require a dose adjustment and should be treated per therecommended dose. Patients with moderate or severe hepatic impairment should be started on

VELCADE at a reduced dose of 0.7 mg/m2 per injection during the first treatment cycle, and asubsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be consideredbased on patient tolerability (see Table 6 and sections 4.4 and 5.2).

Table 6: Recommended starting dose modification for VELCADE in patients with hepaticimpairment

Grade of Bilirubin level SGOT (AST) Modification of starting dosehepatic levelsimpairment*≤ 1.0 x ULN > ULN None

Mild> 1.0 x 1.5 x ULN Any None

Moderate > 1.5 x 3 x ULN Any Reduce VELCADE to 0.7 mg/m2 in

Severe > 3 x ULN Any the first treatment cycle. Considerdose escalation to 1.0 mg/m2 orfurther dose reduction to 0.5 mg/m2 insubsequent cycles based on patienttolerability.

Abbreviations: SGOT=serum glutamic oxaloacetic transaminase;

AST=aspartate aminotransferase; ULN=upper limit of the normal range.

* Based on NCI Organ Dysfunction Working Group classification for categorising hepatic impairment (mild, moderate,severe).

The pharmacokinetics of bortezomib are not influenced in patients with mild to moderate renalimpairment (Creatinine Clearance [CrCL] > 20 ml/min/1.73 m2); therefore, dose adjustments are notnecessary for these patients. It is unknown if the pharmacokinetics of bortezomib are influenced inpatients with severe renal impairment not undergoing dialysis (CrCL < 20 ml/min/1.73 m2). Sincedialysis may reduce bortezomib concentrations, VELCADE should be administered after the dialysisprocedure (see section 5.2).

The safety and efficacy of VELCADE in children below 18 years of age have not been established(see sections 5.1 and 5.2). Currently available data are described in section 5.1 but no recommendationon a posology can be made.

VELCADE 1 mg powder for solution for injection is available for intravenous administration only.

VELCADE 3.5 mg powder for solution for injection is available for intravenous or subcutaneousadministration.

VELCADE should not be given by other routes. Intrathecal administration has resulted in death.

Intravenous injection

VELCADE 1 mg powder for solution for injection is for intravenous administration only. Thereconstituted solution is administered as a 3-5 second bolus intravenous injection through a peripheralor central intravenous catheter followed by a flush with sodium chloride 9 mg/ml (0.9%) solution forinjection. At least 72 hours should elapse between consecutive doses of VELCADE.

When VELCADE is given in combination with other medicinal products, refer to the Summary of

Product Characteristics of these products for instructions for administration.

Hypersensitivity to the active substance, to boron or to any of the excipients listed in section 6.1.

Acute diffuse infiltrative pulmonary and pericardial disease.

When VELCADE is given in combination with other medicinal products, refer to their Summaries of

Product Characteristics for additional contraindications.

When VELCADE is given in combination with other medicinal products, the Summary of Product

Characteristics of these other medicinal products must be consulted prior to initiation of treatment with

VELCADE. When thalidomide is used, particular attention to pregnancy testing and preventionrequirements is needed (see section 4.6).

Intrathecal administration

There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE 1 mgpowder for solution for injection is for intravenous use only, while VELCADE 3.5 mg powder forsolution for injection is for intravenous or subcutaneous use. VELCADE should not be administeredintrathecally.

Gastrointestinal toxicity

Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very commonwith VELCADE treatment. Cases of ileus have been uncommonly reported (see section 4.8).

Therefore, patients who experience constipation should be closely monitored.

VELCADE treatment is very commonly associated with haematological toxicities (thrombocytopenia,neutropenia and anaemia). In studies in patients with relapsed multiple myeloma treated with

VELCADE and in patients with previously untreated MCL treated with VELCADE in combinationwith rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), one of the mostcommon haematologic toxicity was transient thrombocytopenia. Platelets were lowest at Day 11 ofeach cycle of VELCADE treatment and typically recovered to baseline by the next cycle. There wasno evidence of cumulative thrombocytopenia. The mean platelet count nadir measured wasapproximately 40% of baseline in the single-agent multiple myeloma studies and 50% in the MCLstudy. In patients with advanced myeloma the severity of thrombocytopenia was related topre-treatment platelet count: for baseline platelet counts < 75,000/l, 90% of 21 patients had a count≤ 25,000/l during the study, including 14% < 10,000/l; in contrast, with a baseline platelet count> 75,000/l, only 14% of 309 patients had a count ≤ 25,000/l during the study.

In patients with MCL (study LYM-3002), there was a higher incidence (56.7% versus 5.8%) of

Grade ≥ 3 thrombocytopenia in the VELCADE treatment group (VcR-CAP) as compared to thenon-VELCADE treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, andprednisone [R-CHOP]). The two treatment groups were similar with regard to the overall incidence ofall-grade bleeding events (6.3% in the VcR-CAP group and 5.0% in the R-CHOP group) as well as

Grade 3 and higher bleeding events (VcR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). In the

VcR-CAP group, 22.5% of patients received platelet transfusions compared to 2.9% of patients in the

R-CHOP group.

Gastrointestinal and intracerebral haemorrhage, have been reported in association with VELCADEtreatment. Therefore, platelet counts should be monitored prior to each dose of VELCADE.

VELCADE therapy should be withheld when the platelet count is < 25,000/l or, in the case ofcombination with melphalan and prednisone, when the platelet count is ≤ 30,000/l (see section 4.2).

Potential benefit of the treatment should be carefully weighed against the risks, particularly in case ofmoderate to severe thrombocytopenia and risk factors for bleeding.

Complete blood counts (CBC) with differential and including platelet counts should be frequentlymonitored throughout treatment with VELCADE. Platelet transfusion should be considered whenclinically appropriate (see section 4.2).

In patients with MCL, transient neutropenia that was reversible between cycles was observed, with noevidence of cumulative neutropenia. Neutrophils were lowest at Day 11 of each cycle of VELCADEtreatment and typically recovered to baseline by the next cycle. In study LYM-3002, colonystimulating factor support was given to 78% of patients in the VcR-CAP arm and 61% of patients inthe R-CHOP arm. Since patients with neutropenia are at increased risk of infections, they should bemonitored for signs and symptoms of infection and treated promptly. Granulocyte colony stimulatingfactors may be administered for haematologic toxicity according to local standard practice.

Prophylactic use of granulocyte colony stimulating factors should be considered in case of repeateddelays in cycle administration (see section 4.2).

Herpes zoster virus reactivation

Antiviral prophylaxis is recommended in patients being treated with VELCADE.

In the Phase III study in patients with previously untreated multiple myeloma, the overall incidence ofherpes zoster reactivation was more common in patients treated with

VELCADE+Melphalan+Prednisone compared with Melphalan+Prednisone (14% versus 4%respectively).

In patients with MCL (study LYM-3002), the incidence of herpes zoster infection was 6.7% in the

VcR-CAP arm and 1.2% in the R-CHOP arm (see section 4.8).

Hepatitis B Virus (HBV) reactivation and infection

When rituximab is used in combination with VELCADE, HBV screening must always be performedin patients at risk of infection with HBV before initiation of treatment. Carriers of hepatitis B andpatients with a history of hepatitis B must be closely monitored for clinical and laboratory signs ofactive HBV infection during and following rituximab combination treatment with VELCADE.

Antiviral prophylaxis should be considered. Refer to the Summary of Product Characteristics ofrituximab for more information.

Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in PMLand death, have been reported in patients treated with VELCADE. Patients diagnosed with PML hadprior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 monthsof their first dose of VELCADE. Patients should be monitored at regular intervals for any new orworsening neurological symptoms or signs that may be suggestive of PML as part of the differentialdiagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be referred to aspecialist in PML and appropriate diagnostic measures for PML should be initiated. Discontinue

VELCADE if PML is diagnosed.

Treatment with VELCADE is very commonly associated with peripheral neuropathy, which ispredominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheralneuropathy have been reported. The incidence of peripheral neuropathy increases early in thetreatment and has been observed to peak during cycle 5.

It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burningsensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness.

Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluationand may require a change in the dose or schedule of VELCADE (see section 4.2). Neuropathy hasbeen managed with supportive care and other therapies.

Early and regular monitoring for symptoms of treatment-emergent neuropathy with neurologicalevaluation should be considered in patients receiving VELCADE in combination with medicinalproducts known to be associated with neuropathy (e.g. thalidomide) and appropriate dose reduction ortreatment discontinuation should be considered.

In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to someadverse reactions such as postural hypotension and severe constipation with ileus. Information onautonomic neuropathy and its contribution to these undesirable effects is limited.

Seizures have been uncommonly reported in patients without previous history of seizures or epilepsy.

Special care is required when treating patients with any risk factors for seizures.

VELCADE treatment is commonly associated with orthostatic/postural hypotension. Most adversereactions are mild to moderate in nature and are observed throughout treatment. Patients whodeveloped orthostatic hypotension on VELCADE (injected intravenously) did not have evidence oforthostatic hypotension prior to treatment with VELCADE. Most patients required treatment for theirorthostatic hypotension. A minority of patients with orthostatic hypotension experienced syncopalevents. Orthostatic/postural hypotension was not acutely related to bolus infusion of VELCADE. Themechanism of this event is unknown although a component may be due to autonomic neuropathy.

