Bortezomib Fresenius Kabi

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ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 

 

 

 
 

 

 
 

 

 
 

 

 

 
 

 

 
 

 

 

 
 

 

 
 

 

 
 

 

 

 
 

 

 



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1. NAME OF THE MEDICINAL PRODUCT 

 
Bortezomib Fresenius Kabi 1 mg powder for solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

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

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

 

For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for solution for injection. 
 
White to off-white lyophilized powder or cake. 
 
 
4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Bortezomib as monotherapy or in combination with pegylated liposomal doxorubicin or 

dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma 

who have received at least 1 prior therapy and who have already undergone or are unsuitable for 
haematopoietic stem cell transplantation. 

 

Bortezomib in combination with melphalan and prednisone is indicated for the treatment of adult 
patients with previously untreated multiple myeloma who are not eligible for high-dose 

chemotherapy with haematopoietic stem cell transplantation. 

 
Bortezomib in combination with dexamethasone, or with dexamethasone and thalidomide, is 

indicated for the induction treatment of adult patients with previously untreated multiple myeloma 

who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation. 

 
Bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone is 

indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who 

are unsuitable for haematopoietic stem cell transplantation. 
 

4.2 Posology and method of administration 
 

Bortezomib treatment must be initiated under supervision of a physician experienced in the 
treatment of cancer patients, however bortezomib may be administered by a healthcare professional 

experienced in use of chemotherapeutic agents. Bortezomib must be reconstituted by a healthcare 

professional (see section 6.6). 

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

prior therapy) 

Monotherapy 
Bortezomib Fresenius Kabi 1 mg powder for solution for injection is administered via intravenous 

injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on 

days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment 

cycle. It is recommended that patients receive 2 cycles of bortezomib following a confirmation of a 
complete response. It is also recommended that responding patients who do not achieve a complete 



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remission receive a total of 8 cycles of bortezomib therapy. At least 72 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 any 
grade 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 a 

25% reduced dose (1.3 mg/m2 reduced to 1.0 mg/m2; 1.0 mg/m2 reduced to 0.7 mg/m2). If the 

toxicity is not resolved or if it recurs at the lowest dose, discontinuation of bortezomib must be 
considered 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 to 

be managed as presented in table 1 (see section 4.4). Patients with pre-existing severe neuropathy 

may 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 

reflexes or paresthesia) with no pain or loss of 

function 

None 

Grade 1 with pain or grade 2 (moderate 

symptoms; limiting instrumental Activities of 

Daily Living (ADL)**) 

Reduce bortezomib to 1.0 mg/m2 

or 

Change bortezomib treatment schedule to 

1.3 mg/m2 once per week. 

Grade 2 with pain or grade 3 (severe symptoms; 

limiting self care ADL***) 

Withhold bortezomib treatment until symptoms 

of toxicity have resolved. When toxicity resolves 

re-initiate bortezomib treatment and reduce dose 

to 0.7 mg/m2 once per week 

Grade 4 (life-threatening consequences; urgent 

intervention indicated)  

and/or severe autonomic neuropathy 

Discontinue bortezomib 

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

experience. 

Grading based on NCI Common Toxicity Criteria CTCAE v 4.0. 

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

money, etc; 

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

products, and not bedridden. 

 

Combination therapy with pegylated liposomal doxorubicin 

Bortezomib Fresenius Kabi 1 mg powder for solution for injection is administered via intravenous 

injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on 

days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment 

cycle. At least 72 hours should elapse between consecutive doses of bortezomib. 

 

Pegylated liposomal doxorubicin is administered at 30 mg/m2 on day 4 of the bortezomib treatment 

cycle 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 not 

progressed and tolerate treatment. Patients achieving a complete response can continue treatment 

for at least 2 cycles after the first evidence of complete response, even if this requires treatment for 

more than 8 cycles. Patients whose levels of paraprotein continue to decrease after 8 cycles can also 

continue for as long as treatment is tolerated and they continue to respond. 

For additional information concerning pegylated liposomal doxorubicin, see the corresponding 



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Summary of Product Characteristics. 

Combination with dexamethasone 

Bortezomib Fresenius Kabi 1 mg powder for solution for injection is administered via intravenous 

injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on 

days 1, 4, 8, and 11 in a 21 day treatment cycle. This 3-week period is considered a treatment cycle. 

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

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

bortezomib treatment cycle. 

Patients achieving a response or a stable disease after 4 cycles of this combination therapy can 

continue 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 guidelines 

described under monotherapy above. 

 

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

cell transplantation 

Combination therapy with melphalan and prednisone 

Bortezomib Fresenius Kabi 1 mg powder for solution for injection is administered via intravenous 

injection in combination with oral melphalan and oral prednisone as shown in table 2. A 6-week 

period is considered a treatment cycle. In cycles 1-4, bortezomib is administered twice weekly on 

days 1, 4, 8, 11, 22, 25, 29 and 32. In cycles 5-9, bortezomib is administered once weekly on days 

1, 8, 22 and 29. At least 72 hours should elapse between consecutive doses of bortezomib. 

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

each 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 
(1.3 mg/m2) 

Day 
1 

-- -- Day 
4 

Day 
8 

Day 
11 

rest 
period 

Day 
22 

Day 
25 

Day 
29 

Day 
32 

rest 
period 

M (9 mg/m2) 
P (60 mg/m2) 

Day 
1 

Day 
2 

Day 
3 

Day 
4 

-- -- rest 
period 

-- -- -- -- rest 
period 

Once weekly bortezomib (cycles 5-9) 

Week 1 2 3 4 5 6 

B 

(1.3 mg/m2) 

Day 

1 

-- -- -- Day 

8 

rest 

period 

Day 

22 

Day 

29 

rest 

period 

M (9 mg/m2) 

P (60 mg/m2) 

Day 

1 

Day 

2 

Day 

3 

Day 

4 

-- rest 

period 

-- 
 

rest 

period 

B=bortezomib; M=melphalan, P=prednisone 

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

melphalan 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 
 
 



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Table 3:  Posology modifications during subsequent cycles of bortezomib therapy in 

 combination with melphalan and prednisone 

Toxicity Posology modification or delay 

Haematological toxicity during a cycle 
 

• If prolonged grade 4 neutropenia or 
thrombocytopenia, or thrombocytopenia with 

bleeding is observed in the previous cycle 

Consider reduction of the melphalan dose by 

25% in the next cycle. 

• If platelet counts ≤ 30 x 109/l or ANC 
≤ 0.75 x 109/l on a bortezomib dosing day 

(other than day 1) 

Bortezomib therapy should be withheld 

• If several bortezomib doses in a cycle are 
withheld (≥ 3 doses during twice weekly 

administration or ≥ 2 doses during weekly 
administration) 

Bortezomib dose should be reduced by 1 dose 

level (from 1.3 mg/m2 to 1 mg/m2, or from 
1 mg/m2 to 0.7 mg/m2) 

Grade ≥ 3 non-haematological toxicities Bortezomib therapy should be withheld until 
symptoms of the toxicity have resolved to 

grade 1 or baseline. Then, bortezomib may be 

reinitiated with one dose level reduction (from 
1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 

0.7 mg/m2). For bortezomib-related neuropathic 

pain and/or peripheral neuropathy, hold and/or 
modify bortezomib as outlined in table 1. 

