BORTEZOMIB FRESENIUS KABI 3.5mg powder for injection medication leaflet

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection

Each vial contains 2.5 mg bortezomib (as a mannitol boronic ester).

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection

Each vial contains 3.5 mg bortezomib (as a mannitol boronic ester).

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

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 lyophilized powder or cake.

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

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

Bortezomib in combination with dexamethasone, or with dexamethasone and thalidomide, isindicated for the induction treatment of adult patients with previously untreated multiple myelomawho are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.

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

Bortezomib treatment must be initiated under supervision of a physician experienced in thetreatment of cancer patients, however bortezomib may be administered by a healthcare professionalexperienced in use of chemotherapeutic agents. Bortezomib must be reconstituted by a healthcareprofessional (see section 6.6).

Posology for treatment of progressive multiple myeloma (patients who have received at least oneprior therapy)

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg powder for solution for injection is administered viaintravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface areatwice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week periodis considered a treatment cycle. It is recommended that patients receive 2 cycles of bortezomibfollowing a confirmation of a complete response. It is also recommended that responding patientswho do not achieve a complete remission receive a total of 8 cycles of bortezomib therapy. At least72 hours should elapse between consecutive doses of bortezomib.

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

Bortezomib treatment must be withheld at the onset of any grade 3 non-haematological or anygrade 4 haematological toxicities, excluding neuropathy as discussed below (see also section 4.4).

Once the symptoms of the toxicity have resolved, bortezomib 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 thetoxicity is not resolved or if it recurs at the lowest dose, discontinuation of bortezomib must beconsidered unless 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 tobe managed as presented in table 1 (see section 4.4). Patients with pre-existing severe neuropathymay be treated with bortezomib 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 bortezomib to 1.0 mg/m2symptoms; limiting instrumental Activities of or

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

Grade 2 with pain or grade 3 (severe symptoms; Withhold bortezomib treatment until symptomslimiting self care ADL***) of toxicity have resolved. When toxicity resolvesre-initiate bortezomib treatment and reduce doseto 0.7 mg/m2 once per week

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

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

Grading based on NCI Common Toxicity Criteria CTCAE v 4.0.

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

*** Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medicinalproducts, and not bedridden.

Combination therapy with pegylated liposomal doxorubicin

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg powder for solution for injection is administered viaintravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface areatwice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week periodis considered a treatment cycle. At least 72 hours should elapse between consecutive doses ofbortezomib.

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

Up to 8 cycles of this combination therapy can be administered as long as patients have notprogressed and tolerate treatment. Patients achieving a complete response can continue treatmentfor at least 2 cycles after the first evidence of complete response, even if this requires treatment formore than 8 cycles. Patients whose levels of paraprotein continue to decrease after 8 cycles can alsocontinue for as 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

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg powder for solution for injection is administered viaintravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface areatwice weekly for two weeks on days 1, 4, 8, and 11 in a 21 day treatment cycle. This 3-week periodis considered a treatment cycle. At least 72 hours should elapse between consecutive doses ofbortezomib.

Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of thebortezomib treatment 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 bortezomib dosage adjustments for combination therapy follow dose modification guidelinesdescribed under monotherapy above.

Posology for previously untreated multiple myeloma patients not eligible for haematopoietic stemcell transplantation

Combination therapy with melphalan and prednisone

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg powder for solution for injection is administered viaintravenous or subcutaneous injection in combination with oral melphalan and oral prednisone asshown in table 2. A 6-week period is considered a treatment cycle. In cycles 1-4, bortezomib isadministered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In cycles 5-9, bortezomib isadministered once weekly on days 1, 8, 22 and 29. At least 72 hours should elapse betweenconsecutive doses of bortezomib.

Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week ofeach bortezomib treatment cycle.

Nine treatment cycles of this combination therapy are administered.

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

Twice weekly bortezomib (cycles 1-4)

Week 1 2 3 4 5 6

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

M Day 1 Day 2 Day 3 Day 4 -- -- rest -- -- -- -- rest(9 mg/m2) period period

P(60 mg/m2)

Once weekly bortezomib (cycles 5-9)

Week 1 2 3 4 5 6

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

M Day 1 Day 2 Day 3 Day 4 -- rest -- rest(9 mg/m2) period period

P(60 mg/m2)

B=bortezomib; 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 bortezomib therapy incombination with 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 with 25% in the next cycle.

bleeding is observed in the previous cycle

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

- If several bortezomib doses in a cycle are Bortezomib dose should be reduced by 1 dosewithheld (≥ 3 doses during twice weekly level (from 1.3 mg/m2 to 1 mg/m2, or from2 2administration or ≥ 2 doses during weekly 1 mg/m to 0.7 mg/m )administration)

Grade ≥ 3 non-haematological toxicities Bortezomib therapy should be withheld untilsymptoms of the toxicity have resolved tograde 1 or baseline. Then, bortezomib 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 bortezomib-related neuropathicpain and/or peripheral neuropathy, hold and/ormodify bortezomib as outlined in table 1.

For additional information concerning melphalan and prednisone, see the corresponding Summaryof Product Characteristics.

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

Combination therapy with dexamethasone

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg powder for solution for injection is administered viaintravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface areatwice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week periodis considered a treatment cycle. At least 72 hours should elapse between consecutive doses ofbortezomib.

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

Four treatment cycles of this combination therapy are administered.

Combination therapy with dexamethasone and thalidomide

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg powder for solution for injection is administered viaintravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface areatwice weekly for two weeks on days 1, 4, 8, and 11 in a 28-day treatment cycle. This 4-week periodis considered a treatment cycle. At least 72 hours should elapse between consecutive doses ofbortezomib.

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

Thalidomide is administered orally at 50 mg daily on days 1-14 and if tolerated the dose isincreased to 100 mg on days 15-28, and thereafter may be further increased to 200 mg daily fromcycle 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 bortezomib combination therapy for patients with previously untreatedmultiple myeloma eligible for haematopoietic stem cell transplantation

B+Dx Cycles 1 to 4

Week 1 2 3

B (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 -

B+Dx+T Cycle 1

Week 1 2 3 4

B (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 - -b

Cycles 2 to 4

B (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 - -

B=bortezomib; 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 mgfrom cycle 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 bortezomib dosage adjustments, dose modification guidelines described for monotherapyshould be followed.

In addition, when bortezomib is given in combination with other chemotherapeutic medicinalproducts, appropriate dose reductions for these products should be considered in the event oftoxicities according 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 (BR-CAP)

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg powder for solution for injection is administered viaintravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface areatwice weekly for two weeks on days 1, 4, 8, and 11, followed by a 10-day rest period ondays 12-21. This 3-week period is considered a treatment cycle. Six bortezomib cycles arerecommended, although for patients with a response first documented at cycle 6, two additionalbortezomib cycles may be given. At least 72 hours should elapse between consecutive doses ofbortezomib.

The following medicinal products are administered on day 1 of each bortezomib 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 bortezomibtreatment cycle.

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.

Bortezomib treatment must be withheld at the onset of any ≥ grade 3 bortezomib-relatednon-haematological toxicities (excluding neuropathy) or ≥ grade 3 haematological toxicities (seealso section 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 treatmentof thrombocytopenia 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 Bortezomib 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 bortezomib has been held, thetoxicity does not resolve, as defined above,then bortezomib must be discontinued.

- If toxicity resolves i.e. patient has an ANC≥ 750 cells/μL and a platelet count≥ 25,000 cells/μL, bortezomib 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 Bortezomib therapy should be withheld< 750 cells/μL on a bortezomib dosing day(other than Day 1 of each cycle)

Grade ≥ 3 non-haematological toxicities Bortezomib therapy should be withheld untilconsidered to be related to bortezomib symptoms of the toxicity have resolved tograde 2 or better. Then, bortezomib 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 bortezomib-related neuropathicpain and/or peripheral neuropathy, hold and/ormodify bortezomib as outlined in table 1.