Autonomic neuropathy may be related to bortezomib or bortezomib may aggravate an underlyingcondition such as diabetic or amyloidotic neuropathy. Caution is advised when treating patients with ahistory of syncope receiving medicinal products known to be associated with hypotension; or who aredehydrated due to recurrent diarrhoea or vomiting. Management of orthostatic/postural hypotensionmay include adjustment of antihypertensive medicinal products, rehydration or administration ofmineralocorticosteroids and/or sympathomimetics. Patients should be instructed to seek medicaladvice if they experience symptoms of dizziness, light-headedness or fainting spells.

Posterior Reversible Encephalopathy Syndrome (PRES)

There have been reports of PRES in patients receiving VELCADE. PRES is a rare, often reversible,rapidly evolving neurological condition, which can present with seizure, hypertension, headache,lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging,preferably Magnetic Resonance Imaging (MRI), is used to confirm the diagnosis. In patientsdeveloping PRES, VELCADE should be discontinued.

Acute development or exacerbation of congestive heart failure, and/or new onset of decreased leftventricular ejection fraction has been reported during bortezomib treatment. Fluid retention may be apredisposing factor for signs and symptoms of heart failure. Patients with risk factors for or existingheart disease should be closely monitored.

Electrocardiogram investigations

There have been isolated cases of QT-interval prolongation in clinical studies, causality has not beenestablished.

Pulmonary disorders

There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology suchas pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome(ARDS) in patients receiving VELCADE (see section 4.8). Some of these events have been fatal. Apre-treatment chest radiograph is recommended to serve as a baseline for potential post-treatmentpulmonary changes.

In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnosticevaluation should be performed and patients treated appropriately. The benefit/risk ratio should beconsidered prior to continuing VELCADE therapy.

In a clinical trial, two patients (out of 2) given high-dose cytarabine (2 g/m2 per day) by continuousinfusion over 24 hours with daunorubicin and VELCADE for relapsed acute myelogenous leukaemiadied of ARDS early in the course of therapy, and the study was terminated. Therefore, this specificregimen with concomitant administration with high-dose cytarabine (2 g/m2 per day) by continuousinfusion over 24 hours is not recommended.

Renal complications are frequent in patients with multiple myeloma. Patients with renal impairmentshould be monitored closely (see sections 4.2 and 5.2).

Bortezomib is metabolised by liver enzymes. Bortezomib exposure is increased in patients withmoderate or severe hepatic impairment; these patients should be treated with VELCADE at reduceddoses and closely monitored for toxicities (see sections 4.2 and 5.2).

Rare cases of hepatic failure have been reported in patients receiving VELCADE and concomitantmedicinal products and with serious underlying medical conditions. Other reported hepatic reactionsinclude increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may bereversible upon discontinuation of bortezomib (see section 4.8).

Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells and MCL cells,the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndromeare those with high tumour burden prior to treatment. These patients should be monitored closely andappropriate precautions taken.

Patients should be closely monitored when given bortezomib in combination with potent

CYP3A4-inhibitors. Caution should be exercised when bortezomib is combined with CYP3A4- or

CYP2C19 substrates (see section 4.5).

Normal liver function should be confirmed and caution should be exercised in patients receiving oralhypoglycemics (see section 4.5).

Potentially immunocomplex-mediated reactions

Potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritiswith rash and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should bediscontinued if serious reactions occur.

In vitro studies indicate that bortezomib is a weak inhibitor of the cytochrome P450 (CYP) isozymes1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution (7%) of CYP2D6 to the metabolismof bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affect the overalldisposition of bortezomib.

A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on thepharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of35% (CI90% [1.032 to 1.772]) based on data from 12 patients. Therefore, patients should be closelymonitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole,ritonavir).

In a drug-drug interaction study assessing the effect of omeprazole, a potent CYP2C19 inhibitor, onthe pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on thepharmacokinetics of bortezomib based on data from 17 patients.

A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on thepharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC reductionof 45% based on data from 6 patients. Therefore, the concomitant use of bortezomib with strong

CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s Wort) isnot recommended, as efficacy may be reduced.

In the same drug-drug interaction study assessing the effect of dexamethasone, a weaker CYP3A4inducer, on the pharmacokinetics of bortezomib (injected intravenously), there was no significanteffect on the pharmacokinetics of bortezomib based on data from 7 patients.

A drug-drug interaction study assessing the effect of melphalan-prednisone on the pharmacokinetics ofbortezomib (injected intravenously), showed a mean bortezomib AUC increase of 17% based on datafrom 21 patients. This is not considered clinically relevant.

During clinical trials, hypoglycemia and hyperglycemia were uncommonly and commonly reported indiabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving

VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of thedose of their antidiabetics.

Male and female patients of childbearing potential must use effective contraceptive measures duringand for 3 months following treatment.

No clinical data are available for bortezomib with regard to exposure during pregnancy. Theteratogenic potential of bortezomib has not been fully investigated.

In non-clinical studies, bortezomib had no effects on embryonal/foetal development in rats and rabbitsat the highest maternally tolerated doses. Animal studies to determine the effects of bortezomib onparturition and post-natal development were not conducted (see section 5.3). VELCADE should not beused during pregnancy unless the clinical condition of the woman requires treatment with VELCADE.

If VELCADE is used during pregnancy, or if the patient becomes pregnant while receiving thismedicinal product, the patient should be informed of potential for hazard to the foetus.

Thalidomide is a known human teratogenic active substance that causes severe life-threatening birthdefects. Thalidomide is contraindicated during pregnancy and in women of childbearing potentialunless all the conditions of the thalidomide pregnancy prevention programme are met. Patientsreceiving VELCADE in combination with thalidomide should adhere to the pregnancy preventionprogramme of thalidomide. Refer to the Summary of Product Characteristics of thalidomide foradditional information.

It is not known whether bortezomib is excreted in human milk. Because of the potential for seriousadverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with

VELCADE.

Fertility studies were not conducted with VELCADE (see section 5.3).

VELCADE may have a moderate influence on the ability to drive and use machines. VELCADE maybe associated with fatigue very commonly, dizziness commonly, syncope uncommonly andorthostatic/postural hypotension or blurred vision commonly. Therefore, patients must be cautiouswhen driving or using machines and should be advised not to drive or operate machinery if theyexperience these symptoms (see section 4.8).

Serious adverse reactions uncommonly reported during treatment with VELCADE include cardiacfailure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathysyndrome, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy.

The most commonly reported adverse reactions during treatment with VELCADE are nausea,diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia,peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash,herpes zoster and myalgia.

Multiple Myeloma

Undesirable effects in Table 7 were considered by the investigators to have at least a possible orprobable causal relationship to VELCADE. These adverse reactions are based on an integrated data setof 5,476 patients of whom 3,996 were treated with VELCADE at 1.3 mg/m2 and included in Table 7.

Overall, VELCADE was administered for the treatment of multiple myeloma in 3,974 patients.

Adverse reactions are listed below by system organ class and frequency grouping. Frequencies aredefined as: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from theavailable data). Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness. Table 7 has been generated using Version 14.1 of the MedDRA.

Post-marketing adverse reactions not seen in clinical trials are also included.

Table 7: Adverse reactions in patients with Multiple Myeloma treated with VELCADE in clinicaltrials, and all post-marketing adverse reactions regardless of indication#

System Organ

Class Incidence Adverse reaction

Infections and Common Herpes zoster (inc disseminated & ophthalmic), Pneumonia*,infestations Herpes simplex*, Fungal infection*

Uncommon Infection*, Bacterial infections*, Viral infections*, Sepsis(inc septic shock)*, Bronchopneumonia, Herpes virusinfection*, Meningoencephalitis herpetic#, Bacteraemia (incstaphylococcal), Hordeolum, Influenza, Cellulitis, Devicerelated infection, Skin infection*, Ear infection*,

Staphylococcal infection, Tooth infection*

Rare Meningitis (inc bacterial), Epstein-Barr virus infection,

Genital herpes, Tonsillitis, Mastoiditis, Post viral fatiguesyndrome

Neoplasms Rare Neoplasm malignant, Leukaemia plasmacytic, Renal cellbenign, malignant carcinoma, Mass, Mycosis fungoides, Neoplasm benign*and unspecified(incl cysts andpolyps)

Blood and Very Common Thrombocytopenia*, Neutropenia*, Anaemia*lymphatic system Common Leukopenia*, Lymphopenia*disorders Uncommon Pancytopenia*, Febrile neutropenia, Coagulopathy*,

Leukocytosis*, Lymphadenopathy, Haemolytic anaemia#

Rare Disseminated intravascular coagulation, Thrombocytosis*,

Hyperviscosity syndrome, Platelet disorder NOS, Thromboticmicroangiopathy (inc thrombocytopenic purpura) #, Blooddisorder NOS, Haemorrhagic diathesis, Lymphocyticinfiltration

Immune system Uncommon Angioedema#, Hypersensitivity*disorders Rare Anaphylactic shock, Amyloidosis, Type III immune complexmediated reaction

Endocrine Uncommon Cushing's syndrome*, Hyperthyroidism*, Inappropriatedisorders antidiuretic hormone secretion