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

of Product Characteristics. 

 
Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell 

transplantation (induction therapy) 

Combination therapy with dexamethasone 
Bortezomib Fresenius Kabi 1 mg powder for solution for injection is administered via intravenous 

injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on 

days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment 

cycle. At least 72 hours should elapse between consecutive doses of bortezomib. 
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the bortezomib 

treatment cycle. 

Four treatment cycles of this combination therapy are administered. 
 

Combination therapy with dexamethasone and thalidomide 

Bortezomib Fresenius Kabi 1 mg powder for solution for injection is administered via intravenous 
injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on 

days 1, 4, 8, and 11 in a 28-day treatment cycle. This 4-week period is considered a treatment 

cycle. At least 72 hours should elapse between consecutive doses of bortezomib. 

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

Thalidomide is administered orally at 50 mg daily on days 1-14 and if tolerated the dose is 

increased to 100 mg on days 15-28, and thereafter may be further increased to 200 mg daily from 
cycle 2 (see table 4). 

Four treatment cycles of this combination are administered. It is recommended that patients with at 

least partial response receive 2 additional cycles. 

 
Table 4:  Posology for bortezomib combination therapy for patients with previously untreated 

multiple myeloma eligible for haematopoietic stem cell transplantation 

 
 



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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 - - 

Cycles 2 to 4
b
 

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=thalidomide 
a Thalidomide dose is increased to 100 mg from week 3 of cycle 1 only if 50 mg is tolerated and to 200 mg 

from 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 monotherapy 

should be followed. 
In addition, when bortezomib is given in combination with other chemotherapeutic medicinal 

products, appropriate dose reductions for these products should be considered in the event of 

toxicities 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 1 mg powder for solution for injection is administered via intravenous 

injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on 

days 1, 4, 8, and 11, followed by a 10-day rest period on days 12-21. This 3-week period is 

considered a treatment cycle. Six bortezomib cycles are recommended, although for patients with a 
response first documented at cycle 6, two additional bortezomib cycles may be given. At least 72 

hours should elapse between consecutive doses of bortezomib. 

 
The following medicinal products are administered on day 1 of each bortezomib 3 week treatment 

cycle as intravenous infusions: rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2 and 

doxorubicin at 50 mg/m2. 
Prednisone is administered orally at 100 mg/m2 on days 1, 2, 3, 4 and 5 of each bortezomib 

treatment 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) should 
be ≥ 1,500 cells/μL 

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

- Haemoglobin ≥ 8 g/dL 
- Non-haematological toxicities should have resolved to grade 1 or baseline. 
 



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Bortezomib treatment must be withheld at the onset of any ≥ grade 3 bortezomib -related 

non-haematological toxicities (excluding neuropathy) or ≥ grade 3 haematological toxicities (see 
also section 4.4). For dose adjustments, see table 5 below. 

Granulocyte colony stimulating factors may be administered for haematologic toxicity according to 

local standard practice. Prophylactic use of granulocyte colony stimulating factors should be 
considered in case of repeated delays in cycle administration. Platelet transfusion for the treatment 

of thrombocytopenia should be considered when clinically appropriate. 

 

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

Toxicity Posology modification or delay 

Haematological toxicity 

- ≥ Grade 3 neutropenia with fever, grade 4 
neutropenia lasting more than 7 days, a 
platelet count < 10,000 cells/μL 

Bortezomib therapy should be withheld for up to 

2 weeks until the patient has an ANC 
≥ 750 cells/μL and a platelet count 

≥ 25,000 cells/μL. 

- If, after bortezomib has been held, the 
toxicity 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 be 

reinitiated at a dose reduced by one dose 

level (from 1.3 mg/m2 to 1 mg/m2, or from 
1 mg/m2 to 0.7 mg/m2). 

- If platelet counts < 25,000 cells/μL. or ANC 
< 750 cells/μL on a bortezomib dosing day 

(other than Day 1 of each cycle) 

Bortezomib therapy should be withheld 

Grade ≥ 3 non-haematological toxicities 

considered to be related to bortezomib  

Bortezomib therapy should be withheld until 

symptoms of the toxicity have resolved to 

grade 2 or better. Then, bortezomib may be 
reinitiated at a dose reduced by one dose level 

(from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 

0.7 mg/m2). For bortezomib-related neuropathic 

pain and/or peripheral neuropathy, hold and/or 
modify bortezomib as outlined in table 1. 

 

In addition, when bortezomib is given in combination with other chemotherapeutic medicinal 

products, appropriate dose reductions for these medicinal products should be considered in the 
event of toxicities, according to the recommendations in the respective Summary of Product 

Characteristics. 

 

Special populations 
 

Elderly 

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

There are no studies on the use of bortezomib in elderly patients with previously untreated multiple 

myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell 
transplantation. Therefore no dose recommendations can be made in this population. 

In a study in previously untreated mantle cell lymphoma patients, 42.9% and 10.4% of patients 

exposed to bortezomib were in the range 65-74 years and ≥ 75 years of age, respectively. In 

patients aged ≥ 75 years, both regimens, BR-CAP as well as R-CHOP, were less tolerated (see 
section 4.8). 

 



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Hepatic impairment 

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

bortezomib at a reduced dose of 0.7 mg/m2 per injection during the first treatment cycle, and a 

subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered 
based on patient tolerability (see table 6 and sections 4.4 and 5.2). 

 

Table 6:  Recommended starting dose modification for bortezomib in patients with hepatic 

impairment 

Grade of hepatic 

impairment* 
Bilirubin level SGOT (AST) 

levels 
Modification of starting 

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 to 

0.7 mg/m2 in the first 

treatment cycle. Consider 
dose escalation to 1.0 mg/m2 

or further dose reduction to 

0.5 mg/m2 in subsequent 
cycles based on patient 

tolerability. 

Severe > 3 x ULN Any 

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). 

 

Renal impairment 
The pharmacokinetics of bortezomib are not influenced in patients with mild to moderate renal 

impairment (Creatinine Clearance [CrCL] > 20 ml/min/1.73 m2); therefore, dose adjustments are 

not necessary for these patients. It is unknown if the pharmacokinetics of bortezomib are influenced 
in 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 the 

dialysis procedure (see section 5.2). 
 

Paediatric population 

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 no 
recommendation on a posology can be made. 

 

Method of administration 
 

Bortezomib Fresenius Kabi 1 mg powder for solution for injection is available for intravenous 

administration only.  
 

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection is available for intravenous or 

subcutaneous administration. 

 
Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection is available for intravenous or 

subcutaneous administration. 

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

 

Intravenous injection 

Bortezomib Fresenius Kabi 1 mg powder for solution for injection is for intravenous administration 
only. The reconstituted solution is administered as a 3-5 second bolus intravenous injection through 



9 

 

a peripheral or central intravenous catheter followed by a flush with sodium chloride 9 mg/ml 

(0.9%) solution for injection. At least 72 hours should elapse between consecutive doses of 
bortezomib. 