In addition, when bortezomib is given in combination with other chemotherapeutic medicinalproducts, appropriate dose reductions for these medicinal products should be considered in theevent of 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 bortezomib in elderly patients with previously untreated multiplemyeloma who are eligible for high-dose chemotherapy with haematopoietic stem celltransplantation. 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 bortezomib were in the range 65-74 years and ≥ 75 years of age, respectively. Inpatients aged ≥ 75 years, both regimens, BR-CAP as well as R-CHOP, were less tolerated (seesection 4.8).

Patients with mild hepatic impairment do not require a dose adjustment and should be treated perthe recommended dose. Patients with moderate or severe hepatic impairment should be started onbortezomib 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 bortezomib in patients with hepaticimpairment

Grade of hepatic Bilirubin level SGOT (AST) Modification of startingimpairment* levels dose

Mild ≤ 1.0 x ULN > ULN None> 1.0 x-1.5 x ULN Any None

Moderate > 1.5 x-3 x ULN Any Reduce bortezomib to0.7 mg/m2

Severe > 3 x ULN Any in the firsttreatment cycle. Considerdose escalation to 1.0 mg/m2or further dose reduction to0.5 mg/m2 in subsequentcycles 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 arenot necessary for these patients. It is unknown if the pharmacokinetics of bortezomib are influencedin patients with severe renal impairment not undergoing dialysis (CrCL < 20 ml/min/1.73 m2).

Since dialysis may reduce bortezomib concentrations, bortezomib should be administered after thedialysis procedure (see section 5.2).

The safety and efficacy of bortezomib 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 norecommendation on a posology can be made.

Bortezomib Fresenius Kabi 1 mg powder for solution for injection is available for intravenousadministration only.

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection is available for intravenous orsubcutaneous administration.

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection is available for intravenous orsubcutaneous administration.

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

Intravenous injection

Bortezomib reconstituted solution is administered as a 3-5 second bolus intravenous injectionthrough a peripheral or central intravenous catheter followed by a flush with sodium chloride9 mg/ml (0.9%) solution for injection. At least 72 hours should elapse between consecutive dosesof bortezomib.

Bortezomib reconstituted solution is administered subcutaneously through the thighs (right or left)or abdomen (right or left). The solution should be injected subcutaneously, at a 45-90°angle.

Injection sites should be rotated for successive injections.

If local injection site reactions occur following bortezomib subcutaneous injection, either a lessconcentrated bortezomib solution (bortezomib to be reconstituted to 1 mg/ml instead of 2.5 mg/ml)may be administered subcutaneously or a switch to intravenous injection is recommended.

When bortezomib 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 bortezomib is given in combination with other medicinal products, refer to their Summariesof Product Characteristics for additional contraindications.

When bortezomib 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 treatmentwith bortezomib. When thalidomide is used, particular attention to pregnancy testing andprevention requirements is needed (see section 4.6).

Intrathecal administration

There have been fatal cases of inadvertent intrathecal administration of bortezomib. Bortezomib

Fresenius Kabi 1 mg powder for solution for injection is for intravenous use only, while

Bortezomib Fresenius Kabi 2.5 and 3.5 mg powder for solution for injection is for intravenous orsubcutaneous use. Bortezomib should not be administered intrathecally.

Gastrointestinal toxicity

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

Therefore, patients who experience constipation should be closely monitored.

Bortezomib treatment is very commonly associated with haematological toxicities(thrombocytopenia, neutropenia and anaemia). In studies in patients with relapsed multiplemyeloma treated with bortezomib and in patients with previously untreated MCL treated withbortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone(BR-CAP), one of the most common haematologic toxicity was transient thrombocytopenia.

Platelets were lowest at Day 11 of each cycle of bortezomib treatment and typically recovered tobaseline by the next cycle. There was no evidence of cumulative thrombocytopenia. The meanplatelet count nadir measured was approximately 40% of baseline in the single-agent multiplemyeloma studies and 50% in the MCL study. In patients with advanced myeloma the severity ofthrombocytopenia was related to pre-treatment platelet count: for baseline platelet counts< 75,000/μl, 90% of 21 patients had a count ≤ 25,000/μl during the study, including 14%< 10,000/μl; in contrast, with a baseline platelet count > 75,000/μl, only 14% of 309 patients had acount ≤ 25,000/μl during the study.

In patients with MCL (study LYM-3002), there was a higher incidence (56.7% versus 5.8%) ofgrade ≥ 3 thrombocytopenia in the bortezomib treatment group (BR-CAP) as compared to thenon-bortezomib treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, andprednisone [R-CHOP]). The two treatment groups were similar with regard to the overall incidenceof all-grade bleeding events (6.3% in the BR-CAP group and 5.0% in the R-CHOP group) as wellas grade 3 and higher bleeding events (BR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). Inthe BR-CAP group, 22.5% of patients received platelet transfusions compared to 2.9% of patientsin the R-CHOP group.

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

Bortezomib therapy should be withheld when the platelet count is < 25,000/μl or, in the case ofcombination with melphalan and prednisone, when the platelet count is ≤ 30,000/μl (seesection 4.2). Potential benefit of the treatment should be carefully weighed against the risks,particularly in case of moderate to severe thrombocytopenia and risk factors for bleeding.

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

In patients with MCL, transient neutropenia that was reversible between cycles was observed, withno evidence of cumulative neutropenia. Neutrophils were lowest at Day 11 of each cycle ofbortezomib treatment and typically recovered to baseline by the next cycle. In study LYM-3002,colony stimulating factor support was given to 78% of patients in the BR-CAP arm and 61% ofpatients in the R-CHOP arm. Since patients with neutropenia are at increased risk of infections,they should be monitored for signs and symptoms of infection and treated promptly. Granulocytecolony stimulating factors may be administered for haematologic toxicity according to localstandard practice. Prophylactic use of granulocyte colony stimulating factors should be consideredin case of repeated delays in cycle administration (see section 4.2).

Herpes zoster virus reactivation

Antiviral prophylaxis is recommended in patients being treated with bortezomib.

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

Bortezomib+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

BR-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 bortezomib, HBV screening must always beperformed in patients at risk of infection with HBV before initiation of treatment. Carriers ofhepatitis B and patients with a history of hepatitis B must be closely monitored for clinical andlaboratory signs of active HBV infection during and following rituximab combination treatmentwith bortezomib. Antiviral prophylaxis should be considered. Refer to the Summary of Product

Characteristics of rituximab 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 bortezomib. Patients diagnosed with PMLhad prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within12 months of their first dose of bortezomib. Patients should be monitored at regular intervals forany new or worsening neurological symptoms or signs that may be suggestive of PML as part ofthe differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should bereferred to a specialist in PML and appropriate diagnostic measures for PML should be initiated.

Discontinue bortezomib if PML is diagnosed.

Treatment with bortezomib is very commonly associated with peripheral neuropathy, which ispredominantly sensory. However, cases of severe motor neuropathy with or without sensoryperipheral neuropathy have been reported. The incidence of peripheral neuropathy increases earlyin the treatment and has been observed to peak during cycle 5.

It is recommended that patients be carefully monitored for symptoms of neuropathy such as aburning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain orweakness.

In the Phase III study comparing bortezomib administered intravenously versus subcutaneously, theincidence of grade ≥ 2 peripheral neuropathy events was 24% for the subcutaneous injection groupand 41% for the intravenous injection group (p=0.0124). Grade ≥ 3 peripheral neuropathy occurredin 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenoustreatment group (p=0.0264). The incidence of all grade peripheral neuropathy with bortezomibadministered intravenously was lower in the historical studies with bortezomib administeredintravenously than in study MMY-3021.

Patients experiencing new or worsening peripheral neuropathy should undergo neurologicalevaluation and may require a change in the dose, schedule or route of administration tosubcutaneous (see section 4.2). Neuropathy has been managed with supportive care and othertherapies.

Early and regular monitoring for symptoms of treatment-emergent neuropathy with neurologicalevaluation should be considered in patients receiving bortezomib in combination with medicinalproducts known to be associated with neuropathy (e.g. thalidomide) and appropriate dose reductionor treatment 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 orepilepsy. Special care is required when treating patients with any risk factors for seizures.