Rare Hypothyroidism

Metabolism and Very Common Decreased appetitenutrition disorders Common Dehydration, Hypokalaemia*, Hyponatraemia*, Bloodglucose abnormal*, Hypocalcaemia*, Enzyme abnormality*

Uncommon Tumour lysis syndrome, Failure to thrive*,

Hypomagnesaemia*, Hypophosphataemia*, Hyperkalaemia*,

Hypercalcaemia*, Hypernatraemia*, Uric acid abnormal*,

Diabetes mellitus*, Fluid retention

Rare Hypermagnesaemia*, Acidosis, Electrolyte imbalance*, Fluidoverload, Hypochloraemia*, Hypovolaemia,

Hyperchloraemia*, Hyperphosphataemia*, Metabolicdisorder, Vitamin B complex deficiency, Vitamin B12deficiency, Gout, Increased appetite, Alcohol intolerance

Psychiatric Common Mood disorders and disturbances*, Anxiety disorder*, Sleepdisorders disorders and disturbances*

Uncommon Mental disorder*, Hallucination*, Psychotic disorder*,

Confusion*, Restlessness

Rare Suicidal ideation*, Adjustment disorder, Delirium, Libidodecreased

Nervous system Very Common Neuropathies*, Peripheral sensory neuropathy, Dysaesthesia*,disorders Neuralgia*

Common Motor neuropathy*, Loss of consciousness (inc syncope),

Dizziness*, Dysgeusia*, Lethargy, Headache*

Uncommon Tremor, Peripheral sensorimotor neuropathy, Dyskinesia*,

Cerebellar coordination and balance disturbances*, Memoryloss (exc dementia)*, Encephalopathy*, Posterior Reversible

Encephalopathy Syndrome#, Neurotoxicity, Seizuredisorders*, Post herpetic neuralgia, Speech disorder*,

Restless legs syndrome, Migraine, Sciatica, Disturbance inattention, Reflexes abnormal*, Parosmia

Rare Cerebral haemorrhage*, Haemorrhage intracranial (incsubarachnoid)*, Brain oedema, Transient ischaemic attack,

Coma, Autonomic nervous system imbalance, Autonomicneuropathy, Cranial palsy*, Paralysis*, Paresis*, Presyncope,

Brain stem syndrome, Cerebrovascular disorder, Nerve rootlesion, Psychomotor hyperactivity, Spinal cord compression,

Cognitive disorder NOS, Motor dysfunction, Nervous systemdisorder NOS, Radiculitis, Drooling, Hypotonia, Guillain-

Barré syndrome#, Demyelinating polyneuropathy#

Eye disorders Common Eye swelling*, Vision abnormal*, Conjunctivitis*

Uncommon Eye haemorrhage*, Eyelid infection*, Chalazion# ,

Blepharitis#, Eye inflammation*, Diplopia, Dry eye*, Eyeirritation*, Eye pain, Lacrimation increased, Eye discharge

Rare Corneal lesion*, Exophthalmos, Retinitis, Scotoma, Eyedisorder (inc. eyelid) NOS, Dacryoadenitis acquired,

Photophobia, Photopsia, Optic neuropathy#, Different degreesof visual impairment (up to blindness)*

Ear and labyrinth Common Vertigo*disorders Uncommon Dysacusis (inc tinnitus)*,Hearing impaired (up to and incdeafness), Ear discomfort*

Rare Ear haemorrhage, Vestibular neuronitis, Ear disorder NOS

Cardiac disorders Uncommon Cardiac tamponade#, Cardio-pulmonary arrest*, Cardiacfibrillation (inc atrial), Cardiac failure (inc left and rightventricular)*, Arrhythmia*, Tachycardia*, Palpitations,

Angina pectoris, Pericarditis (inc pericardial effusion)*,

Cardiomyopathy*, Ventricular dysfunction*, Bradycardia

Rare Atrial flutter, Myocardial infarction*, Atrioventricular block*,

Cardiovascular disorder (inc cardiogenic shock), Torsade depointes, Angina unstable, Cardiac valve disorders*, Coronaryartery insufficiency, Sinus arrest

Vascular disorders Common Hypotension*, Orthostatic hypotension, Hypertension*

Uncommon Cerebrovascular accident#, Deep vein thrombosis*,

Haemorrhage*, Thrombophlebitis (inc superficial),

Circulatory collapse (inc hypovolaemic shock), Phlebitis,

Flushing*, Haematoma (inc perirenal)*, Poor peripheralcirculation*, Vasculitis, Hyperaemia (inc ocular)*

Rare Peripheral embolism, Lymphoedema, Pallor, Erythromelalgia,

Vasodilatation, Vein discolouration, Venous insufficiency

Respiratory, Common Dyspnoea*, Epistaxis, Upper/lower respiratory tractthoracic and infection*, Cough*mediastinal Uncommon Pulmonary embolism, Pleural effusion, Pulmonary oedemadisorders (inc acute), Pulmonary alveolar haemorrhage#,

Bronchospasm, Chronic obstructive pulmonary disease*,

Hypoxaemia*, Respiratory tract congestion*, Hypoxia,

Pleurisy*, Hiccups, Rhinorrhoea, Dysphonia, Wheezing

Rare Respiratory failure, Acute respiratory distress syndrome,

Apnoea, Pneumothorax, Atelectasis, Pulmonary hypertension,

Haemoptysis, Hyperventilation, Orthopnoea, Pneumonitis,

Respiratory alkalosis, Tachypnoea, Pulmonary fibrosis,

Bronchial disorder*, Hypocapnia*, Interstitial lung disease,

Lung infiltration, Throat tightness, Dry throat, Increasedupper airway secretion, Throat irritation, Upper-airway coughsyndrome

Gastrointestinal Very Common Nausea and vomiting symptoms*, Diarrhoea*, Constipationdisorders Common Gastrointestinal haemorrhage (inc mucosal)*, Dyspepsia,

Stomatitis*, Abdominal distension, Oropharyngeal pain*,

Abdominal pain (inc gastrointestinal and splenic pain)*, Oraldisorder*, Flatulence

Uncommon Pancreatitis (inc chronic)*, Haematemesis, Lip swelling*,

Gastrointestinal obstruction (inc small intestinal obstruction,ileus)*, Abdominal discomfort, Oral ulceration*, Enteritis*,

Gastritis*, Gingival bleeding, Gastrooesophageal refluxdisease*, Colitis (inc clostridium difficile)*, Colitisischaemic#, Gastrointestinal inflammation*, Dysphagia,

Irritable bowel syndrome, Gastrointestinal disorder NOS,

Tongue coated, Gastrointestinal motility disorder*, Salivarygland disorder*

Rare Pancreatitis acute, Peritonitis*, Tongue oedema*, Ascites,

Oesophagitis, Cheilitis, Faecal incontinence, Anal sphincteratony, Faecaloma*, Gastrointestinal ulceration andperforation*, Gingival hypertrophy, Megacolon, Rectaldischarge, Oropharyngeal blistering*, Lip pain, Periodontitis,

Anal fissure, Change of bowel habit, Proctalgia, Abnormalfaeces

Hepatobiliary Common Hepatic enzyme abnormality*disorders Uncommon Hepatotoxicity (inc liver disorder), Hepatitis*, Cholestasis

Rare Hepatic failure, Hepatomegaly, Budd-Chiari syndrome,

Cytomegalovirus hepatitis, Hepatic haemorrhage,

Skin and Common Rash*, Pruritus*, Erythema, Dry skinsubcutaneous Uncommon Erythema multiforme, Urticaria, Acute febrile neutrophilictissue disorders dermatosis, Toxic skin eruption, Toxic epidermal necrolysis#,

Stevens-Johnson syndrome#, Dermatitis*, Hair disorder*,

Petechiae, Ecchymosis, Skin lesion, Purpura, Skin mass*,

Psoriasis, Hyperhidrosis, Night sweats, Decubitus ulcer#,

Acne*, Blister*, Pigmentation disorder*

Rare Skin reaction, Jessner's lymphocytic infiltration, Palmar-plantar erythrodysaesthesia syndrome, Haemorrhagesubcutaneous, Livedo reticularis, Skin induration, Papule,

Photosensitivity reaction, Seborrhoea, Cold sweat, Skindisorder NOS, Erythrosis, Skin ulcer, Nail disorder

Musculoskeletal Very Common Musculoskeletal pain*and connective Common Muscle spasms*, Pain in extremity, Muscular weaknesstissue disorders Uncommon Muscle twitching, Joint swelling, Arthritis*, Joint stiffness,

Myopathies*,Sensation of heaviness

Rare Rhabdomyolysis, Temporomandibular joint syndrome,

Fistula, Joint effusion, Pain in jaw, Bone disorder,

Musculoskeletal and connective tissue infections andinflammations*, Synovial cyst

Renal and urinary Common Renal impairment*disorders Uncommon Renal failure acute, Renal failure chronic*, Urinary tractinfection*, Urinary tract signs and symptoms*, Haematuria*,