 

When bortezomib is given in combination with other medicinal products, refer to the Summary of 
Product Characteristics of these products for instructions for administration. 

 

4.3 Contraindications 
 
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 Summaries 

of Product Characteristics for additional contraindications. 

 
4.4 Special warnings and precautions for use 

 

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 treatment 
with bortezomib. When thalidomide is used, particular attention to pregnancy testing and 

prevention 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 or 
subcutaneous use. Bortezomib should not be administered intrathecally. 

 

Gastrointestinal toxicity 
Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common 

with bortezomib treatment. Cases of ileus have been uncommonly reported (see section 4.8). 

Therefore, patients who experience constipation should be closely monitored. 
 

Haematological toxicity 

Bortezomib treatment is very commonly associated with haematological toxicities 

(thrombocytopenia, neutropenia and anaemia). In studies in patients with relapsed multiple 
myeloma treated with bortezomib and in patients with previously untreated MCL treated with 

bortezomib 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 to 

baseline by the next cycle. There was no evidence of cumulative thrombocytopenia. The mean 

platelet count nadir measured was approximately 40% of baseline in the single-agent multiple 
myeloma studies and 50% in the MCL study. In patients with advanced myeloma the severity of 

thrombocytopenia 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 a 
count ≤ 25,000/μl during the study. 

 

In patients with MCL (study LYM-3002), there was a higher incidence (56.7% versus 5.8%) of 
grade ≥ 3 thrombocytopenia in the bortezomib treatment group (BR-CAP) as compared to the 

non-bortezomib treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and 

prednisone [R-CHOP]). The two treatment groups were similar with regard to the overall incidence 

of all-grade bleeding events (6.3% in the BR-CAP group and 5.0% in the R-CHOP group) as well 
as grade 3 and higher bleeding events (BR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). In 

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

in the R-CHOP group. 



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Gastrointestinal and intracerebral haemorrhage, have been reported in association with bortezomib 

treatment. 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 of 

combination with melphalan and prednisone, when the platelet count is ≤ 30,000/μl (see 

section 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 frequently 

monitored throughout treatment with bortezomib. Platelet transfusion should be considered when 
clinically appropriate (see section 4.2). 

 

In patients with MCL, transient neutropenia that was reversible between cycles was observed, with 
no evidence of cumulative neutropenia. Neutrophils were lowest at Day 11 of each cycle of 

bortezomib 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% of 

patients 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. Granulocyte 

colony stimulating factors may be administered for haematologic toxicity according to local 

standard practice. Prophylactic use of granulocyte colony stimulating factors should be considered 
in 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 incidence 

of 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 be 

performed in patients at risk of infection with HBV before initiation of treatment. Carriers of 

hepatitis B and patients with a history of hepatitis B must be closely monitored for clinical and 

laboratory signs of active HBV infection during and following rituximab combination treatment 
with bortezomib. Antiviral prophylaxis should be considered. Refer to the Summary of Product 

Characteristics of rituximab for more information. 

 
Progressive multifocal leukoencephalopathy (PML) 

Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML 

and death, have been reported in patients treated with bortezomib. Patients diagnosed with PML 

had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 
12 months of their first dose of bortezomib. Patients should be monitored at regular intervals for 

any new or worsening neurological symptoms or signs that may be suggestive of PML as part of 

the differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be 
referred to a specialist in PML and appropriate diagnostic measures for PML should be initiated. 

Discontinue bortezomib if PML is diagnosed. 

 
Peripheral neuropathy 

Treatment with bortezomib is very commonly associated with peripheral neuropathy, which is 

predominantly sensory. However, cases of severe motor neuropathy with or without sensory 

peripheral neuropathy have been reported. The incidence of peripheral neuropathy increases early 
in the treatment and has been observed to peak during cycle 5. 

 



11 

 

It is recommended that patients be carefully monitored for symptoms of neuropathy such as a 

burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or 
weakness. 

 

Patients experiencing new or worsening peripheral neuropathy should undergo 

neurological evaluation and may require a change in the dose or schedule of bortezomib 

(see section 4.2). Neuropathy has been managed with supportive care and other therapies. 
 

Early and regular monitoring for symptoms of treatment-emergent neuropathy with neurological 

evaluation should be considered in patients receiving bortezomib in combination with medicinal 
products known to be associated with neuropathy (e.g. thalidomide) and appropriate dose reduction 

or treatment discontinuation should be considered. 

 
In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to some 

adverse reactions such as postural hypotension and severe constipation with ileus. Information on 

autonomic neuropathy and its contribution to these undesirable effects is limited. 

 
Seizures 

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

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

Hypotension 

Bortezomib treatment is commonly associated with orthostatic/postural hypotension. Most adverse 

reactions are mild to moderate in nature and are observed throughout treatment. Patients who 
developed orthostatic hypotension on bortezomib (injected intravenously) did not have evidence of 

orthostatic hypotension prior to treatment with bortezomib. Most patients required treatment for 

their orthostatic hypotension. A minority of patients with orthostatic hypotension experienced 
syncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion of 

bortezomib. The mechanism of this event is unknown although a component may be due to 

autonomic neuropathy. Autonomic neuropathy may be related to bortezomib or bortezomib may 
aggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advised 

when treating patients with a history of syncope receiving medicinal products known to be 

associated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting. 

Management of orthostatic/postural hypotension may include adjustment of antihypertensive 
medicinal products, rehydration or administration of mineralocorticosteroids and/or 

sympathomimetics. Patients should be instructed to seek medical advice if they experience 

symptoms of dizziness, light-headedness or fainting spells. 
 

Posterior Reversible Encephalopathy Syndrome (PRES) 

There have been reports of PRES in patients receiving 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 patients 

developing PRES, bortezomib should be discontinued. 
 

Heart failure 

Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left 
ventricular ejection fraction has been reported during bortezomib treatment. Fluid retention may be 

a predisposing factor for signs and symptoms of heart failure. Patients with risk factors for or 

existing heart disease should be closely monitored. 

 
Electrocardiogram investigations 

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

been established. 
 

 



12 

 

Pulmonary disorders 

There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology 
such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress 

syndrome (ARDS) in patients receiving bortezomib (see section 4.8). Some of these events have 

been fatal. A pre-treatment chest radiograph is recommended to serve as a baseline for potential 
post-treatment pulmonary changes. 

 

In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt 

diagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratio 
should 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 continuous 
infusion over 24 hours with daunorubicin and bortezomib for relapsed acute myelogenous 

leukaemia 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 impairment 

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

 

Hepatic impairment 
Bortezomib is metabolised by liver enzymes. Bortezomib exposure is increased in patients with 

moderate or severe hepatic impairment; these patients should be treated with bortezomib at reduced 

doses and closely monitored for toxicities (see sections 4.2 and 5.2). 

 
Hepatic reactions 

Rare cases of hepatic failure have been reported in patients receiving bortezomib and concomitant 

medicinal products and with serious underlying medical conditions. Other reported hepatic 
reactions include increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may 

be reversible upon discontinuation of bortezomib (see section 4.8). 

 
Tumour lysis syndrome 

Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells and MCL cells, 

the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis 

syndrome are those with high tumour burden prior to treatment. These patients should be monitored 
closely and appropriate precautions taken. 