Bortezomib 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 bortezomib (injected intravenously) did not have evidence oforthostatic hypotension prior to treatment with bortezomib. Most patients required treatment fortheir orthostatic hypotension. A minority of patients with orthostatic hypotension experiencedsyncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion ofbortezomib. The mechanism of this event is unknown although a component may be due toautonomic neuropathy. Autonomic neuropathy may be related to bortezomib or bortezomib mayaggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advisedwhen treating patients with a history of syncope receiving medicinal products known to beassociated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting.

Management of orthostatic/postural hypotension may include adjustment of antihypertensivemedicinal products, rehydration or administration of mineralocorticosteroids and/orsympathomimetics. Patients should be instructed to seek medical advice if they experiencesymptoms of dizziness, light-headedness or fainting spells.

Posterior Reversible Encephalopathy Syndrome (PRES)

There have been reports of PRES in patients receiving bortezomib. 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, bortezomib 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 bea predisposing factor for signs and symptoms of heart failure. Patients with risk factors for orexisting heart disease should be closely monitored.

Electrocardiogram investigations

There have been isolated cases of QT-interval prolongation in clinical studies, causality has notbeen established.

Pulmonary disorders

There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiologysuch as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distresssyndrome (ARDS) in patients receiving bortezomib (see section 4.8). Some of these events havebeen fatal. A pre-treatment chest radiograph is recommended to serve as a baseline for potentialpost-treatment pulmonary changes.

In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a promptdiagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratioshould be considered prior to continuing bortezomib 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 bortezomib for relapsed acute myelogenousleukaemia died of ARDS early in the course of therapy, and the study was terminated. Therefore,this specific regimen with concomitant administration with high-dose cytarabine (2 g/m2 per day)by continuous infusion over 24 hours is not recommended.

Renal complications are frequent in patients with multiple myeloma. Patients with renalimpairment should 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 bortezomib 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 bortezomib and concomitantmedicinal products and with serious underlying medical conditions. Other reported hepaticreactions include increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes maybe reversible 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 lysissyndrome are those with high tumour burden prior to treatment. These patients should be monitoredclosely and appropriate 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 receivingoral hypoglycemics (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 shouldbe discontinued if serious reactions occur.

In vitro studies indicate that bortezomib is a weak inhibitor of the cytochrome P450 (CYP)isozymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution (7%) of CYP2D6 tothe metabolism of bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affectthe overall disposition of bortezomib.

A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, onthe pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUCincrease of 35% (CI90% [1.032 to 1.772]) based on data from 12 patients. Therefore, patients shouldbe closely monitored 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 AUCreduction of 45% based on data from 6 patients. Therefore, the concomitant use of bortezomib withstrong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's

Wort) is not 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 thepharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUCincrease of 17% based on data from 21 patients. This is not considered clinically relevant.

During clinical trials, hypoglycemia and hyperglycemia were uncommonly and commonly reportedin diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receivingbortezomib treatment may require close monitoring of their blood glucose levels and adjustment ofthe dose of their antidiabetics.

Due to the genotoxic potential of bortezomib (see section 5.3), women of childbearing potentialmust use effective contraceptive measures and avoid becoming pregnant while being treated withbortezomib and for 8 months following treatment. Male patients should use effective contraceptivemeasures and be advised not to father a child while receiving bortezomib and for 5 monthsfollowing completion of treatment (see section 5.3).

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 andrabbits at the highest maternally tolerated doses. Animal studies to determine the effects ofbortezomib on parturition and post-natal development were not conducted (see section 5.3).

Bortezomib should not be used during pregnancy unless the clinical condition of the womanrequires treatment with bortezomib.

If bortezomib 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-threateningbirth defects. Thalidomide is contraindicated during pregnancy and in women of childbearingpotential unless all the conditions of the thalidomide pregnancy prevention programme are met.

Patients receiving bortezomib in combination with thalidomide should adhere to the pregnancyprevention programme of thalidomide. Refer to the Summary of Product Characteristics ofthalidomide for additional 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 withbortezomib.

Fertility studies were not conducted with bortezomib (see section 5.3). Due to the genotoxicpotential of bortezomib (see section 5.3), male patients should seek advice on conservation ofsperm and women of childbearing potential should seek consultation regarding oocytecryopreservation prior to initiation of treatment.

Bortezomib may have a moderate influence on the ability to drive and use machines.

Bortezomib may be associated with fatigue very commonly, dizziness commonly, syncopeuncommonly and orthostatic/postural hypotension or blurred vision commonly. Therefore,patients must be cautious when driving or using machines and should be advised not to drive oroperate machinery if they experience these symptoms (see section 4.8).

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

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

Overall, bortezomib 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 estimatedfrom the available data). Within each frequency grouping, undesirable effects are presented in orderof decreasing 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 bortezomib inclinical trials and all post-marketing adverse reactions regardless of indication#

System Organ Class Incidence Adverse reaction

Infections and infestations Common Herpes zoster (inc disseminated & ophthalmic),

Pneumonia*, Herpes simplex*, Fungal infection*

Uncommon Infection*, Bacterial infections*, Viral infections*,

Sepsis (inc septic shock)*, Bronchopneumonia,

Herpes virus infection*, Meningoencephalitisherpetic#, Bacteraemia (inc staphylococcal),

Hordeolum, Influenza, Cellulitis, Device relatedinfection, Skin infection*, Ear infection*,

Staphylococcal infection, Tooth infection*

Rare Meningitis (inc bacterial), Epstein-Barr virusinfection, Genital herpes, Tonsillitis, Mastoiditis,

Post viral fatigue syndrome

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

Blood and lymphatic system Very common Thrombocytopenia*, Neutropenia*, Anaemia*disorders Common Leukopenia*, Lymphopenia*

Uncommon Pancytopenia*, Febrile neutropenia,

Coagulopathy*, Leukocytosis*,

Lymphadenopathy, Haemolytic anaemia#

Rare Disseminated intravascular coagulation,

Thrombocytosis*, Hyperviscosity syndrome,

Platelet disorder NOS, Thromboticmicroangiopathy (including thrombocytopenicpurpura)#, Blood disorder NOS, Haemorrhagicdiathesis, Lymphocytic infiltration

Immune system disorders Uncommon Angioedema#, Hypersensitivity*

Rare Anaphylactic shock, Amyloidosis, Type IIIimmune complex mediated reaction

Endocrine disorders Uncommon Cushing's syndrome*, Hyperthyroidism*,

Inappropriate antidiuretic hormone secretion

System Organ Class Incidence Adverse reaction

Rare Hypothyroidism

Metabolism and nutrition Very common Decreased appetitedisorders Common Dehydration, Hypokalaemia*, Hyponatraemia*,

Blood glucose abnormal*, Hypocalcaemia*,

Enzyme abnormality*

Uncommon Tumour lysis syndrome, Failure to thrive*,

Hypomagnesaemia*, Hypophosphataemia*,

Hyperkalaemia*, Hypercalcaemia*,

Hypernatraemia*, Uric acid abnormal*, Diabetesmellitus*, Fluid retention

Rare Hypermagnesaemia*, Acidosis, Electrolyteimbalance*, Fluid overload, Hypochloraemia*,

Hypovolaemia, Hyperchloraemia*,

Hyperphosphataemia*, Metabolic disorder,

Vitamin B complex deficiency, Vitamin B12deficiency, Gout, Increased appetite, Alcoholintolerance

Psychiatric disorders Common Mood disorders and disturbances*, Anxietydisorder*, Sleep disorders and disturbances*

Uncommon Mental disorder*, Hallucination*, Psychoticdisorder*, Confusion*, Restlessness

Rare Suicidal ideation*, Adjustment disorder, Delirium,

Libido decreased

Nervous system disorders Very common Neuropathies*, Peripheral sensory neuropathy,

Dysaesthesia*, Neuralgia*

Common Motor neuropathy*, Loss of consciousness (incsyncope), Dizziness*, Dysgeusia*, Lethargy,

Headache*

Uncommon Tremor, Peripheral sensorimotor neuropathy,

Dyskinesia*, Cerebellar coordination and balancedisturbances*, Memory loss (exc dementia)*,