Urinary retention, Micturition disorder*, Proteinuria,

Azotaemia, Oliguria*, Pollakiuria

Rare Bladder irritation

Reproductive Uncommon Vaginal haemorrhage, Genital pain*, Erectile dysfunction,system and breast Rare Testicular disorder*, Prostatitis, Breast disorder female,disorders Epididymal tenderness, Epididymitis, Pelvic pain, Vulvalulceration

Congenital, Rare Aplasia, Gastrointestinal malformation, Ichthyosisfamilial andgenetic disorders

General disorders Very Common Pyrexia*, Fatigue, Astheniaand administration Common Oedema (inc peripheral), Chills, Pain*, Malaise*site conditions Uncommon General physical health deterioration*, Face oedema*,

Injection site reaction*, Mucosal disorder*, Chest pain, Gaitdisturbance, Feeling cold, Extravasation*, Catheter relatedcomplication*, Change in thirst*, Chest discomfort, Feelingof body temperature change*, Injection site pain*

Rare Death (inc sudden), Multi-organ failure, Injection sitehaemorrhage*, Hernia(inc hiatus)*, Impaired healing*,

Inflammation, Injection site phlebitis*, Tenderness, Ulcer,

Irritability, Non-cardiac chest pain, Catheter site pain,

Sensation of foreign body

Investigations Common Weight decreased

Uncommon Hyperbilirubinaemia*, Protein analyses abnormal*, Weightincreased, Blood test abnormal*,C-reactive protein increased

Rare Blood gases abnormal*, Electrocardiogram abnormalities (inc

QT prolongation)*, International normalised ratio abnormal*,

Gastric pH decreased, Platelet aggregation increased,

Troponin I increased, Virus identification and serology*,

Urine analysis abnormal*

Injury, poisoning Uncommon Fall, Contusionand procedural Rare Transfusion reaction, Fractures*, Rigors*, Face injury, Jointcomplications injury*, Burns, Laceration, Procedural pain, Radiationinjuries*

Surgical and Rare Macrophage activationmedicalprocedures

NOS=not otherwise specified

* Grouping of more than one MedDRA preferred term.# Post-marketing adverse reaction regardless of indication

Mantle Cell Lymphoma (MCL)

The safety profile of VELCADE in 240 MCL patients treated with VELCADE at 1.3 mg/m2 incombination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), versus242 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone[R-CHOP] was relatively consistent to that observed in patients with multiple myeloma with maindifferences described below. Additional adverse drug reactions identified associated with the use ofthe combination therapy (VcR-CAP) were hepatitis B infection (< 1%) and myocardial ischaemia(1.3%). The similar incidences of these events in both treatment arms, indicated that these adversedrug reactions are not attributable to VELCADE alone. Notable differences in the MCL patientpopulation as compared to patients in the multiple myeloma studies were a ≥ 5% higher incidence ofthe haematological adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia,lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and hairdisorders.

Adverse drug reactions identified as those with a ≥ 1% incidence, similar or higher incidence in the

VcR-CAP arm and with at least a possible or probable causal relationship to the components of the

VcR-CAP arm, are listed in Table 8 below. Also included are adverse drug reactions identified in the

VcR-CAP arm that were considered by investigators to have at least a possible or probable causalrelationship to VELCADE based on historical data in the multiple myeloma studies.

Adverse reactions are listed below by system organ class and frequency grouping. Frequencies aredefined as: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from theavailable data). Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness. Table 8 has been generated using Version 16 of the MedDRA.

Table 8: Adverse reactions in patients with Mantle Cell Lymphoma treated with VcR-CAP in aclinical trial

System Organ

Class Incidence Adverse reaction

Infections and Very Common Pneumonia*infestations Common Sepsis (inc septic shock)*, Herpes zoster (inc disseminated &ophthalmic), Herpes virus infection*, Bacterial infections*,

Upper/lower respiratory tract infection*, Fungal infection*,

Herpes simplex*

Uncommon Hepatitis B, Infection*, Bronchopneumonia

Blood and Very Common Thrombocytopenia*, Febrile neutropenia, Neutropenia*,lymphatic system Leukopenia*, Anaemia*, Lymphopenia*disorders Uncommon Pancytopenia*

Immune system Common Hypersensitivity*disorders Uncommon Anaphylactic reaction

Metabolism and Very Common Decreased appetitenutrition disorders Common Hypokalaemia*, Blood glucose abnormal*, Hyponatraemia*,

Diabetes mellitus*, Fluid retention

Uncommon Tumour lysis syndrome

Psychiatric Common Sleep disorders and disturbances*disorders

Nervous system Very Common Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia*disorders Common Neuropathies*, Motor neuropathy*, Loss of consciousness (incsyncope), Encephalopathy*, Peripheral sensorimotorneuropathy, Dizziness*, Dysgeusia*, Autonomic neuropathy

Uncommon Autonomic nervous system imbalance

Eye disorders Common Vision abnormal*

Ear and labyrinth Common Dysacusis (inc tinnitus)*disorders Uncommon Vertigo*, Hearing impaired (up to and inc deafness)

Cardiac disorders Common Cardiac fibrillation (inc atrial), Arrhythmia*, Cardiac failure(inc left and right ventricular)*, Myocardial ischaemia,

Ventricular dysfunction*

Uncommon Cardiovascular disorder (inc cardiogenic shock)

Vascular disorders Common Hypertension*, Hypotension*, Orthostatic hypotension

Respiratory, Common Dyspnoea*, Cough*, Hiccupsthoracic and Uncommon Acute respiratory distress syndrome, Pulmonary embolism,mediastinal Pneumonitis, Pulmonary hypertension, Pulmonary oedema (incdisorders acute)

Gastrointestinal Very Common Nausea and vomiting symptoms*, Diarrhoea*, Stomatitis*,disorders Constipation

Common Gastrointestinal haemorrhage (inc mucosal)*, Abdominaldistension, Dyspepsia, Oropharyngeal pain*, Gastritis*, Oralulceration*, Abdominal discomfort, Dysphagia, Gastrointestinalinflammation*, Abdominal pain (inc gastrointestinal and splenicpain)*, Oral disorder*

Uncommon Colitis (inc clostridium difficile)*

Hepatobiliary Common Hepatotoxicity (inc liver disorder)disorders Uncommon Hepatic failure

Skin and Very Common Hair disorder*subcutaneous Common Pruritus*, Dermatitis*, Rash*tissue disorders

Musculoskeletal Common Muscle spasms*, Musculoskeletal pain*, Pain in extremityand connectivetissue disorders

Renal and urinary Common Urinary tract infection*disorders

General disorders Very Common Pyrexia*, Fatigue, Astheniaand administration Common Oedema (inc peripheral), Chills, Injection site reaction*,site conditions Malaise*

Investigations Common Hyperbilirubinaemia*, Protein analyses abnormal*, Weightdecreased, Weight increased

* Grouping of more than one MedDRA preferred term.

Herpes zoster virus reactivation

Multiple Myeloma

Antiviral prophylaxis was administered to 26% of the patients in the Vc+M+P arm. The incidence ofherpes zoster among patients in the Vc+M+P treatment group was 17% for patients not administeredantiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis.

Antiviral prophylaxis was administered to 137 of 240 patients (57%) in the VcR-CAP arm. Theincidence of herpes zoster among patients in the VcR-CAP arm was 10.7% for patients notadministered antiviral prophylaxis compared to 3.6% for patients administered antiviral prophylaxis(see section 4.4).

Hepatitis B Virus (HBV) reactivation and infection

HBV infection with fatal outcomes occurred in 0.8% (n=2) of patients in the non-VELCADEtreatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP )and 0.4% (n=1) of patients receiving VELCADE in combination with rituximab, cyclophosphamide,doxorubicin, and prednisone (VcR-CAP). The overall incidence of hepatitis B infections was similarin patients treated with VcR-CAP or with R-CHOP (0.8% vs 1.2% respectively).

Peripheral neuropathy in combination regimens

Multiple Myeloma

In trials in which VELCADE was administered as induction treatment in combination withdexamethasone (study IFM-2005-01), and dexamethasone-thalidomide (study MMY-3010), theincidence of peripheral neuropathy in the combination regimens is presented in the table below:

Table 9: Incidence of peripheral neuropathy during induction treatment by toxicity and treatmentdiscontinuation due to peripheral neuropathy

IFM-2005-01 MMY-3010

VDDx VcDx TDx VcTDx(N=239) (N=239) (N=126) (N=130)

Incidence of PN (%)

All GradePN 3 15 12 45 Grade 2 PN 1 10 2 31 Grade 3 PN < 1 5 0 5

Discontinuation due to PN (%) < 1 2 1 5

VDDx=vincristine, doxorubicin, dexamethasone; VcDx=VELCADE, dexamethasone; TDx=thalidomide, dexamethasone;

VcTDx=VELCADE, thalidomide, dexamethasone; PN=peripheral neuropathy

Note: Peripheral neuropathy included the preferred terms: neuropathy peripheral, peripheral motor neuropathy, peripheralsensory neuropathy, and polyneuropathy.