 

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

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

CYP2C19 substrates (see section 4.5). 

 
Normal liver function should be confirmed and caution should be exercised in patients receiving 

oral hypoglycemics (see section 4.5). 

 
Potentially immunocomplex-mediated reactions 

Potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis 

with rash and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should 
be discontinued if serious reactions occur. 
 

4.5 Interaction with other medicinal products and other forms of interaction 

 

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 to 



13 

 

the metabolism of bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affect 

the overall disposition of bortezomib. 
A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on 

the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC 

increase of 35% (CI90% [1.032 to 1.772]) based on data from 12 patients. Therefore, patients should 
be 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, on 
the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the 

pharmacokinetics of bortezomib based on data from 17 patients. 

 
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the 

pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC 

reduction of 45% based on data from 6 patients. Therefore, the concomitant use of bortezomib with 

strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's 
Wort) is not recommended, as efficacy may be reduced. 

 

In the same drug-drug interaction study assessing the effect of dexamethasone, a weaker CYP3A4 
inducer, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant 

effect on the pharmacokinetics of bortezomib based on data from 7 patients. 

 
A drug-drug interaction study assessing the effect of melphalan-prednisone on the 

pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC 

increase of 17% based on data from 21 patients. This is not considered clinically relevant. 

 
During clinical trials, hypoglycemia and hyperglycemia were uncommonly and commonly reported 

in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving 

bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of 
the dose of their antidiabetics. 

 

4.6 Fertility, pregnancy and lactation 
 

Contraception in males and females 

Male and female patients of childbearing potential must use effective contraceptive measures 

during and for 3 months following treatment. 
 

Pregnancy 

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

 

In non-clinical studies, bortezomib had no effects on embryonal/foetal development in rats and 

rabbits at the highest maternally tolerated doses. Animal studies to determine the effects of 
bortezomib 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 woman 

requires treatment with bortezomib. 
If bortezomib is used during pregnancy, or if the patient becomes pregnant while receiving this 

medicinal product, the patient should be informed of potential for hazard to the foetus. 

 
Thalidomide is a known human teratogenic active substance that causes severe life-threatening 

birth defects. Thalidomide is contraindicated during pregnancy and in women of childbearing 

potential unless all the conditions of the thalidomide pregnancy prevention programme are met. 

Patients receiving bortezomib in combination with thalidomide should adhere to the pregnancy 
prevention programme of thalidomide. Refer to the Summary of Product Characteristics of 

thalidomide for additional information. 

 



14 

 

Breast-feeding 

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

bortezomib. 

 
Fertility 

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

 

4.7 Effects on ability to drive and use machines 

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

Bortezomib may be associated with fatigue very commonly, dizziness commonly, syncope 

uncommonly 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 or 

operate machinery if they experience these symptoms (see section 4.8). 

 
4.8 Undesirable effects 

 

Summary of the safety profile 

Serious adverse reactions uncommonly reported during treatment with bortezomib include cardiac 

failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy 
syndrome, 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. 

 

Tabulated list of adverse reactions 
Multiple myeloma 

Undesirable effects in table 7 were considered by the investigators to have at least a possible or 

probable causal relationship to bortezomib. These adverse reactions are based on an integrated data 
set of 5,476 patients of whom 3,996 were treated with bortezomib at 1.3 mg/m2 and included in 

table 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 are 

defined as: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to 

< 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated 
from the available data). Within each frequency grouping, undesirable effects are presented in order 

of 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 in 

clinical 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*, Meningoencephalitis 

herpetic#, Bacteraemia (inc staphylococcal), 

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

Staphylococcal infection, Tooth infection* 



15 

 

System Organ Class Incidence Adverse reaction 

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

Post viral fatigue syndrome 

Neoplasms benign, 

malignant and unspecified 

(incl cysts and polyps) 

Rare Neoplasm malignant, Leukaemia plasmacytic, 

Renal cell carcinoma, Mass, Mycosis fungoides, 

Neoplasm benign* 

Blood and lymphatic system 

disorders 

Very common Thrombocytopenia*, Neutropenia*, Anaemia* 

Common Leukopenia*, Lymphopenia* 

Uncommon Pancytopenia*, Febrile neutropenia, 
Coagulopathy*, Leukocytosis*, 

Lymphadenopathy, Haemolytic anaemia# 

Rare Disseminated intravascular coagulation, 

Thrombocytosis*, Hyperviscosity syndrome, 

Platelet disorder NOS, Thrombotic 
microangiopathy (including thrombocytopenic 

purpura)#, Blood disorder NOS, Haemorrhagic 

diathesis, Lymphocytic infiltration 

Immune system disorders Uncommon Angioedema#, Hypersensitivity* 

Rare Anaphylactic shock, Amyloidosis, Type III 

immune complex mediated reaction 

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

Inappropriate antidiuretic hormone secretion 

Rare Hypothyroidism 

Metabolism and nutrition 
disorders 

Very common Decreased appetite 

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*, Diabetes 
mellitus*, Fluid retention 

Rare Hypermagnesaemia*, Acidosis, Electrolyte 
imbalance*, Fluid overload, Hypochloraemia*, 

Hypovolaemia, Hyperchloraemia*, 

Hyperphosphataemia*, Metabolic disorder, 
Vitamin B complex deficiency, Vitamin B12 

deficiency, Gout, Increased appetite, Alcohol 

intolerance 

Psychiatric disorders Common Mood disorders and disturbances*, Anxiety 

disorder*, Sleep disorders and disturbances* 

Uncommon Mental disorder*, Hallucination*, Psychotic 

disorder*, 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 (inc 

syncope), Dizziness*, Dysgeusia*, Lethargy, 

Headache* 



16 

 

System Organ Class Incidence Adverse reaction 

Uncommon Tremor, Peripheral sensorimotor neuropathy, 
Dyskinesia*, Cerebellar coordination and balance 

disturbances*, Memory loss (exc dementia)*, 

Encephalopathy*, Posterior Reversible 
Encephalopathy Syndrome#, Neurotoxicity, 

Seizure disorders*, Post herpetic neuralgia, Speech 

disorder*, Restless legs syndrome, Migraine, 

Sciatica, Disturbance in attention, Reflexes 
abnormal*, Parosmia 

Rare Cerebral haemorrhage*, Haemorrhage intracranial 

(inc subarachnoid)*, Brain oedema, Transient 

ischaemic attack, Coma, Autonomic nervous 

system imbalance, Autonomic neuropathy, Cranial 
palsy*, Paralysis*, Paresis*, Presyncope, Brain 

stem syndrome, Cerebrovascular disorder, Nerve 

root lesion, Psychomotor hyperactivity, Spinal cord 
compression, Cognitive disorder NOS, Motor 

dysfunction, Nervous system disorder NOS, 

Radiculitis, Drooling, Hypotonia 

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

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

Blepharitis#, Eye inflammation*, Diplopia, Dry 

eye*, Eye irritation*, Eye pain, Lacrimation 

increased, Eye discharge 

Rare Corneal lesion*, Exophthalmos, Retinitis, 

Scotoma, Eye disorder (inc. eyelid) NOS, 
Dacryoadenitis acquired, Photophobia, Photopsia, 