Encephalopathy*, Posterior Reversible#

Encephalopathy Syndrome , Neurotoxicity,

Seizure disorders*, Post herpetic neuralgia, Speechdisorder*, Restless legs syndrome, Migraine,

Sciatica, Disturbance in attention, Reflexesabnormal*, Parosmia

Rare Cerebral haemorrhage*, Haemorrhage intracranial(inc subarachnoid)*, Brain oedema, Transientischaemic attack, Coma, Autonomic nervoussystem imbalance, Autonomic neuropathy, Cranialpalsy*, Paralysis*, Paresis*, Presyncope, Brainstem syndrome, Cerebrovascular disorder, Nerveroot lesion, Psychomotor hyperactivity, Spinal cordcompression, Cognitive disorder NOS, Motordysfunction, Nervous system disorder NOS,

Radiculitis, Drooling, Hypotonia, Guillain-Barrésyndrome #, Demyelinating polyneuropathy #

System Organ Class Incidence Adverse reaction

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

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

Blepharitis#, Eye inflammation*, Diplopia, Dryeye*, Eye irritation*, Eye pain, Lacrimationincreased, Eye discharge

Rare Corneal lesion*, Exophthalmos, Retinitis,

Scotoma, Eye disorder (inc. eyelid) NOS,

Dacryoadenitis acquired, Photophobia, Photopsia,

Optic neuropathy#, Different degrees of visualimpairment (up to blindness)*

Ear and labyrinth disorders Common Vertigo*

Uncommon Dysacusis (inc tinnitus)*,Hearing impaired (up toand inc deafness), Ear discomfort*

Rare Ear haemorrhage, Vestibular neuronitis, Eardisorder NOS

Cardiac disorders Uncommon Cardiac tamponade#, Cardio-pulmonary arrest*,

Cardiac fibrillation (inc atrial), Cardiac failure (incleft and right ventricular)*, 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 de pointes,

Angina unstable, Cardiac valve disorders*,

Coronary artery 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 peripheral circulation*, Vasculitis,

Hyperaemia (inc ocular)*

Rare Peripheral embolism, Lymphoedema, Pallor,

Erythromelalgia, Vasodilatation, Veindiscolouration, Venous insufficiency

System Organ Class Incidence Adverse reaction

Respiratory, thoracic and Common Dyspnoea*, Epistaxis, Upper/lower respiratorymediastinal disorders tract infection*, Cough*

Uncommon Pulmonary embolism, Pleural effusion, Pulmonaryoedema (inc acute), Pulmonary alveolarhaemorrhage#, Bronchospasm, Chronic obstructivepulmonary disease*, Hypoxaemia*, Respiratorytract congestion*, Hypoxia, Pleurisy*, Hiccups,

Rhinorrhoea, Dysphonia, Wheezing

Rare Respiratory failure, Acute respiratory distresssyndrome, Apnoea, Pneumothorax, Atelectasis,

Pulmonary hypertension, Haemoptysis,

Hyperventilation, Orthopnoea, Pneumonitis,

Respiratory alkalosis, Tachypnoea, Pulmonaryfibrosis, Bronchial disorder*, Hypocapnia*,

Interstitial lung disease, Lung infiltration, Throattightness, Dry throat, Increased upper airwaysecretion, Throat irritation, Upper-airway coughsyndrome

Gastrointestinal disorders Very common Nausea and vomiting symptoms*, Diarrhoea*,

Common Gastrointestinal haemorrhage (inc mucosal)*,

Dyspepsia, Stomatitis*, Abdominal distension,

Oropharyngeal pain*, Abdominal pain (incgastrointestinal and splenic pain)*, Oral disorder*,

Flatulence

Uncommon Pancreatitis (inc chronic)*, Haematemesis, Lipswelling*, Gastrointestinal obstruction (inc smallintestinal obstruction, ileus)*, Abdominaldiscomfort, 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*, Salivary glanddisorder*

Rare Pancreatitis acute, Peritonitis*, Tongue oedema*,

Ascites, Oesophagitis, Cheilitis, Faecalincontinence, Anal sphincter atony, Faecaloma*,

Gastrointestinal ulceration and perforation*,

Gingival hypertrophy, Megacolon, Rectaldischarge, Oropharyngeal blistering*, Lip pain,

Periodontitis, Anal fissure, Change of bowel habit,

Proctalgia, Abnormal faeces

Hepatobiliary disorders Common Hepatic enzyme abnormality*

Uncommon Hepatotoxicity (inc liver disorder), Hepatitis*,

Cholestasis

Rare Hepatic failure, Hepatomegaly, Budd-Chiarisyndrome, Cytomegalovirus hepatitis, Hepatichaemorrhage, Cholelithiasis

System Organ Class Incidence Adverse reaction

Skin and subcutaneous tissue Common Rash*, Pruritus*, Erythema, Dry skindisorders Uncommon Erythema multiforme, Urticaria, Acute febrileneutrophilic dermatosis, Toxic skin eruption, Toxicepidermal necrolysis#, Stevens-Johnson syndrome#,

Dermatitis*, Hair disorder*, Petechiae,

Ecchymosis, Skin lesion, Purpura, Skin mass*,

Psoriasis, Hyperhidrosis, Night sweats, Decubitusulcer#, Acne*, Blister*, Pigmentation disorder*

Rare Skin reaction, Jessner's lymphocytic infiltration,

Palmar-plantar erythrodysaesthesia syndrome,

Haemorrhage subcutaneous, Livedo reticularis,

Skin induration, Papule, Photosensitivity reaction,

Seborrhoea, Cold sweat, Skin disorder NOS,

Erythrosis, Skin ulcer, Nail disorder

Musculoskeletal and Very common Musculoskeletal pain*connective tissue disorders Common Muscle spasms*, Pain in extremity, Muscularweakness

Uncommon Muscle twitching, Joint swelling, Arthritis*, Jointstiffness, Myopathies*,Sensation of heaviness

Rare Rhabdomyolysis, Temporomandibular jointsyndrome, Fistula, Joint effusion, Pain in jaw,

Bone disorder, Musculoskeletal and connectivetissue infections and inflammations*, Synovial cyst

Renal and urinary disorders Common Renal impairment*

Uncommon Renal failure acute, Renal failure chronic*, Urinarytract infection*, Urinary tract signs andsymptoms*, Haematuria*, Urinary retention,

Micturition disorder*, Proteinuria, Azotaemia,

Oliguria*, Pollakiuria

Rare Bladder irritation

Reproductive system and Uncommon Vaginal haemorrhage, Genital pain*, Erectilebreast disorders dysfunction,

Rare Testicular disorder*, Prostatitis, Breast disorderfemale, Epididymal tenderness, Epididymitis,

Pelvic pain, Vulval ulceration

Congenital, familial and Rare Aplasia, Gastrointestinal malformation, Ichthyosisgenetic disorders

System Organ Class Incidence Adverse reaction

General disorders and Very common Pyrexia*, Fatigue, Astheniaadministration site Common Oedema (inc peripheral), Chills, Pain*, Malaise*conditions

Uncommon General physical health deterioration*, Faceoedema*, Injection site reaction*, Mucosaldisorder*, Chest pain, Gait disturbance, Feelingcold, Extravasation*, Catheter relatedcomplication*, Change in thirst*, Chestdiscomfort, Feeling of body temperature change*,

Injection site pain*

Rare Death (inc sudden), Multi-organ failure, Injectionsite haemorrhage*, Hernia (inc hiatus)*, Impairedhealing*, Inflammation, Injection site phlebitis*,

Tenderness, Ulcer, Irritability, Non-cardiac chestpain, Catheter site pain, Sensation of foreign body

Investigations Common Weight decreased

Uncommon Hyperbilirubinaemia*, Protein analyses abnormal*,

Weight increased, Blood test abnormal*,C-reactiveprotein increased

Rare Blood gases abnormal*, Electrocardiogramabnormalities (inc QT prolongation)*, Internationalnormalised ratio abnormal*, Gastric pH decreased,

Platelet aggregation increased, Troponin Iincreased, Virus identification and serology*,

Urine analysis abnormal*

Injury, poisoning and Uncommon Fall, Contusionprocedural complications Rare Transfusion reaction, Fractures*, Rigors*, Faceinjury, Joint injury*, Burns, Laceration, Proceduralpain, Radiation injuries*

Surgical and medical Rare Macrophage activationprocedures

NOS=not otherwise specified

* Grouping of more than one MedDRA preferred term.