In study LYM-3002 in which VELCADE was administered with rituximab, cyclophosphamide,doxorubicin, and prednisone (R-CAP), the incidence of peripheral neuropathy in the combinationregimens is presented in the table below:

Table 10: Incidence of peripheral neuropathy in study LYM-3002 by toxicity and treatmentdiscontinuation due to peripheral neuropathy

VcR-CAP R-CHOP(N=240) (N=242)

Incidence of PN (%)

All GradePN 30 29 Grade 2 PN 18 9 Grade 3 PN 8 4

Discontinuation due to PN (%) 2 < 1

VcR-CAP=VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP= rituximab,cyclophosphamide, doxorubicin, vincristine, and prednisone; PN=peripheral neuropathy

Peripheral neuropathy included the preferred terms: peripheral sensory neuropathy, neuropathy peripheral, peripheralmotor neuropathy, and peripheral sensorimotor neuropathy

Elderly MCL patients42.9% and 10.4% of patients in the VcR-CAP arm were in the range 65-74 years and ≥ 75 years ofage, respectively. Although in patients aged ≥ 75 years, both VcR-CAP and R-CHOP were lesstolerated, the serious adverse event rate in the VcR-CAP groups was 68%, compared to 42% in the

R-CHOP group.

Retreatment of patients with relapsed multiple myeloma

In a study in which VELCADE retreatment was administered in 130 patients with relapsed multiplemyeloma, who previously had at least partial response on a VELCADE-containing regimen, the mostcommon all-grade adverse events occurring in at least 25% of patients were thrombocytopenia (55%),neuropathy (40%), anaemia (37%), diarrhoea (35%), and constipation (28%). All grade peripheralneuropathy and grade ≥ 3 peripheral neuropathy were observed in 40% and 8.5% of patients,respectively.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In patients, overdose more than twice the recommended dose has been associated with the acute onsetof symptomatic hypotension and thrombocytopenia with fatal outcomes. For preclinical cardiovascularsafety pharmacology studies, see section 5.3.

There is no known specific antidote for bortezomib overdose. In the event of an overdose, the patient’svital signs should be monitored and appropriate supportive care given to maintain blood pressure (suchas fluids, pressors, and/or inotropic agents) and body temperature (see sections 4.2 and 4.4).

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XG01.

Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-likeactivity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complexthat degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role inregulating the turnover of specific proteins, thereby maintaining homeostasis within cells. Inhibition ofthe 26S proteasome prevents this targeted proteolysis and affects multiple signalling cascades withinthe cell, ultimately resulting in cancer cell death.

Bortezomib is highly selective for the proteasome. At 10 M concentrations, bortezomib does notinhibit any of a wide variety of receptors and proteases screened and is more than 1,500-fold moreselective for the proteasome than for its next preferable enzyme. The kinetics of proteasome inhibitionwere evaluated in vitro, and bortezomib was shown to dissociate from the proteasome with a t½ of20 minutes, thus demonstrating that proteasome inhibition by bortezomib is reversible.

Bortezomib mediated proteasome inhibition affects cancer cells in a number of ways, including, butnot limited to, altering regulatory proteins, which control cell cycle progression and nuclear factorkappa B (NF-kB) activation. Inhibition of the proteasome results in cell cycle arrest and apoptosis.

NF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis,including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma,bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.

Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types and thatcancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than normal cells.

Bortezomib causes reduction of tumour growth in vivo in many preclinical tumour models, includingmultiple myeloma.

Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblastdifferentiation and activity and inhibits osteoclast function. These effects have been observed inpatients with multiple myeloma affected by an advanced osteolytic disease and treated withbortezomib.

Clinical efficacy in previously untreated multiple myeloma

A prospective Phase III, international, randomised (1:1), open-label clinical study (MMY-3002

VISTA) of 682 patients was conducted to determine whether VELCADE (1.3 mg/m2 injectedintravenously) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted inimprovement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone(60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered for amaximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease progression orunacceptable toxicity. The median age of the patients in the study was 71 years, 50% were male, 88%were Caucasian and the median Karnofsky performance status score for the patients was 80. Patientshad IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of 105 g/l, and amedian platelet count of 221.5 x 109/l. Similar proportions of patients had creatinine clearance≤ 30 ml/min (3% in each arm).

At the time of a pre-specified interim analysis, the primary endpoint, time to progression, was met andpatients in the M+P arm were offered Vc+M+P treatment. Median follow-up was 16.3 months. Thefinal survival update was performed with a median duration of follow-up of 60.1 months. Astatistically significant survival benefit in favour of the Vc+M+P treatment group was observed(HR=0.695; p=0.00043) despite subsequent therapies including VELCADE-based regimens. Mediansurvival for the Vc+M+P treatment group was 56.4 months compared to 43.1 for the M+P treatmentgroup. Efficacy results are presented in Table 11:

Table 11: Efficacy results following the final survival update to VISTA study

Efficacy endpoint Vc+M+P M+Pn=344 n=338

Time to progression

Events n (%) 101 (29) 152 (45)

Mediana (95% CI) 20.7 mo 15.0 mo(17.6, 24,7) (14.1, 17.9)

Hazard ratiob 0.54(95% CI) (0.42, 0.70)p-valuec 0.000002

Progression-free survival

Events n (%) 135 (39) 190 (56)

Mediana (95% CI) 18.3 mo 14.0 mo(16.6, 21.7) (11.1, 15.0)

Hazard ratiob 0.61(95% CI) (0.49, 0.76)p-value c 0.00001

Overall survival*

Events (deaths) n (%) 176 (51.2) 211 (62.4)

Mediana 56.4 mo 43.1 mo(95% CI) (52.8, 60.9) (35.3, 48.3)

Hazard ratiob 0.695(95% CI) (0.567, 0.852)p-valuec 0.00043

Response rate n=337 n=331populatione n=668

CRf n (%) 102 (30) 12 (4)

PRf n (%) 136 (40) 103 (31)nCR n (%) 5 (1) 0

CR+PRf n (%) 238 (71) 115 (35)p-valued < 10-10

Reduction in serum M-protein n=336 n=331populationg n=667≥90% n (%) 151 (45) 34 (10)

Time to first response in CR + PR

Median 1.4 mo 4.2 mo

Mediana response duration

CRf 24.0 mo 12.8 mo

CR+PRf 19.9 mo 13.1 mo

Time to next therapy

Events n (%) 224 (65.1) 260 (76.9)

Mediana 27.0 mo 19.2 mo(95% CI) (24.7, 31.1) (17.0, 21.0)

Hazard ratiob 0.557(95% CI) (0.462, 0.671)p-valuec < 0.000001a Kaplan-Meier estimate.b Hazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors:

2-microglobulin, albumin, and region. A hazard ratio less than 1 indicates an advantage for VMPc Nominal p-value based on the stratified log-rank test adjusted for stratification factors: 2-microglobulin, albumin, andregiond p-value for Response Rate (CR+PR) from the Cochran Mantel-Haenszel chi-square test adjusted for the stratificationfactorse Response population includes patients who had measurable disease at baselinef CR=Complete Response; PR=Partial Response. EBMT criteriag All randomised patients with secretory disease

* Survival update based on a median duration of follow-up at 60.1 monthsmo: months

CI=Confidence Interval

Patients eligible for stem cell transplantation

Two randomised, open-label, multicenter Phase III trials (IFM-2005-01, MMY-3010) were conductedto demonstrate the safety and efficacy of VELCADE in dual and triple combinations with otherchemotherapeutic agents, as induction therapy prior to stem cell transplantation in patients withpreviously untreated multiple myeloma.

In study IFM-2005-01 VELCADE combined with dexamethasone [VcDx, n=240] was compared tovincristine- doxorubicin-dexamethasone [VDDx, n=242]. Patients in the VcDx group received four21 day cycles, each consisting of VELCADE (1.3 mg/m2 administered intravenously twice weekly ondays 1, 4, 8, and 11), and oral dexamethasone (40 mg/day on days 1 to 4 and days 9 to 12, in Cycles 1and 2, and on days 1 to 4 in Cycles 3 and 4).

Autologous stem cell transplants were received by 198 (82%) patients and 208 (87%) patients in the

VDDx and VcDx groups respectively; the majority of patients underwent one single transplantprocedure. Patient demographic and baseline disease charateristics were similar between the treatmentgroups. Median age of the patients in the study was 57 years, 55% were male and 48% of patients hadhigh-risk cytogenetics. The median duration of treatment was 13 weeks for the VDDx group and11 weeks for the VcDx group. The median number of cycles received for both groups was 4 cycles.

The primary efficacy endpoint of the study was post-induction response rate (CR+nCR). A statisticallysignificant difference in CR+nCR was observed in favour of the VELCADE combined withdexamethasone group. Secondary efficacy endpoints included post-transplant response rates(CR+nCR, CR+nCR+VGPR+PR), Progression Free Survival and Overall Survival. Main efficacyresults are presented in Table 12.

Table 12: Efficacy results from study IFM-2005-01

Endpoints VcDx VDDx OR; 95% CI; P valuea

IFM-2005-01 N=240 (ITT population) N=242 (ITT population)

RR (Post-induction)

*CR+nCR 14.6 (10.4, 19.7) 6.2 (3.5, 10.0) 2.58 (1.37, pct. 4.85); 0.003

CR+nCR+VGPR+PR 77.1 (71.2, 82.2) 60.7 (54.3, 66.9) 2.18 (1.46, 3.24); < 0.001% (95% CI)

RR (Post-transplant)b

CR+nCR 37.5 (31.4, 44.0) 23.1 (18.0, 29.0) 1.98 (1.33, 2.95); 0.001

CR+nCR+VGPR+PR 79.6 (73.9, 84.5) 74.4 (68.4, 79.8) 1.34 (0.87, 2.05); 0.179% (95% CI)

CI=confidence interval; CR=complete response; nCR=near complete response; ITT=intent to treat; RR=response rate;

Vc=VELCADE; VcDx=VELCADE, dexamethasone; VDDx=vincristine, doxorubicin, dexamethasone; VGPR=very goodpartial response; PR=partial response; OR=odds ratio.