Optic neuropathy#, Different degrees of visual 

impairment (up to blindness)* 

Ear and labyrinth disorders Common Vertigo* 

Uncommon Dysacusis (inc tinnitus)*,Hearing impaired (up to 

and inc deafness), Ear discomfort* 

Rare Ear haemorrhage, Vestibular neuronitis, Ear 

disorder NOS 

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

Cardiac fibrillation (inc atrial), Cardiac failure (inc 

left 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)*, 



17 

 

System Organ Class Incidence Adverse reaction 

Poor peripheral circulation*, Vasculitis, 
Hyperaemia (inc ocular)* 

Rare Peripheral embolism, Lymphoedema, Pallor, 
Erythromelalgia, Vasodilatation, Vein 

discolouration, Venous insufficiency 

Respiratory, thoracic and 

mediastinal disorders 

Common Dyspnoea*, Epistaxis, Upper/lower respiratory 

tract infection*, Cough* 

Uncommon Pulmonary embolism, Pleural effusion, Pulmonary 

oedema (inc acute), Pulmonary alveolar 

haemorrhage#, Bronchospasm, Chronic obstructive 
pulmonary disease*, Hypoxaemia*, Respiratory 

tract congestion*, Hypoxia, Pleurisy*, Hiccups, 

Rhinorrhoea, Dysphonia, Wheezing 

Rare Respiratory failure, Acute respiratory distress 

syndrome, Apnoea, Pneumothorax, Atelectasis, 
Pulmonary hypertension, Haemoptysis, 

Hyperventilation, Orthopnoea, Pneumonitis, 

Respiratory alkalosis, Tachypnoea, Pulmonary 

fibrosis, Bronchial disorder*, Hypocapnia*, 
Interstitial lung disease, Lung infiltration, Throat 

tightness, Dry throat, Increased upper airway 

secretion, Throat irritation, Upper-airway cough 
syndrome 

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

Common Gastrointestinal haemorrhage (inc mucosal)*, 
Dyspepsia, Stomatitis*, Abdominal distension, 

Oropharyngeal pain*, Abdominal pain (inc 

gastrointestinal and splenic pain)*, Oral disorder*, 
Flatulence 

Uncommon Pancreatitis (inc chronic)*, Haematemesis, Lip 
swelling*, Gastrointestinal obstruction (inc small 

intestinal obstruction, ileus)*, Abdominal 

discomfort, Oral ulceration*, Enteritis*, Gastritis*, 

Gingival bleeding, Gastrooesophageal reflux 
disease*, Colitis (inc clostridium difficile)*, Colitis 

ischaemic#, Gastrointestinal inflammation*, 

Dysphagia, Irritable bowel syndrome, 
Gastrointestinal disorder NOS, Tongue coated, 

Gastrointestinal motility disorder*, Salivary gland 

disorder* 

Rare Pancreatitis acute, Peritonitis*, Tongue oedema*, 

Ascites, Oesophagitis, Cheilitis, Faecal 

incontinence, Anal sphincter atony, Faecaloma*, 
Gastrointestinal ulceration and perforation*, 

Gingival hypertrophy, Megacolon, Rectal 

discharge, 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 



18 

 

System Organ Class Incidence Adverse reaction 

Rare Hepatic failure, Hepatomegaly, Budd-Chiari 
syndrome, Cytomegalovirus hepatitis, Hepatic 

haemorrhage, Cholelithiasis 

Skin and subcutaneous tissue 

disorders 

Common Rash*, Pruritus*, Erythema, Dry skin 

Uncommon Erythema multiforme, Urticaria, Acute febrile 
neutrophilic dermatosis, Toxic skin eruption, Toxic 

epidermal necrolysis#, Stevens-Johnson syndrome#, 

Dermatitis*, Hair disorder*, Petechiae, 
Ecchymosis, Skin lesion, Purpura, Skin mass*, 

Psoriasis, Hyperhidrosis, Night sweats, Decubitus 

ulcer#, Acne*, Blister*, Pigmentation disorder* 

Rare Skin reaction, Jessner's lymphocytic infiltration, 

Palmar-plantar erythrodysaesthesia syndrome, 
Haemorrhage subcutaneous, Livedo reticularis, 

Skin induration, Papule, Photosensitivity reaction, 

Seborrhoea, Cold sweat, Skin disorder NOS, 

Erythrosis, Skin ulcer, Nail disorder 

Musculoskeletal and 

connective tissue disorders 

Very common Musculoskeletal pain* 

Common Muscle spasms*, Pain in extremity, Muscular 

weakness 

Uncommon Muscle twitching, Joint swelling, Arthritis*, Joint 

stiffness, Myopathies*,Sensation of heaviness 

Rare Rhabdomyolysis, Temporomandibular joint 

syndrome, Fistula, Joint effusion, Pain in jaw, 

Bone disorder, Musculoskeletal and connective 
tissue infections and inflammations*, Synovial cyst 

Renal and urinary disorders Common Renal impairment* 

Uncommon Renal failure acute, Renal failure chronic*, Urinary 

tract infection*, Urinary tract signs and 
symptoms*, Haematuria*, Urinary retention, 

Micturition disorder*, Proteinuria, Azotaemia, 

Oliguria*, Pollakiuria 

Rare Bladder irritation 

Reproductive system and 

breast disorders 

Uncommon Vaginal haemorrhage, Genital pain*, Erectile 

dysfunction, 

Rare Testicular disorder*, Prostatitis, Breast disorder 

female, Epididymal tenderness, Epididymitis, 

Pelvic pain, Vulval ulceration 

Congenital, familial and 

genetic disorders 

Rare Aplasia, Gastrointestinal malformation, Ichthyosis 

General disorders and 

administration site 
conditions 

Very common Pyrexia*, Fatigue, Asthenia 

Common Oedema (inc peripheral), Chills, Pain*, Malaise* 

Uncommon General physical health deterioration*, Face 

oedema*, Injection site reaction*, Mucosal 

disorder*, Chest pain, Gait disturbance, Feeling 

cold, Extravasation*, Catheter related 
complication*, Change in thirst*, Chest 

discomfort, Feeling of body temperature change*, 

Injection site pain* 

Rare Death (inc sudden), Multi-organ failure, Injection 



19 

 

System Organ Class Incidence Adverse reaction 

site haemorrhage*, Hernia (inc hiatus)*, Impaired 
healing*, Inflammation, Injection site phlebitis*, 

Tenderness, Ulcer, Irritability, Non-cardiac chest 

pain, Catheter site pain, Sensation of foreign body 

Investigations Common Weight decreased 

Uncommon Hyperbilirubinaemia*, Protein analyses abnormal*, 

Weight increased, Blood test abnormal*,C-reactive 

protein increased 

Rare Blood gases abnormal*, Electrocardiogram 

abnormalities (inc QT prolongation)*, International 
normalised ratio abnormal*, Gastric pH decreased, 

Platelet aggregation increased, Troponin I 

increased, Virus identification and serology*, 
Urine analysis abnormal* 

Injury, poisoning and 
procedural complications 

Uncommon Fall, Contusion 

Rare Transfusion reaction, Fractures*, Rigors*, Face 

injury, Joint injury*, Burns, Laceration, Procedural 
pain, Radiation injuries* 

Surgical and medical 
procedures 

Rare Macrophage activation 

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 in 
combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BR-CAP) versus 

242 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 

[R-CHOP] was relatively consistent to that observed in patients with multiple myeloma with main 
differences described below. Additional adverse drug reactions identified associated with the use of 

the 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 adverse 

drug reactions are not attributable to bortezomib alone. Notable differences in the MCL patient 
population as compared to patients in the multiple myeloma studies were a ≥ 5% higher incidence 

of the haematological adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, 

lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and 
hair 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 causal 

relationship to bortezomib based on historical data in the multiple myeloma studies. 