# Postmarketing adverse reaction regardless of indication

Mantle cell lymphoma (MCL)

The safety profile of bortezomib in 240 MCL patients treated with bortezomib at 1.3 mg/m2 incombination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BR-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 (BR-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 bortezomib alone. Notable differences in the MCL patientpopulation as compared to patients in the multiple myeloma studies were a ≥ 5% higher incidenceof the haematological adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia,lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, andhair disorders.

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

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

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

BR-CAP arm that were considered by investigators to have at least a possible or probable causalrelationship to bortezomib 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 estimatedfrom the available data). Within each frequency grouping, undesirable effects are presented in orderof decreasing seriousness. Table 8 has been generated using Version 16 of the MedDRA.

Table 8: Adverse reactions in patients with mantle cell lymphoma treated with BR-CAP in aclinical trial

System Organ Class Incidence Adverse reaction

Infections and infestations Very common Pneumonia*

Common Sepsis (inc septic shock)*, Herpes zoster (incdisseminated & ophthalmic), Herpes virusinfection*, Bacterial infections*, Upper/lowerrespiratory tract infection*, Fungal infection*,

Herpes simplex*

Uncommon Hepatitis B, Infection*, Bronchopneumonia

Blood and lymphatic system Very common Thrombocytopenia*, Febrile neutropenia,disorders Neutropenia*, Leukopenia*, Anaemia*,

Lymphopenia*

Uncommon Pancytopenia*

Immune system disorders Common Hypersensitivity*

Uncommon Anaphylactic reaction

Metabolism and nutrition Very common Decreased appetitedisorders Common Hypokalaemia*, Blood glucose abnormal*,

Hyponatraemia*, Diabetes mellitus*, Fluidretention

Uncommon Tumour lysis syndrome

Psychiatric disorders Common Sleep disorders and disturbances*

Nervous system disorders Very common Peripheral sensory neuropathy, Dysaesthesia*,

Neuralgia*

Common Neuropathies*, Motor neuropathy*, Loss ofconsciousness (inc syncope), Encephalopathy*,

Peripheral sensorimotor neuropathy, Dizziness*,

Dysgeusia*, Autonomic neuropathy

Uncommon Autonomic nervous system imbalance

Eye disorders Common Vision abnormal*

Ear and labyrinth disorders Common Dysacusis (inc tinnitus)*

Uncommon Vertigo*, Hearing impaired (up to and incdeafness)

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*, Orthostatichypotension

Respiratory, thoracic and Common Dyspnoea*, Cough*, Hiccupsmediastinal disorders Uncommon Acute respiratory distress syndrome, Pulmonaryembolism, Pneumonitis, Pulmonary hypertension,

Pulmonary oedema (inc acute)

System Organ Class Incidence Adverse reaction

Gastrointestinal disorders Very common Nausea and vomiting symptoms*, Diarrhoea*,

Stomatitis*, Constipation

Common Gastrointestinal haemorrhage (inc mucosal)*,

Abdominal distension, Dyspepsia, Oropharyngealpain*, Gastritis*, Oral ulceration*, Abdominaldiscomfort, Dysphagia, Gastrointestinalinflammation*, Abdominal pain (incgastrointestinal and splenic pain)*, Oral disorder*

Uncommon Colitis (inc clostridium difficile)*

Hepatobiliary disorders Common Hepatotoxicity (inc liver disorder)

Uncommon Hepatic failure

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

Musculoskeletal and Common Muscle spasms*, Musculoskeletal pain*, Pain inconnective tissue disorders extremity

Renal and urinary disorders Common Urinary tract infection*

General disorders and Very common Pyrexia*, Fatigue, Astheniaadministration site Common Oedema (inc peripheral), Chills, Injection siteconditions reaction*, Malaise*

Investigations Common Hyperbilirubinaemia*, Protein analyses abnormal*,

Weight decreased, Weight increased

* Grouping of more than one MedDRA preferred term.

Herpes zoster virus reactivation

Antiviral prophylaxis was administered to 26% of the patients in the B+M+P arm. The incidence ofherpes zoster among patients in the B+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 BR-CAP arm. Theincidence of herpes zoster among patients in the BR-CAP arm was 10.7% for patients notadministered antiviral prophylaxis compared to 3.6% for patients administered antiviralprophylaxis (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-bortezomibtreatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP)and 0.4% (n=1) of patients receiving bortezomib in combination with rituximab,cyclophosphamide, doxorubicin, and prednisone (BR-CAP). The overall incidence of hepatitis Binfections was similar in patients treated with BR-CAP or with R-CHOP (0.8% vs 1.2%respectively).

Peripheral neuropathy in combination regimens

In trials in which bortezomib 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 andtreatment discontinuation due to peripheral neuropathy

IFM-2005-01 MMY-3010

VDDx BDx TDx BTDx(N=239) (N=239) (N=126) (N=130)

Incidence of PN (%)

All Grade PN 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; BDx=bortezomib, dexamethasone; TDx=thalidomide,dexamethasone; BTDx=bortezomib, thalidomide, dexamethasone; PN=peripheral neuropathy

Note: Peripheral neuropathy included the preferred terms: neuropathy peripheral, peripheral motorneuropathy, peripheral sensory neuropathy, and polyneuropathy.

In study LYM-3002 in which bortezomib was administered with rituximab, cyclophosphamide,doxorubicin, and prednisone (BR-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

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

Incidence of PN (%)

All Grade PN 30 29≥ Grade 2 PN 18 9≥ Grade 3 PN 8 4

Discontinuation due to PN (%) 2 < 1

BR-CAP=bortezomib, 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,peripheral motor neuropathy, and peripheral sensorimotor neuropathy

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

R-CHOP group.

Notable differences in the safety profile of bortezomib administered subcutaneously versusintravenously as single agent

In the Phase III study patients who received bortezomib subcutaneously compared to intravenousadministration had 13% lower overall incidence of treatment emergent adverse reactions that weregrade 3 or higher in toxicity, and a 5% lower incidence of discontinuation of bortezomib. Theoverall incidence of diarrhoea, gastrointestinal and abdominal pain, asthenic conditions, upperrespiratory tract infections and peripheral neuropathies were 12%-15% lower in the subcutaneousgroup than in the intravenous group. In addition, the incidence of grade 3 or higher peripheralneuropathies was 10% lower, and the discontinuation rate due to peripheral neuropathies 8% lowerfor the subcutaneous group as compared to the intravenous group.

Six percent of patients had an adverse local reaction to subcutaneous administration, mostlyredness. Cases resolved in a median of 6 days, dose modification was required in two patients. Two(1%) of the patients had severe reactions; 1 case of pruritus and 1 case of redness.

The incidence of death on treatment was 5% in the subcutaneous treatment group and 7% in theintravenous treatment group. Incidence of death from “Progressive disease” was 18% in thesubcutaneous group and 9% in the intravenous group.

Retreatment of patients with relapsed multiple myeloma

In a study in which bortezomib retreatment was administered in 130 patients with relapsed multiplemyeloma, who previously had at least partial response on a bortezomib-containing regimen, themost common all-grade adverse events occurring in at least 25% of patients werethrombocytopenia (55%), neuropathy (40%), anaemia (37%), diarrhoea (35%), and constipation(28%). All grade peripheral neuropathy 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.

It allows 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 acuteonset of symptomatic hypotension and thrombocytopenia with fatal outcomes. For preclinicalcardiovascular safety pharmacology studies, see section 5.3.

There is no known specific antidote for bortezomib overdose. In the event of an overdose, thepatient's vital signs should be monitored and appropriate supportive care given to maintain bloodpressure (such as fluids, pressors, and/or inotropic agents) and body temperature (see sections 4.2and 4.4).