* Primary endpointa OR for response rates based on Mantel-Haenszel estimate of the common odds ratio for stratified tables; p-values by

Cochran Mantel-Haenszel test.b Refers to response rate after second transplant for subjects who received a second transplant (42/240 [18% ] in VcDxgroup and 52/242 [21%] in VDDx group).

Note: An OR > 1 indicates an advantage for Vc-containing induction therapy.

In study MMY-3010 induction treatment withVELCADE combined with thalidomide anddexamethasone [VcTDx, n=130] was compared to thalidomide-dexamethasone [TDx, n=127]. Patientsin the VcTDx group received six 4-week cycles, each consisting of VELCADE (1.3 mg/m2administered twice weekly days 1, 4, 8, and 11, followed by a 17-day rest period from day 12 today 28), dexamethasone (40 mg administered orally on days 1 to 4 and days 8 to 11), and thalidomide(administered orally at 50 mg daily on days 1-14, increased to 100 mg on days 15-28 and thereafter to200 mg daily).

One single autologous stem cell transplant was received by 105 (81%) patients and 78 (61%) patientsin the VcTDx and TDx groups, respectively. Patient demographic and baseline disease charateristicswere similar between the treatment groups. Patients in the VcTDx and TDx groups respectively had amedian age of 57 versus 56 years, 99% versus 98% patients were Caucasians, and 58% versus 54%were males. In the VcTDx group 12% of patients were cytogenetically classified as high risk versus16% of patients in the TDx group. The median duration of treatment was 24.0 weeks and the mediannumber of treatment cycles received was 6.0, and was consistent across treatment groups.

The primary efficacy endpoints of the study were post-induction and post-transplant response rates(CR+nCR). A statistically significant difference in CR+nCR was observed in favour of the VELCADEcombined with dexamethasone and thalidomide group. Secondary efficacy endpoints included

Progression Free Survival and Overall Survival. Main efficacy results are presented in Table 13.

Table 13: Efficacy results from study MMY-3010

Endpoints VcTDx TDx OR; 95% CI; P valuea

MMY-3010 N=130 (ITT population) N=127 (ITT population)

*RR (Post-induction)

CR+nCR 49.2 (40.4, 58.1) 17.3 (11.2, 25.0) 4.63 (2.61, 8.22); < 0.001a

CR+nCR+PR % (95% 84.6 (77.2, 90.3) 61.4 (52.4, 69.9) 3.46 (1.90, 6.27); < 0.001a

CI)

*RR (Post-transplant)

CR+nCR 55.4 (46.4, 64.1) 34.6 (26.4, 43.6) 2.34 (1.42, 3.87); 0.001a

CR+nCR+PR % (95% 77.7 (69.6, 84.5) 56.7 (47.6, 65.5) 2.66 (1.55, 4.57); < 0.001a

CI)

CI=confidence interval; CR=complete response; nCR=near complete response; ITT=intent to treat; RR=response rate;

Vc=VELCADE; VcTDx=VELCADE, thalidomide, dexamethasone; TDx=thalidomide, dexamethasone; PR=partialresponse; OR=odds ratio

* Primary endpointa OR for response rates based on Mantel-Haenszel estimate of the common odds ratio for stratified tables; p-values by

Cochran Mantel-Haenszel test.

Note: An OR > 1 indicates an advantage for Vc-containing induction therapy

Clinical efficacy in relapsed or refractory multiple myeloma

The safety and efficacy of VELCADE (injected intravenously) were evaluated in 2 studies at therecommended dose of 1.3 mg/m2: a Phase III randomised, comparative study (APEX), versusdexamethasone (Dex), of 669 patients with relapsed or refractory multiple myeloma who had received1-3 prior lines of therapy, and a Phase II single-arm study of 202 patients with relapsed and refractorymultiple myeloma, who had received at least 2 prior lines of treatment and who were progressing ontheir most recent treatment.

In the Phase III study, treatment with VELCADE led to a significantly longer time to progression, asignificantly prolonged survival and a significantly higher response rate, compared to treatment withdexamethasone (see Table 14), in all patients as well as in patients who have received 1 prior line oftherapy. As a result of a pre-planned interim analysis, the dexamethasone arm was halted at therecommendation of the data monitoring committee and all patients randomised to dexamethasone werethen offered VELCADE, regardless of disease status. Due to this early crossover, the median durationof follow-up for surviving patients is 8.3 months. Both in patients who were refractory to their lastprior therapy and those who were not refractory, overall survival was significantly longer and responserate was significantly higher on the VELCADE arm.

Of the 669 patients enrolled, 245 (37%) were 65 years of age or older. Response parameters as well as

TTP remained significantly better for VELCADE independently of age. Regardless of2-microglobulin levels at baseline, all efficacy parameters (time to progression and overall survival,as well as response rate) were significantly improved on the VELCADE arm.

In the refractory population of the Phase II study, responses were determined by an independentreview committee and the response criteria were those of the European Bone Marrow Transplant

Group. The median survival of all patients enrolled was 17 months (range < 1 to 36+ months). Thissurvival was greater than the six-to-nine month median survival anticipated by consultant clinicalinvestigators for a similar patient population. By multivariate analysis, the response rate wasindependent of myeloma type, performance status, chromosome 13 deletion status, or the number ortype of previous therapies. Patients who had received 2 to 3 prior therapeutic regimens had a responserate of 32% (10/32) and patients who received greater than 7 prior therapeutic regimens had a responserate of 31% (21/67).

Table 14: Summary of disease outcomes from the Phase III (APEX) and Phase II studies

Phase III Phase III Phase III Phase II> 1 prior line of ≥ 2 prior

All patients 1 prior line of therapytherapy lines

Time related Vc Dex Vc Dex Vc Dex Vcevents n=333a n=336a n=132a n=119a n=200a n=217a n=202a189b 148b

TTP, days 106b 212d 169d 87b 210[148, [129,[95% CI] [86, 128] [188, 267] [105, 191] [84, 107] [154, 281]211] 192]1 year survival,% 80d 66d 89d 72d 73 62[95% CI] [74,85] [59,72] [82,95] [62,83] [64,82] [53,71] 60

Best response Vc Dex Vc Dex Vc Dex Vc(%) n=315c n=312c n=128 n=110 n=187 n=202 n=193

CR 20 (6)b 2 (< 1)b 8 (6) 2 (2) 12 (6) 0 (0) (4)**

CR+nCR 41 (13)b 5 (2)b 16 (13) 4 (4) 25 (13) 1 (< 1) (10)**

CR+nCR+PR 121 (38)b 56 (18)b 57 (45)d 29 (26)d 64 (34)b 27 (13)b (27)**

CR+nCR+146 (46) 108 (35) 66 (52) 45 (41) 80 (43) 63 (31) (35)**

PR+MR

Medianduration 242 (8.0) 169 (5.6) 246 (8.1) 189 (6.2) 238 (7.8) 126 (4.1) 385*

Days (months)

Time toresponse 43 43 44 46 41 27 38*

CR+PR (days)a Intent to Treat (ITT) populationb p-value from the stratified log-rank test; analysis by line of therapy excludes stratification for therapeutic history; p < 0.0001c Response population includes patients who had measurable disease at baseline and received at least 1 dose of study medicinalproduct.d p-value from the Cochran Mantel-Haenszel chi-square test adjusted for the stratification factors; analysis by line of therapy excludesstratification for therapeutic history

* CR+PR+MR **CR=CR, (IF-); nCR=CR (IF+)

NA=not applicable, NE=not estimated

TTP-Time to Progression

CI=Confidence Interval

Vc=VELCADE; Dex=dexamethasone

CR=Complete Response; nCR=near Complete response

PR=Partial Response; MR=Minimal response

In the Phase II study, patients who did not obtain an optimal response to therapy with VELCADEalone were able to receive high-dose dexamethasone in conjunction with VELCADE. The protocolallowed patients to receive dexamethasone if they had had a less than optimal response to VELCADEalone. A total of 74 evaluable patients were administered dexamethasone in combination with

VELCADE. Eighteen percent of patients achieved, or had an improved response [MR (11%) or PR(7%)] with combination treatment.

VELCADE combination treatment with pegylated liposomal doxorubicin (study DOXIL-MMY-3001)

A Phase III randomised, parallel-group, open-label, multicentre study was conducted in 646 patientscomparing the safety and efficacy of VELCADE plus pegylated liposomal doxorubicin versus

VELCADE monotherapy in patients with multiple myeloma who had received at least 1 prior therapyand who did not progress while receiving anthracycline-based therapy. The primary efficacy endpointwas TTP while the secondary efficacy endpoints were OS and ORR (CR+PR), using the European

Group for Blood and Marrow Transplantation (EBMT) criteria.