 
Adverse reactions are listed below by system organ class and frequency grouping. Frequencies are 

defined as: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to 

< 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated 
from the available data). Within each frequency grouping, undesirable effects are presented in order 

of decreasing seriousness. Table 8 has been generated using Version 16 of the MedDRA. 

 

 
 

 



20 

 

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

clinical trial 

System Organ Class Incidence Adverse reaction 

Infections and infestations Very common Pneumonia* 

Common Sepsis (inc septic shock)*, Herpes zoster (inc 

disseminated & ophthalmic), Herpes virus 

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

Herpes simplex* 

Uncommon Hepatitis B, Infection*, Bronchopneumonia 

Blood and lymphatic system 
disorders 

Very common Thrombocytopenia*, Febrile neutropenia, 
Neutropenia*, Leukopenia*, Anaemia*, 

Lymphopenia* 

Uncommon Pancytopenia* 

Immune system disorders Common Hypersensitivity* 

Uncommon Anaphylactic reaction 

Metabolism and nutrition 

disorders 

Very common Decreased appetite 

Common Hypokalaemia*, Blood glucose abnormal*, 
Hyponatraemia*, Diabetes mellitus*, Fluid 

retention 

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 of 
consciousness (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 inc 

deafness) 

Cardiac disorders Common Cardiac fibrillation (inc atrial), Arrhythmia*, 

Cardiac failure (inc left and right ventricular)*, 
Myocardial ischaemia, Ventricular dysfunction* 

Uncommon Cardiovascular disorder (inc cardiogenic shock) 

Vascular disorders Common Hypertension*, Hypotension*, Orthostatic 

hypotension 

Respiratory, thoracic and 

mediastinal disorders 

Common Dyspnoea*, Cough*, Hiccups 

Uncommon Acute respiratory distress syndrome, Pulmonary 

embolism, Pneumonitis, Pulmonary hypertension, 

Pulmonary oedema (inc acute) 

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

Stomatitis*, Constipation 

Common Gastrointestinal haemorrhage (inc mucosal)*, 

Abdominal distension, Dyspepsia, Oropharyngeal 
pain*, Gastritis*, Oral ulceration*, Abdominal 

discomfort, Dysphagia, Gastrointestinal 



21 

 

System Organ Class Incidence Adverse reaction 

inflammation*, Abdominal pain (inc 
gastrointestinal and splenic pain)*, Oral disorder* 

Uncommon Colitis (inc clostridium difficile)* 

Hepatobiliary disorders Common Hepatotoxicity (inc liver disorder) 

Uncommon Hepatic failure 

Skin and subcutaneous tissue 

disorders 

Very common Hair disorder* 

Common Pruritus*, Dermatitis*, Rash* 

Musculoskeletal and 

connective tissue disorders 

Common Muscle spasms*, Musculoskeletal pain*, Pain in 

extremity 

Renal and urinary disorders Common Urinary tract infection* 

General disorders and 

administration site 

conditions 

Very common Pyrexia*, Fatigue, Asthenia 

Common Oedema (inc peripheral), Chills, Injection site 
reaction*, Malaise* 

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

* Grouping of more than one MedDRA preferred term. 
 

Description of selected adverse reactions 

Herpes zoster virus reactivation 
Multiple myeloma 

Antiviral prophylaxis was administered to 26% of the patients in the B+M+P arm. The incidence of 

herpes zoster among patients in the B+M+P treatment group was 17% for patients not administered 
antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis. 

 

Mantle cell lymphoma 

Antiviral prophylaxis was administered to 137 of 240 patients (57%) in the BR-CAP arm. The 
incidence of herpes zoster among patients in the BR-CAP arm was 10.7% for patients not 

administered antiviral prophylaxis compared to 3.6% for patients administered antiviral 

prophylaxis (see section 4.4). 
 

Hepatitis B virus (HBV) reactivation and infection 

Mantle cell lymphoma 
HBV infection with fatal outcomes occurred in 0.8% (n=2) of patients in the non-bortezomib 

treatment 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 B 
infections was similar in patients treated with BR-CAP or with R-CHOP (0.8% vs 1.2% 

respectively). 

 
Peripheral neuropathy in combination regimens 

Multiple myeloma 

In trials in which bortezomib was administered as induction treatment in combination with 

dexamethasone (study IFM-2005-01), and dexamethasone-thalidomide (study MMY-3010), the 
incidence of peripheral neuropathy in the combination regimens is presented in the table below: 

 

 
 

 

 
 

 



22 

 

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

  treatment discontinuation due to peripheral neuropathy  
IFM-2005-01 MMY-3010 

 
VDDx 

(N=239) 

BDx 

(N=239) 

TDx 

(N=126) 

BTDx 

(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 motor 

neuropathy, peripheral sensory neuropathy, and polyneuropathy. 

 

Mantle cell lymphoma 

In study LYM-3002 in which bortezomib was administered with rituximab, cyclophosphamide, 

doxorubicin, and prednisone (BR-CAP), the incidence of peripheral neuropathy in the combination 
regimens is presented in the table below: 

 

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

BR-CAP 

(N=240) 

R-CHOP 

(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 patients 
42.9% and 10.4% of patients in the BR-CAP arm were in the range 65-74 years and ≥ 75 years of 

age, respectively. Although in patients aged ≥ 75 years, both BR-CAP and R-CHOP were less 

tolerated, the serious adverse event rate in the BR-CAP groups was 68%, compared to 42% in the 

R-CHOP group. 
 

Retreatment of patients with relapsed multiple myeloma 

In a study in which bortezomib retreatment was administered in 130 patients with relapsed multiple 
myeloma, who previously had at least partial response on a bortezomib-containing regimen, the 

most common all-grade adverse events occurring in at least 25% of patients were 

thrombocytopenia (55%), neuropathy (40%), anaemia (37%), diarrhoea (35%), and constipation 
(28%). All grade peripheral neuropathy and grade ≥ 3 peripheral neuropathy were observed in 40% 

and 8.5% of patients, respectively. 

 

Reporting of suspected adverse reactions 
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. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


23 

 

4.9 Overdose 
 

In patients, overdose more than twice the recommended dose has been associated with the acute 
onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. For preclinical 

cardiovascular safety pharmacology studies, see section 5.3. 

 
There is no known specific antidote for bortezomib overdose. In the event of an overdose, the 

patient's vital signs should be monitored and appropriate supportive care given to maintain blood 

pressure (such as fluids, pressors, and/or inotropic agents) and body temperature (see sections 4.2 

and 4.4). 
5 PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: 

L01XX32. 
 