5 PHARMACOLOGICAL PROPERTIES

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 of the 26S proteasome prevents this targeted proteolysis and affects multiple signallingcascades within the cell, ultimately resulting in cancer cell death.

Bortezomib is highly selective for the proteasome. At 10 μM 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 proteasomeinhibition were evaluated in vitro, and bortezomib was shown to dissociate from the proteasomewith a t½ of 20 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 marrowmicroenvironment.

Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types andthat cancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition thannormal cells. Bortezomib causes reduction of tumour growth in vivo in many preclinical tumourmodels, including multiple 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 bortezomib (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 administeredfor a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for diseaseprogression or unacceptable 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 thepatients was 80. Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a medianhemoglobin of 105 g/l, and a median platelet count of 221.5 x 109/l. Similar proportions of patientshad 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 metand patients in the M+P arm were offered B+M+P treatment. Median follow-up was 16.3 months.

The final survival update was performed with a median duration of follow-up of 60.1 months. Astatistically significant survival benefit in favour of the B+M+P treatment group was observed(HR=0.695; p=0.00043) despite subsequent therapies including bortezomib-based regimens.

Median survival for the B+M+P treatment group was 56.4 months compared to 43.1 for the M+Ptreatment group. Efficacy results are presented in table 11:

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

Efficacy endpoint B+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-valuec 0.00001

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

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 moa

Median 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)cp-value < 0.000001a Kaplan-Meier estimateb Hazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors:

β2-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: β2-microglobulin,albumin, and regiond p-value for Response Rate (CR+PR) from the Cochran Mantel-Haenszel chi-square test adjusted for thestratification factorse 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) wereconducted to demonstrate the safety and efficacy of bortezomib in dual and triple combinationswith other chemotherapeutic agents, as induction therapy prior to stem cell transplantation inpatients with previously untreated multiple myeloma.

In study IFM-2005-01 bortezomib combined with dexamethasone [BDx, n=240] was compared tovincristine-doxorubicin-dexamethasone [VDDx, n=242]. Patients in the BDx group received four21 day cycles, each consisting of bortezomib (1.3 mg/m2 administered intravenously twice weeklyon days 1, 4, 8, and 11), and oral dexamethasone (40 mg/day on days 1 to 4 and days 9 to 12, incycles 1 and 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 inthe VDDx and BDx groups respectively; the majority of patients underwent one single transplantprocedure. Patient demographic and baseline disease charateristics were similar between thetreatment groups. Median age of the patients in the study was 57 years, 55% were male and 48% ofpatients had high-risk cytogenetics. The median duration of treatment was 13 weeks for the VDDxgroup and 11 weeks for the BDx group. The median number of cycles received for both groups was4 cycles.

The primary efficacy endpoint of the study was post-induction response rate (CR+nCR). Astatistically significant difference in CR+nCR was observed in favour of the bortezomib combinedwith dexamethasone 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-2005-01a

Endpoints BDx VDDx OR; 95% CI; P value

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; B=bortezomib; BDx=bortezomib, dexamethasone; VDDx=vincristine, doxorubicin,dexamethasone; VGPR=very good partial 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 BDx group and 52/242 [21%] in VDDx group).

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

In study MMY-3010 induction treatment with bortezomib combined with thalidomide anddexamethasone [BTDx, n=130] was compared to thalidomide-dexamethasone [TDx, n=127].

Patients in the BTDx group received six 4-week cycles, each consisting of bortezomib (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), andthalidomide (administered orally at 50 mg daily on days 1-14, increased to 100 mg on days 15-28and thereafter to 200 mg daily).

One single autologous stem cell transplant was received by 105 (81%) patients and 78 (61%)patients in the BTDx and TDx groups, respectively. Patient demographic and baseline diseasecharacteristics were similar between the treatment groups. Patients in the BTDx and TDx groupsrespectively had a median age of 57 versus 56 years, 99% versus 98% patients were Caucasians,and 58% versus 54% were males. In the BTDx group 12% of patients were cytogeneticallyclassified as high risk versus 16% of patients in the TDx group. The median duration of treatmentwas 24.0 weeks and the median number of treatment cycles received was 6.0, and was consistentacross 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 thebortezomib combined with dexamethasone and thalidomide group. Secondary efficacy endpointsincluded Progression Free Survival and Overall Survival. Main efficacy results are presented intable 13.

Table 13: Efficacy results from study MMY-3010a

Endpoints BTDx TDx OR; 95% CI; P value

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 84.6 (77.2, 90.3) 61.4 (52.4, 69.9) 3.46 (1.90, 6.27);% (95% CI) < 0.001a

*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 77.7 (69.6, 84.5) 56.7 (47.6, 65.5) 2.66 (1.55, 4.57);% (95% CI) < 0.001a

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

RR=response rate; BTDx=bortezomib, thalidomide, dexamethasone; TDx=thalidomide, dexamethasone;

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.

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

Clinical efficacy in relapsed or refractory multiple myeloma

The safety and efficacy of bortezomib (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 hadreceived 1-3 prior lines of therapy, and a Phase II single-arm study of 202 patients with relapsedand refractory multiple myeloma, who had received at least 2 prior lines of treatment and who wereprogressing on their most recent treatment.

In the Phase III study, treatment with bortezomib led to a significantly longer time to progression, asignificantly prolonged survival and a significantly higher response rate, compared to treatmentwith dexamethasone (see table 14), in all patients as well as in patients who have received 1 priorline of therapy. As a result of a pre-planned interim analysis, the dexamethasone arm was halted atthe recommendation of the data monitoring committee and all patients randomised todexamethasone were then offered bortezomib, regardless of disease status. Due to this earlycrossover, the median duration of follow-up for surviving patients is 8.3 months. Both in patientswho were refractory to their last prior therapy and those who were not refractory, overall survivalwas significantly longer and response rate was significantly higher on the bortezomib arm.

Of the 669 patients enrolled, 245 (37%) were 65 years of age or older. Response parameters as wellas TTP remained significantly better for bortezomib independently of age. Regardless ofβ2-microglobulin levels at baseline, all efficacy parameters (time to progression and overallsurvival, as well as response rate) were significantly improved on the bortezomib 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 numberor type of previous therapies. Patients who had received 2 to 3 prior therapeutic regimens had aresponse rate of 32% (10/32) and patients who received greater than 7 prior therapeutic regimenshad a response rate 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

All patients 1 prior line of > 1 prior line of ≥ 2 priortherapy therapy lines

Time related B Dex B Dex B Dex Ba a a a aevents n=333 n=336 n=132 n=119 n=200 a an=217 n=202

TTP, days 189b 106b 212d 169d 148b 87b 210[95% CI] [148, 211] [86, 128] [188, 267] [105, 191] [129, 192] [84, 107] [154, 281]1 year survival, %[95% CI] 80d 66d 89d 72d 73 62[74,85] [59,72] [82,95] [62,83] [64,82] [53,71] 60

Best response B Dex B Dex B Dex Bc c(%) n=315 n=312 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+PR+MR 146 (46) 108 (35) 66 (52) 45 (41) 80 (43) 63 (31) (35)**

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

Days (months)

Time to response 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 therapeutichistory; p < 0.0001c Response population includes patients who had measurable disease at baseline and received at least 1 doseof study medicinal product.d p-value from the Cochran Mantel-Haenszel chi-square test adjusted for the stratification factors; analysis byline of therapy excludes stratification 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

B=bortezomib; 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 bortezomibalone were able to receive high-dose dexamethasone in conjunction with bortezomib. The protocolallowed patients to receive dexamethasone if they had had a less than optimal response tobortezomib alone. A total of 74 evaluable patients were administered dexamethasone incombination with bortezomib. Eighteen percent of patients achieved, or had an improved response[MR (11%) or PR (7%)] with combination treatment.