A protocol-defined interim analysis (based on 249 TTP events) triggered early study termination forefficacy. This interim analysis showed a TTP risk reduction of 45% (95% CI; 29-57%, p < 0.0001) forpatients treated with combination therapy of VELCADE and pegylated liposomal doxorubicin. Themedian TTP was 6.5 months for the VELCADE monotherapy patients compared with 9.3 months forthe VELCADE plus pegylated liposomal doxorubicin combination therapy patients. These results,though not mature, constituted the protocol defined final analysis.

The final analysis for OS performed after a median follow-up of 8.6 years showed no significantdifference in OS between the two treatment arms. The median OS was 30.8 months (95% CI;25.2-36.5 months) for the VELCADE monotherapy patients and 33.0 months (95% CI;28.9-37.1 months) for the VELCADE plus pegylated liposomal doxorubicin combination therapypatients.

VELCADE combination treatment with dexamethasone

In the absence of any direct comparison between VELCADE and VELCADE in combination withdexamethasone in patients with progressive multiple myeloma, a statistical matched-pair analysis wasconducted to compare results from the non randomised arm of VELCADE in combination withdexamethasone (Phase II open-label study MMY-2045), with results obtained in the VELCADEmonotherapy arms from different Phase III randomised studies (M34101-039 [APEX] and DOXIL

MMY-3001) in the same indication.

The matched-pair analysis is a statistical method in which patients in the treatment group (e.g.

VELCADE in combination with dexamethasone) and patients in the comparison group (e.g.

VELCADE) are made comparable with respect to confounding factors by individually pairing studysubjects. This minimises the effects of observed confounders when estimating treatment effects usingnon-randomised data.

One hundred and twenty seven matched pairs of patients were identified. The analysis demonstratedimproved ORR (CR+PR) (odds ratio 3.769; 95% CI 2.045-6.947; p < 0.001), PFS (hazard ratio 0.511;95% CI 0.309-0.845; p=0.008), TTP (hazard ratio 0.385; 95% CI 0.212-0.698; p=0.001) for

VELCADE in combination with dexamethasone over VELCADE monotherapy.

Limited information on VELCADE retreatment in relapsed multiple myeloma is available.

Phase II study MMY-2036 (RETRIEVE), single arm, open-label study was conducted to determinethe efficacy and safety of retreatment with VELCADE. One hundred and thirty patients (≥ 18 years ofage) with multiple myeloma who previously had at least partial response on a VELCADE-containingregimen were retreated upon progression. At least 6 months after prior therapy, VELCADE wasstarted at the last tolerated dose of 1.3 mg/m2 (n=93) or ≤ 1.0 mg/m2 (n=37) and given on days 1, 4, 8and 11 every 3 weeks for maximum of 8 cycles either as single agent or in combination withdexamethasone in accordance with the standard of care. Dexamethasone was administered incombination with VELCADE to 83 patients in Cycle 1 with an additional 11 patients receivingdexamethasone during the course of VELCADE retreatment cycles.

The primary endpoint was best confirmed response to retreatment as assessed by EBMT criteria. Theoverall best response rate (CR + PR), to retreatment in 130 patients was 38.5% (95% CI: 30.1, 47.4).

Clinical efficacy in previously untreated mantle cell lymphoma (MCL)

Study LYM-3002 was a Phase III, randomised, open-label study comparing the efficacy and safety ofthe combination of VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone(VcR-CAP; n=243) to that of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone(R-CHOP; n=244) in adult patients with previously untreated MCL (Stage II, III or IV). Patients in the

VcR-CAP treatment arm received VELCADE (1.3 mg/m2; on days 1, 4, 8, 11, rest period days 12-21),rituximab 375 mg/m2 IV on day 1; cyclophosphamide 750 mg/m2 IV on day 1; doxorubicin 50 mg/m2

IV on day 1; and prednisone 100 mg/m2 orally on day 1 through day 5 of the 21 day VELCADEtreatment cycle. For patients with a response first documented at cycle 6, two additional treatmentcycles were given.

The primary efficacy endpoint was progression-free survival based on Independent Review

Committee (IRC) assessment. Secondary endpoints included, time to progression (TTP), time to nextanti-lymphoma treatment (TNT), duration of treatment free interval (TFI), overall response rate (ORR)and complete response (CR/CRu) rate, overall survival (OS) and response duration.

The demographic and baseline disease characteristics were generally well balanced between the twotreatment arms: median patient age was 66 years, 74% were male, 66% were Caucasian and 32%

Asian, 69% of patients had a positive bone marrow aspirate and/or a positive bone marrow biopsy for

MCL, 54% of patients had an International Prognostic Index (IPI) score of ≥ 3, and 76% had Stage IVdisease. Treatment duration (median=17 weeks) and duration of follow-up (median=40 months) werecomparable in both treatment arms. A median of 6 cycles was received by patients in both treatmentarms with 14% of subjects in the VcR-CAP group and 17% of patients in the R-CHOP groupreceiving 2 additional cycles. The majority of the patients in both groups completed treatment, 80% inthe VcR-CAP group and 82% in the R-CHOP group. Efficacy results are presented in Table 15:

Table 15: Efficacy results from study LYM-3002

Efficacy endpoint VcR-CAP R-CHOPn: ITT patients 243 244

Progression free survival (IRC)a

Events n (%) 133 (54.7%) 165 (67.6%) HRb (95% CI)=0.63 (0.50; 0.79)

Medianc(95% CI) (months) 24.7 (19.8; 31.8) 14.4 (12; 16.9) p-valued < 0.001

Response raten: response-evaluable patients 229 228

Overall complete response 122 (53.3%) 95 (41.7%) ORe (95% CI)=1.688 (1.148; 2.481)(CR+CRu)f n(%) p-valueg=0.007

Overall response 211 (92.1%) 204 (89.5%) ORe (95% CI)=1.428 (0.749; 2.722)(CR+CRu+PR)h n(%) p-valueg=0.275a Based on Independent Review Committee (IRC) assessment (radiological data only).b Hazard ratio estimate is based on a Cox’s model stratified by IPI risk and stage of disease. A hazard ratio < 1 indicates an advantagefor VcR-CAP.c Based on Kaplan-Meier product limit estimates.d Based on Log rank test stratified with IPI risk and stage of disease.e Mantel-Haenszel estimate of the common odds ratio for stratified tables is used, with IPI risk and stage of disease as stratificationfactors. An odds ratio (OR) > 1 indicates an advantage for VcR-CAP.f Include all CR+CRu, by IRC, bone marrow and LDH.g P-value from the Cochran Mantel-Haenszel chi-square test, with IPI and stage of disease as stratification factors.h Include all radiological CR+CRu+PR by IRC regardless the verification by bone marrow and LDH.

CR=Complete Response; CRu=Complete Response unconfirmed; PR=Partial Response; CI=Confidence Interval, HR=Hazard Ratio;

OR=Odds Ratio; ITT=Intent to Treat

Median PFS by investigator assessment was 30.7 months in the VcR-CAP group and 16.1 months inthe R-CHOP group (Hazard Ratio [HR]=0.51; p < 0.001). A statistically significant benefit (p < 0.001)in favour of the VcR-CAP treatment group over the R-CHOP group was observed for TTP (median30.5 versus 16.1 months), TNT (median 44.5 versus 24.8 months) and TFI (median 40.6 versus20.5 months). The median duration of complete response was 42.1 months in the VcR-CAP groupcompared with 18 months in the R-CHOP group. The duration of overall response was 21.4 monthslonger in the VcR-CAP group (median 36.5 months versus 15.1 months in the R-CHOP group). Thefinal analysis for OS was performed after a median follow-up of 82 months. Median OS was 90.7months for the VcR-CAP group compared with 55.7 months for the R-CHOP group (HR=0.66;p=0.001). The observed final median difference in the OS between the 2 treatment groups was 35months.

Patients with previously treated light-chain (AL) Amyloidosis

An open label non randomised Phase I/II study was conducted to determine the safety and efficacy of

VELCADE in patients with previously treated light-chain (AL) Amyloidosis. No new safety concernswere observed during the study, and in particular VELCADE did not exacerbate target organ damage(heart, kidney and liver). In an exploratory efficacy analysis, a 67.3% response rate (including a 28.6%

CR rate) as measured by hematologic response (M-protein) was reported in 49 evaluable patientstreated with the maximum allowed doses of 1.6 mg/m2 weekly and 1.3 mg/m2 twice-weekly. For thesedose cohorts, the combined 1-year survival rate was 88.1%.

The European Medicines Agency has waived the obligation to submit the results of studies with

VELCADE in all subsets of the paediatric population in multiple myeloma and in mantle celllymphoma (see section 4.2 for information on paediatric use).

A Phase II, single-arm activity, safety, and pharmacokinetic trial conducted by the Children’s

Oncology Group assessed the activity of the addition of bortezomib to multi-agent re-inductionchemotherapy in paediatric and young adult patients with lymphoid malignancies (pre-B cell acutelymphoblastic leukemia [ALL], T-cell ALL, and T-cell lymphoblastic lymphoma [LL]). An effectivere-induction multi-agent chemotherapy regimen was administered in 3 blocks. VELCADE wasadministered only in Blocks 1 and 2 to avoid potential overlapping toxicities with coadministereddrugs in Block 3.