Mechanism of action 

Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-like 

activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex 
that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in 

regulating the turnover of specific proteins, thereby maintaining homeostasis within cells. 

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

 

Bortezomib is highly selective for the proteasome. At 10 μM concentrations, bortezomib does not 
inhibit any of a wide variety of receptors and proteases screened and is more than 1,500-fold more 

selective for the proteasome than for its next preferable enzyme. The kinetics of proteasome 

inhibition were evaluated in vitro, and bortezomib was shown to dissociate from the proteasome 

with 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, but 

not limited to, altering regulatory proteins, which control cell cycle progression and nuclear factor 
kappa B (NF-kB) activation. Inhibition of the proteasome results in cell cycle arrest and apoptosis. 

NF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis, 

including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma, 

bortezomib affects the ability of myeloma cells to interact with the bone marrow 
microenvironment. 

 

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

normal cells. Bortezomib causes reduction of tumour growth in vivo in many preclinical tumour 

models, including multiple myeloma. 
 

Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast 

differentiation and activity and inhibits osteoclast function. These effects have been observed in 

patients with multiple myeloma affected by an advanced osteolytic disease and treated with 
bortezomib. 

 

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 injected 

intravenously) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in 
improvement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone 

(60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered 

for a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease 

progression or unacceptable toxicity. The median age of the patients in the study was 71 years, 50% 



24 

 

were male, 88% were Caucasian and the median Karnofsky performance status score for the 

patients was 80. Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median 
hemoglobin of 105 g/l, and a median platelet count of 221.5 x 109/l. Similar proportions of patients 

had creatinine clearance ≤ 30 ml/min (3% in each arm). 

At the time of a pre-specified interim analysis, the primary endpoint, time to progression, was met 
and 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. A 

statistically 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+P 

treatment 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 

n=344 

M+P 

n=338 

Time to progression 

Events n (%) 

 

101 (29) 

 

152 (45) 

Mediana (95% CI) 20.7 mo 

(17.6, 24,7) 

15.0 mo 

(14.1, 17.9) 

Hazard ratiob 

(95% CI) 

0.54 

(0.42, 0.70) 

p-valuec 0.000002 

Progression-free survival 
Events n (%) 

 
135 (39) 

 
190 (56) 

Mediana (95% CI) 18.3 mo 
(16.6, 21.7) 

14.0 mo 
(11.1, 15.0) 

Hazard ratiob 
(95% CI) 

0.61 
(0.49, 0.76) 

p-valuec 0.00001 

Overall survival* 

Events (deaths) n (%) 

 

176 (51.2) 

 

211 (62.4) 

Mediana 

(95% CI) 

56.4 mo 

(52.8, 60.9) 

43.1 mo 

(35.3, 48.3) 

Hazard ratiob 

(95% CI) 

0.695 

(0.567, 0.852) 

p-valuec 0.00043 

Response rate 

populatione n=668 

n=337 n=331 

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 
populationg n=667 

n=336 n=331 

≥90% n (%) 151 (45) 34 (10) 

Time to first response in CR + PR 
 

Median 1.4 mo 4.2 mo 

Mediana response duration 
 



25 

 

Efficacy endpoint B+M+P 

n=344 

M+P 

n=338 

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 

(95% CI) 

27.0 mo 

(24.7, 31.1) 

19.2 mo 

(17.0, 21.0) 

Hazard ratiob 

(95% CI) 

0.557 

(0.462, 0.671) 

p-valuec < 0.000001 
a Kaplan-Meier estimate 
b 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 VMP 
c Nominal p-value based on the stratified log-rank test adjusted for stratification factors: β2-microglobulin, 

albumin, and region 
d p-value for Response Rate (CR+PR) from the Cochran Mantel-Haenszel chi-square test adjusted for the 

stratification factors 
e Response population includes patients who had measurable disease at baseline 
f CR=Complete Response; PR=Partial Response. EBMT criteria 
g All randomised patients with secretory disease 

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

mo: months 

CI=Confidence Interval 

 
Patients eligible for stem cell transplantation 

Two randomised, open-label, multicenter Phase III trials (IFM-2005-01, MMY-3010) were 

conducted to demonstrate the safety and efficacy of bortezomib in dual and triple combinations 

with other chemotherapeutic agents, as induction therapy prior to stem cell transplantation in 
patients with previously untreated multiple myeloma. 

 

In study IFM-2005-01 bortezomib combined with dexamethasone [BDx, n=240] was compared to 
vincristine-doxorubicin-dexamethasone [VDDx, n=242]. Patients in the BDx group received four 

21 day cycles, each consisting of bortezomib (1.3 mg/m2 administered intravenously twice weekly 

on days 1, 4, 8, and 11), and oral dexamethasone (40 mg/day on days 1 to 4 and days 9 to 12, in 
cycles 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 in 

the VDDx and BDx groups respectively; the majority of patients underwent one single transplant 

procedure. Patient demographic and baseline disease charateristics were similar between the 
treatment groups. Median age of the patients in the study was 57 years, 55% were male and 48% of 

patients had high-risk cytogenetics. The median duration of treatment was 13 weeks for the VDDx 

group and 11 weeks for the BDx group. The median number of cycles received for both groups was 
4 cycles. 

The primary efficacy endpoint of the study was post-induction response rate (CR+nCR). A 

statistically significant difference in CR+nCR was observed in favour of the bortezomib combined 

with dexamethasone group. Secondary efficacy endpoints included post-transplant response rates 
(CR+nCR, CR+nCR+VGPR+PR), Progression Free Survival and Overall Survival. Main efficacy 

results are presented in table 12. 

 
 

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

Endpoints BDx VDDx OR; 95% CI; P value
a
 

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, 4.85); 0.003 



26 

 

CR+nCR+VGPR+PR 

% (95% CI) 

77.1 (71.2, 82.2) 60.7 (54.3, 66.9) 2.18 (1.46, 3.24); < 0.001 

RR (Post-transplant)b 

CR+nCR 

CR+nCR+VGPR+PR 
% (95% CI) 

 

37.5 (31.4, 44.0) 

79.6 (73.9, 84.5) 

 

23.1 (18.0, 29.0) 

74.4 (68.4, 79.8) 

 

1.98 (1.33, 2.95); 0.001 

1.34 (0.87, 2.05); 0.179 

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 endpoint 
a 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 and 

dexamethasone [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/m2 
administered twice weekly days 1, 4, 8, and 11, followed by a 17-day rest period from day 12 to 

day 28), dexamethasone (40 mg administered orally on days 1 to 4 and days 8 to 11), and 

thalidomide (administered orally at 50 mg daily on days 1-14, increased to 100 mg on days 15-28 

and thereafter 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 disease 

characteristics were similar between the treatment groups. Patients in the BTDx and TDx groups 
respectively 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 cytogenetically 

classified as high risk versus 16% of patients in the TDx group. The median duration of treatment 
was 24.0 weeks and the median number of treatment cycles received was 6.0, and was consistent 

across treatment groups.  