Clinical efficacy with subcutaneous administration of bortezomib in patients withrelapsed/refractory multiple myeloma

An open label, randomised, Phase III non-inferiority study compared the efficacy and safety of thesubcutaneous administration of bortezomib versus the intravenous administration. This studyincluded 222 patients with relapsed/refractory multiple myeloma, who were randomised in a 2:1ratio to receive 1.3 mg/m2 of bortezomib by either the subcutaneous or intravenous route for8 cycles. Patients who did not obtain an optimal response (less than Complete Response [CR]) totherapy with bortezomib alone after 4 cycles were allowed to receive dexamethasone 20 mg dailyon the day of and after bortezomib administration. Patients with baseline grade ≥ 2 peripheralneuropathy or platelet counts < 50,000/µl were excluded. A total of 218 patients were evaluable forresponse.

This study met its primary objective of non-inferiority for response rate (CR+PR) after 4 cycles ofsingle agent bortezomib for both the subcutaneous and intravenous routes, 42% in both groups. Inaddition, secondary response-related and time to event related efficacy endpoints showed consistentresults for subcutaneous and intravenous administration (table 15).

Table 15: Summary of efficacy analyses comparing subcutaneous and intravenousadministrations of bortezomib

Bortezomib intravenous Bortezomib subcutaneousarm arm

Response Evaluable Population n=73 n=145

Response Rate at 4 cycles n (%)

ORR (CR+PR) 31 (42) 61 (42)p-valuea 0.00201

CR n (%) 6 (8) 9 (6)

PR n (%) 25 (34) 52 (36)nCR n (%) 4 (5) 9 (6)

Response Rate at 8 cycles n (%)

ORR (CR+PR) 38 (52) 76 (52)p-valuea 0.0001

CR n (%) 9 (12) 15 (10)

PR n (%) 29 (40) 61 (42)nCR n (%) 7 (10) 14 (10)b

Intent to Treat Population n=74 n=148

TTP, months 9.4 10.4(95% CI) (7.6, 10.6) (8.5, 11.7)

Hazard ratio (95% CI)c 0.839 (0.564, 1.249)p-valued 0.38657

Progression Free Survival, months 8.0 10.2(95% CI) (6.7, 9.8) (8.1, 10.8)

Hazard ratio (95% CI)c 0.824 (0.574, 1.183)p-valued 0.295e1-year Overall Survival (%) 76.7 72.6(95% CI) (64.1, 85.4) (63.1, 80.0)a p-value is for the non-inferiority hypothesis that the SC arm retains at least 60% of the response rate in the

IV arm.b 222 subjects were enrolled into the study; 221 subjects were treated with bortezomibc Hazards ratio estimate is based on a Cox model adjusted for stratification factors: ISS staging and number ofprior lines.d Log rank test adjusted for stratification factors: ISS staging and number of prior lines.e Median duration of follow up is 11.8 months

Bortezomib combination treatment with pegylated liposomal doxorubicin (study

DOXIL-MMY-3001)

A Phase III randomised, parallel-group, open-label, multicentre study was conducted in646 patients comparing the safety and efficacy of bortezomib plus pegylated liposomal doxorubicinversus bortezomib monotherapy in patients with multiple myeloma who had received at least 1prior therapy and who did not progress while receiving anthracycline-based therapy. The primaryefficacy endpoint was 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 terminationfor efficacy. This interim analysis showed a TTP risk reduction of 45% (95% CI; 29-57%,p < 0.0001) for patients treated with combination therapy of bortezomib and pegylated liposomaldoxorubicin. The median TTP was 6.5 months for the bortezomib monotherapy patients comparedwith 9.3 months for the bortezomib plus pegylated liposomal doxorubicin combination therapypatients. 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 bortezomib monotherapy patients and 33.0 months (95% CI; 28.9-37.1months) for the bortezomib plus pegylated liposomal doxorubicin combination therapy patients.

Bortezomib combination treatment with dexamethasone

In the absence of any direct comparison between bortezomib and bortezomib in combination withdexamethasone in patients with progressive multiple myeloma, a statistical matched-pair analysiswas conducted to compare results from the non randomised arm of bortezomib in combination withdexamethasone (Phase II open-label study MMY-2045), with results obtained in the bortezomibmonotherapy 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.

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

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

One hundred and twenty seven matched pairs of patients were identified. The analysisdemonstrated improved 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 bortezomib in combination with dexamethasone over bortezomib monotherapy.

Limited information on bortezomib 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 bortezomib. One hundred and thirty patients (≥ 18 yearsof age) with multiple myeloma who previously had at least partial response on abortezomib-containing regimen were retreated upon progression. At least 6 months after priortherapy, bortezomib was started 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, 8 and 11 every 3 weeks for maximum of 8 cycles either as singleagent or in combination with dexamethasone in accordance with the standard of care.

Dexamethasone was administered in combination with bortezomib to 83 patients in cycle 1 with anadditional 11 patients receiving dexamethasone during the course of bortezomib retreatment cycles.

The primary endpoint was best confirmed response to retreatment as assessed by EBMT criteria.

The overall 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 safetyof the combination of bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone(BR-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 inthe BR-CAP treatment arm received bortezomib (1.3 mg/m2; on days 1, 4, 8, 11, rest perioddays 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 the21 day bortezomib treatment cycle. For patients with a response first documented at cycle 6, twoadditional treatment cycles 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 tonext anti-lymphoma treatment (TNT), duration of treatment free interval (TFI), overall responserate (ORR) and complete response (CR/CRu) rate, overall survival (OS) and response duration.

The demographic and baseline disease characteristics were generally well balanced between thetwo treatment arms: median patient age was 66 years, 74% were male, 66% were Caucasian and32% Asian, 69% of patients had a positive bone marrow aspirate and/or a positive bone marrowbiopsy for MCL, 54% of patients had an International Prognostic Index (IPI) score of ≥ 3, and 76%had Stage IV disease. Treatment duration (median=17 weeks) and duration of follow-up(median=40 months) were comparable in both treatment arms. A median of 6 cycles was receivedby patients in both treatment arms with 14% of subjects in the BR-CAP group and 17% of patientsin the R-CHOP group receiving 2 additional cycles. The majority of the patients in both groupscompleted treatment, 80% in the BR-CAP group and 82% in the R-CHOP group. Efficacy resultsare presented in table 16:

Table 16: Efficacy results from study LYM-3002

Efficacy endpoint BR-CAP R-CHOPn: ITT patients 243 244a

Progression free survival (IRC)

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

Medianc (95% CI) 24.7 (19.8; 31.8) 14.4 (12; 16.9) (0.50; 0.79)(months) p-valued < 0.001

Response raten: response-evaluable 229 228patientse

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

Overall response 211 (92.1%) 204 (89.5%) OR (95% CI)=1.428(CR+CRu+PR)h n(%) (0.749; 2.722)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 advantage for BR-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 ofdisease as stratification factors. An odds ratio (OR) > 1 indicates an advantage for BR-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 stratificationfactors.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 BR-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 BR-CAP treatment group over the R-CHOP group was observed for

TTP (median 30.5 versus 16.1 months), TNT (median 44.5 versus 24.8 months) and TFI (median40.6 versus 20.5 months). The median duration of complete response was 42.1 months in the

BR-CAP group compared with 18 months in the R-CHOP group. The duration of overall responsewas 21.4 months longer in the BR-CAP group (median 36.5 months versus 15.1 months in the

R-CHOP group). The final analysis for OS was performed after a median follow-up of 82 months.

Median OS was 90.7 months for the BR-CAP group compared with 55.7 months for the R-CHOPgroup (HR=0.66; p=0.001). The observed final median difference in the OS between the 2treatment groups was 35 months.

Patients with previously treated light-chain (AL) Amyloidosis

An open label non randomised Phase I/II study was conducted to determine the safety and efficacyof bortezomib in patients with previously treated light-chain (AL) Amyloidosis. No new safetyconcerns were observed during the study, and in particular bortezomib did not exacerbate targetorgan 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 in49 evaluable patients treated with the maximum allowed doses of 1.6 mg/m2 weekly and 1.3 mg/m2twice-weekly. For these dose cohorts, the combined 1-year survival rate was 88.1%.