Complete response (CR) was evaluated at the end of Block 1. In B-ALL patients with relapse within18 months of diagnosis (n = 27) the CR rate was 67% (95% CI: 46, 84); the 4-month event freesurvival rate was 44% (95% CI: 26, 62). In B-ALL patients with relapse 18-36 months from diagnosis(n = 33) the CR rate was 79% (95% CI: 61, 91) and the 4-month event free survival rate was 73%(95% CI: 54, 85). The CR rate in first-relapsed T-cell ALL patients (n = 22) was 68% (95% CI: 45,86) and the 4-month event free survival rate was 67% (95% CI: 42, 83). The reported efficacy data areconsidered inconclusive (see section 4.2).

There were 140 patients with ALL or LL enrolled and evaluated for safety; median age was 10 years(range 1 to 26). No new safety concerns were observed when VELCADE was added to the standardpediatric pre-B cell ALL chemotherapy backbone. The following adverse reactions (Grade ≥ 3) wereobserved at a higher incidence in the VELCADE containing treatment regimen as compared with ahistorical control study in which the backbone regimen was given alone: in Block 1 peripheral sensoryneuropathy (3% versus 0%); ileus (2.1% versus 0%); hypoxia (8% versus 2%). No information onpossible sequelae or rates of peripheral neuropathy resolution were available in this study. Higherincidences were also noted for infections with Grade ≥ 3 neutropenia (24% versus 19% in Block 1 and22% versus 11% in Block 2), increased ALT (17% versus 8% in Block 2), hypokalaemia (18% versus6% in Block 1 and 21% versus 12% in Block 2) and hyponatraemia (12% versus 5% in Block 1 and4% versus 0 in Block 2).

Following intravenous bolus administration of a 1.0 mg/m2 and 1.3 mg/m2 dose to 11 patients withmultiple myeloma and creatinine clearance values greater than 50 ml/min, the mean first-dosemaximum plasma concentrations of bortezomib were 57 and 112 ng/ml, respectively. In subsequentdoses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/ml for the1.0 mg/m2 dose and 89 to 120 ng/ml for the 1.3 mg/m2 dose.

The mean distribution volume (Vd) of bortezomib ranged from 1,659 l to 3,294 l following single- orrepeated-dose intravenous administration of 1.0 mg/m2 or 1.3 mg/m2 to patients with multiplemyeloma. This suggests that bortezomib distributes widely to peripheral tissues. Over a bortezomibconcentration range of 0.01 to 1.0 μg/ml, the in vitro protein binding averaged 82.9% in humanplasma. The fraction of bortezomib bound to plasma proteins was not concentration-dependent.

In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymesindicate that bortezomib is primarily oxidatively metabolised via cytochrome P450 enzymes, 3A4,2C19, and 1A2. The major metabolic pathway is deboronation to form two deboronated metabolitesthat subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolitesare inactive as 26S proteasome inhibitors.

The mean elimination half-life (t1/2) of bortezomib upon multiple dosing ranged from 40-193 hours.

Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Meantotal body clearances were 102 and 112 l/h following the first dose for doses of 1.0 mg/m2 and1.3 mg/m2, respectively, and ranged from 15 to 32 l/h and 18 to 32 l/h following subsequent doses fordoses of 1.0 mg/m2 and 1.3 mg/m2, respectively.

The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in a Phase Istudy during the first treatment cycle, including 61 patients primarily with solid tumors and varyingdegrees of hepatic impairment at bortezomib doses ranging from 0.5 to 1.3 mg/m2.

When compared to patients with normal hepatic function, mild hepatic impairment did not alterdose-normalised bortezomib AUC. However, the dose-normalised mean AUC values were increasedby approximately 60% in patients with moderate or severe hepatic impairment. A lower starting doseis recommended in patients with moderate or severe hepatic impairment, and those patients should beclosely monitored (see section 4.2, Table 6).

A pharmacokinetic study was conducted in patients with various degrees of renal impairment whowere classified according to their creatinine clearance values (CrCL) into the following groups:

Normal (CrCL ≥ 60 ml/min/1.73 m2, n=12), Mild (CrCL=40-59 ml/min/1.73 m2, n=10), Moderate(CrCL=20-39 ml/min/1.73 m2, n=9), and Severe (CrCL < 20 ml/min/1.73 m2, n=3). A group ofdialysis patients who were dosed after dialysis was also included in the study (n=8). Patients wereadministered intravenous doses of 0.7 to 1.3 mg/m2 of VELCADE twice weekly. Exposure of

VELCADE (dose-normalised AUC and Cmax) was comparable among all the groups (see section 4.2).

The pharmacokinetics of bortezomib were characterized following twice weekly intravenous bolusadministration of 1.3 mg/m2 doses to 104 pediatric patients (2-16 years old) with acute lymphoblasticleukemia (ALL) or acute myeloid leukemia (AML). Based on a population pharmacokinetic analysis,clearance of bortezomib increased with increasing body surface area (BSA). Geometric mean (%CV)clearance was 7.79 (25%) L/hr/m2, volume of distribution at steady-state was 834 (39%) L/m2, and theelimination half-life was 100 (44%) hours. After correcting for the BSA effect, other demographicssuch as age, body weight and sex did not have clinically significant effects on bortezomibclearance. BSA-normalized clearance of bortezomib in pediatric patients was similar to that observedin adults.

Bortezomib was positive for clastogenic activity (structural chromosomal aberrations) in the in vitrochromosomal aberration assay using Chinese hamster ovary (CHO) cells at concentrations as low as3.125 μg/ml, which was the lowest concentration evaluated. Bortezomib was not genotoxic whentested in the in vitro mutagenicity assay (Ames assay) and in vivo micronucleus assay in mice.

Developmental toxicity studies in the rat and rabbit have shown embryo-fetal lethality at maternallytoxic doses, but no direct embryo-foetal toxicity below maternally toxic doses. Fertility studies werenot performed but evaluation of reproductive tissues has been performed in the general toxicitystudies. In the 6-month rat study, degenerative effects in both the testes and the ovary have beenobserved. It is, therefore, likely that bortezomib could have a potential effect on either male or femalefertility. Peri- and postnatal development studies were not conducted.

In multi-cycle general toxicity studies conducted in the rat and monkey, the principal target organsincluded the gastrointestinal tract, resulting in vomiting and/or diarrhoea; haematopoietic andlymphatic tissues, resulting in peripheral blood cytopenias, lymphoid tissue atrophy andhaematopoietic bone marrow hypocellularity; peripheral neuropathy (observed in monkeys, mice anddogs) involving sensory nerve axons; and mild changes in the kidneys. All these target organs haveshown partial to full recovery following discontinuation of treatment.

Based on animal studies, the penetration of bortezomib through the blood-brain barrier appears to belimited, if any and the relevance to humans is unknown.

Cardiovascular safety pharmacology studies in monkeys and dogs show that intravenous dosesapproximately two to three times the recommended clinical dose on a mg/m2 basis are associated withincreases in heart rate, decreases in contractility, hypotension and death. In dogs, the decreased cardiaccontractility and hypotension responded to acute intervention with positive inotropic or pressor agents.

Moreover, in dog studies, a slight increase in the corrected QT interval was observed.

Mannitol (E 421)

Nitrogen

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years

The reconstituted solution should be used immediately after preparation. If not used immediately,in-use storage times and conditions prior to use are the responsibility of the user. However, thechemical and physical in-use stability of the reconstituted solution has been demonstrated for 8 hoursat 25°C stored in the original vial and/or a syringe. The total storage time for the reconstitutedmedicinal product should not exceed 8 hours prior to administration.

Do not store above 30°C.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Type 1 glass 5 ml-vial with a grey bromobutyl stopper and an aluminium seal, with a green capcontaining 1 mg bortezomib.

The vial is contained in a transparent blister pack consisting of a tray with a lid. Each pack contains1 single-use vial.

Bortezomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of

VELCADE. Use of gloves and other protective clothing to prevent skin contact is recommended.

Aseptic technique must be strictly observed throughout the handling of VELCADE, since it containsno preservative.

There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE 1 mgpowder for solution for injection is for intravenous use only, while VELCADE 3.5 mg powder forsolution for injection is for intravenous or subcutaneous use. VELCADE should not be administeredintrathecally.

VELCADE must be reconstituted by a healthcare professional.

Each 5 ml vial of VELCADE must be carefully reconstituted with 1 ml of sodium chloride 9 mg/ml(0.9%) solution for injection, by using a 1 ml syringe, without removing the vial stopper. Dissolutionof the lyophilised powder is completed in less than 2 minutes.

After reconstitution, each ml solution contains 1 mg bortezomib. The reconstituted solution is clearand colourless, with a final pH of 4 to 7.

The reconstituted solution must be inspected visually for particulate matter and discolouration prior toadministration. If any discolouration or particulate matter is observed, the reconstituted solution mustbe discarded.

VELCADE is for single use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

JANSSEN-CILAG INTERNATIONAL NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/04/274/002

Date of first authorisation: 26 April 2004

Date of latest renewal: 10 January 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.