The European Medicines Agency has waived the obligation to submit the results of studies withbortezomib 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]). Aneffective reinduction multiagent chemotherapy regimen was administered in 3 blocks. Bortezomibwas administered only in Blocks 1 and 2 to avoid potential overlapping toxicities withcoadministered drugs in Block 3.

Complete response (CR) was evaluated at the end of Block 1. In B-ALL patients with relapsewithin 18 months of diagnosis (n=27) the CR rate was 67% (95% CI: 46, 84); the 4-month eventfree survival rate was 44% (95% CI: 26, 62). In B-ALL patients with relapse 18-36 months fromdiagnosis (n=33) the CR rate was 79% (95% CI: 61, 91) and the 4-month event free survival ratewas 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 reportedefficacy data are considered inconclusive (see section 4.2).

There were 140 patients with ALL or LL enrolled and evaluated for safety; median age was10 years (range 1 to 26). No new safety concerns were observed when bortezomib was added to thestandard pediatric pre B cell ALL chemotherapy backbone. The following adverse reactions(grade ≥ 3) were observed at a higher incidence in the bortezomib containing treatment regimen ascompared with a historical control study in which the backbone regimen was given alone: in

Block 1 peripheral sensory neuropathy (3% versus 0%); ileus (2.1% versus 0%); hypoxia (8%versus 2%). No information on possible sequelae or rates of peripheral neuropathy resolution wereavailable in this study. Higher incidences were also noted for infections with grade ≥ 3 neutropenia(24% versus 19% in Block 1 and 22% versus 11% in Block 2), increased ALT (17% versus 8% in

Block 2), hypokalaemia (18% versus 6% in Block 1 and 21% versus 12% in Block 2) andhyponatraemia (12% versus 5% in Block 1 and 4% 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.

Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to patients withmultiple myeloma (n=14 in the intravenous group, n=17 in the subcutaneous group), the totalsystemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous andintravenous administrations. The Cmax after subcutaneous administration (20.4 ng/ml) was lowerthan intravenous (223 ng/ml). The AUClast geometric mean ratio was 0.99 and 90% confidenceintervals were 80.18%-122.80%.

The mean distribution volume (Vd) of bortezomib ranged from 1,659 l to 3,294 l following single-or repeated-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 isozymes indicate that bortezomib is primarily oxidatively metabolised via cytochrome P450enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form twodeboronated metabolites that subsequently undergo hydroxylation to several metabolites.

Deboronated-bortezomib metabolites are 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.

Mean total body clearances were 102 and 112 l/h following the first dose for doses of 1.0 mg/m2and 1.3 mg/m2, respectively, and ranged from 15 to 32 l/h and 18 to 32 l/h following subsequentdoses for doses 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 wereincreased by approximately 60% in patients with moderate or severe hepatic impairment. A lowerstarting dose is recommended in patients with moderate or severe hepatic impairment, and thosepatients should be closely 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 bortezomib twice weekly. Exposure ofbortezomib (dose-normalised AUC and Cmax) was comparable among all the groups (seesection 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 acutelymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Based on a populationpharmacokinetic 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 atsteady-state was 834 (39%) L/m2, and the elimination half-life was 100 (44%) hours. Aftercorrecting for the BSA effect, other demographics such as age, body weight and sex did not haveclinically significant effects on bortezomib clearance. BSA-normalized clearance of bortezomib inpediatric patients was similar to that observed in adults.

Bortezomib showed genotoxic potential. Bortezomib was positive for clastogenic activity(structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinesehamster ovary (CHO) cells at concentrations as low as 3.125 μg/ml, which was the lowestconcentration evaluated. Bortezomib was not positive when tested in the in vitro mutagenicityassay (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 studieswere not performed but evaluation of reproductive tissues has been performed in the generaltoxicity studies. In the 6-month rat study, degenerative effects in both the testes and the ovary havebeen observed. It is, therefore, likely that bortezomib could have a potential effect on either male orfemale fertility. 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, miceand dogs) involving sensory nerve axons; and mild changes in the kidneys. All these target organshave shown partial to full recovery following discontinuation of treatment.

Based on animal studies, the penetration of bortezomib through the blood-brain barrier appears tobe limited, 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 associatedwith increases in heart rate, decreases in contractility, hypotension and death. In dogs, thedecreased cardiac contractility and hypotension responded to acute intervention with positiveinotropic or pressor agents. Moreover, in dog studies, a slight increase in the corrected QT intervalwas observed.

6 PHARMACEUTICAL PARTICULARS

Mannitol (E 421)

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

Unopened vial2 years

The chemical and physical in-use stability of the reconstituted solution has been demonstrated atconcentrations of 1 mg/ml and 2.5 mg/ml for 96 hours at 25°C and 8 days at 2-8°C, when stored inthe original vial and/or a syringe.

From a microbiological point of view, the reconstituted solution should be used immediately afterpreparation. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user. The total storage time for the reconstituted medicinal product should notexceed 96 hours (if stored at 25°C) and 8 days (if stored at 2-8 °C) prior to administration.

This medicinal product does not require any special temperature storage condition.

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.

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection10 ml clear Type I glass vial with grey chlorobutyl rubber stopper and yellow aluminium flip-offover seal, containing 2.5 mg bortezomib.

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection10 ml clear Type I glass vial with grey chlorobutyl rubber stopper and blue aluminium flip-off overseal, containing 3.5 mg bortezomib.

The vial is shrink wrapped (without tray) or placed in a tray with a lid. Each pack contains1 single-use vial.

Bortezomib is a cytotoxic agent. Therefore, caution should be used during handling and preparationof bortezomib. Use of gloves and other protective clothing to prevent skin contact is recommended.

Aseptic technique must be strictly observed throughout the handling of bortezomib, since itcontains no preservative.

There have been fatal cases of inadvertent intrathecal administration of bortezomib. Bortezomib

Fresenius Kabi 1 mg powder for solution for injection is for intravenous use only, while

Bortezomib Fresenius Kabi 2.5 and 3.5 mg powder for solution for injection is for intravenous orsubcutaneous use. Bortezomib should not be administered intrathecally.

Bortezomib must be reconstituted by a healthcare professional.

Intravenous injection

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection

Each 10 ml vial of Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection must becarefully reconstituted with 2.5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, byusing a syringe of the appropriate size, without removing the vial stopper. Dissolution of thelyophilised 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 forparticulate matter and discolouration prior to administration. If any discolouration or particulatematter is observed, the reconstituted solution must be discarded.

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection

Each 10 ml vial of Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection must becarefully reconstituted with 3.5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, byusing a syringe of the appropriate size, without removing the vial stopper. Dissolution of thelyophilised 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 priorto administration. If any discolouration or particulate matter is observed, the reconstituted solutionmust be discarded.

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection

Each 10 ml vial of Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection must becarefully reconstituted with 1 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, byusing a syringe of the appropriate size, without removing the vial stopper. Dissolution of thelyophilised powder is completed in less than 2 minutes.

After reconstitution, each ml solution contains 2.5 mg bortezomib. The reconstituted solution isclear and colourless, with a final pH of 4 to 7. The reconstituted solution must be inspected visuallyfor particulate matter and discolouration prior to administration. If any discolouration or particulatematter is observed, the reconstituted solution must be discarded.

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection

Each 10 ml vial of bortezomib must be carefully reconstituted with 1.4 ml of sodium chloride9 mg/ml (0.9%) solution for injection, by using a syringe of the appropriate size, without removingthe vial stopper. Dissolution of the lyophilised powder is completed in less than 2 minutes.

After reconstitution, each ml solution contains 2.5 mg bortezomib. The reconstituted solution isclear and colourless, with a final pH of 4 to 7. The reconstituted solution must be inspected visuallyfor particulate matter and discolouration prior to administration. If any discolouration or particulatematter is observed, the reconstituted solution must be discarded.

Bortezomib is for single use only. Any unused medicinal product or waste material should bedisposed of in accordance with local requirements.

Fresenius Kabi Deutschland GmbH

Else-Kröner-Straße 1,61352 Bad Homburg v.d.Höhe

Germany

EU/1/19/1397/003

EU/1/19/1397/001

Date of first authorisation: 14 November 2019

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

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