The primary efficacy endpoints of the study were post-induction and post-transplant response rates 

(CR+nCR). A statistically significant difference in CR+nCR was observed in favour of the 
bortezomib combined with dexamethasone and thalidomide group. Secondary efficacy endpoints 

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

table 13. 
 

Table 13:  Efficacy results from study MMY-3010 

Endpoints BTDx TDx OR; 95% CI; P value
a
 

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

*RR (Post-induction) 
CR+nCR 

 

CR+nCR+PR 

% (95% CI) 

 
49.2 (40.4, 58.1) 

 

84.6 (77.2, 90.3) 

 
17.3 (11.2, 25.0) 

 

61.4 (52.4, 69.9) 

 
4.63 (2.61, 8.22); 

< 0.001a 

3.46 (1.90, 6.27); 

< 0.001a 

*RR (Post-transplant) 

CR+nCR 
CR+nCR+PR 

% (95% CI) 

 

55.4 (46.4, 64.1) 
77.7 (69.6, 84.5) 

 

34.6 (26.4, 43.6) 
56.7 (47.6, 65.5) 

 

2.34 (1.42, 3.87); 0.001a 
2.66 (1.55, 4.57); 

< 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 endpoint 
a 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 



27 

 

 

Clinical efficacy in relapsed or refractory multiple myeloma 
The safety and efficacy of bortezomib (injected intravenously) were evaluated in 2 studies at the 

recommended dose of 1.3 mg/m2: a Phase III randomised, comparative study (APEX), versus 

dexamethasone (Dex), of 669 patients with relapsed or refractory multiple myeloma who had 
received 1-3 prior lines of therapy, and a Phase II single-arm study of 202 patients with relapsed 

and refractory multiple myeloma, who had received at least 2 prior lines of treatment and who were 

progressing on their most recent treatment. 

 
In the Phase III study, treatment with bortezomib led to a significantly longer time to progression, a 

significantly prolonged survival and a significantly higher response rate, compared to treatment 

with dexamethasone (see table 14), in all patients as well as in patients who have received 1 prior 
line of therapy. As a result of a pre-planned interim analysis, the dexamethasone arm was halted at 

the recommendation of the data monitoring committee and all patients randomised to 

dexamethasone were then offered bortezomib, regardless of disease status. Due to this early 

crossover, the median duration of follow-up for surviving patients is 8.3 months. Both in patients 
who were refractory to their last prior therapy and those who were not refractory, overall survival 

was 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 well 

as TTP remained significantly better for bortezomib independently of age. Regardless of 

β2-microglobulin levels at baseline, all efficacy parameters (time to progression and overall 
survival, 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 independent 

review 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). This 

survival was greater than the six-to-nine month median survival anticipated by consultant clinical 

investigators for a similar patient population. By multivariate analysis, the response rate was 
independent of myeloma type, performance status, chromosome 13 deletion status, or the number 

or type of previous therapies. Patients who had received 2 to 3 prior therapeutic regimens had a 

response rate of 32% (10/32) and patients who received greater than 7 prior therapeutic regimens 
had 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 

therapy 

> 1 prior line of 

therapy 

≥ 2 prior 

lines 

Time related 

events 

B 

n=333
a
 

Dex 

n=336
a
 

B 

n=132
a
 

Dex 

n=119
a
 

B 

n=200
a
 

Dex 

n=217
a
 

B 

n=202
a
 

TTP, days 

[95% CI] 

189b 

[148, 211] 

106b 

[86, 128] 

212d 

[188, 267] 

169d 

[105, 191] 

148b 

[129, 192] 

87b 

[84, 107] 

210 

[154, 281] 

1 year survival, % 

[95% CI] 

 

80d 

[74,85] 

 

66d 

[59,72] 

 

89d 

[82,95] 

 

72d 

[62,83] 

 

73 

[64,82] 

 

62 

[53,71] 

 

 

60 

Best response 

(%) 

B 

n=315c 

Dex 

n=312c 

B 

n=128 

Dex 

n=110 

B 

n=187 

Dex 

n=202 

B 

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 

Days (months) 

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



28 

 

 
Phase III Phase III Phase III Phase II 

 
All patients 1 prior line of 

therapy 
> 1 prior line of 

therapy 
≥ 2 prior 

lines 

Time related 

events 
B 

n=333
a
 

Dex 
n=336

a
 

B 

n=132
a
 

Dex 
n=119

a
 

B 

n=200
a
 

Dex 
n=217

a
 

B 

n=202
a
 

Time to response 
CR+PR (days) 

43 43 44 46 41 27 38* 

a Intent to Treat (ITT) population 
b p-value from the stratified log-rank test; analysis by line of therapy excludes stratification for therapeutic 

history; p < 0.0001 
c Response population includes patients who had measurable disease at baseline and received at least 1 dose 

of study medicinal product. 
d p-value from the Cochran Mantel-Haenszel chi-square test adjusted for the stratification factors; analysis by 

line 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 bortezomib 
alone were able to receive high-dose dexamethasone in conjunction with bortezomib. The protocol 

allowed patients to receive dexamethasone if they had had a less than optimal response to 

bortezomib alone. A total of 74 evaluable patients were administered dexamethasone in 

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

 

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

A Phase III randomised, parallel-group, open-label, multicentre study was conducted in 646 

patients comparing the safety and efficacy of bortezomib plus pegylated liposomal doxorubicin 

versus bortezomib monotherapy in patients with multiple myeloma who had received at least 1 
prior therapy and who did not progress while receiving anthracycline-based therapy. The primary 

efficacy 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 termination 

for 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 liposomal 
doxorubicin. The median TTP was 6.5 months for the bortezomib monotherapy patients compared 

with 9.3 months for the bortezomib plus pegylated liposomal doxorubicin combination therapy 

patients. These results, though not mature, constituted the protocol defined final analysis. 

The final analysis for OS performed after a median follow-up of 8.6 years showed no significant 
difference 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; 28.9-37.1 

months) 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 with 
dexamethasone in patients with progressive multiple myeloma, a statistical matched-pair analysis 

was conducted to compare results from the non randomised arm of bortezomib in combination with 

dexamethasone (Phase II open-label study MMY-2045), with results obtained in the bortezomib 

monotherapy arms from different Phase III randomised studies (M34101-039 [APEX] and DOXIL 
MMY-3001) in the same indication. 

 



29 

 

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 study 

subjects. This minimises the effects of observed confounders when estimating treatment effects 

using non-randomised data. 
 

One hundred and twenty seven matched pairs of patients were identified. The analysis 

demonstrated 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 determine 

the efficacy and safety of retreatment with bortezomib. One hundred and thirty patients (≥ 18 years 

of age) with multiple myeloma who previously had at least partial response on a 

bortezomib-containing regimen were retreated upon progression. At least 6 months after prior 
therapy, 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 single 

agent 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 an 

additional 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 safety 

of 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 in 

the BR-CAP treatment arm received bortezomib (1.3 mg/m2; on days 1, 4, 8, 11, rest period days 

12-21), rituximab 375 mg/m2 IV on day 1; cyclophosphamide 750 mg/m2 IV on day 1; doxorubicin 
50 mg/m2 IV on day 1; and prednisone 100 mg/m2 orally on day 1 through day 5 of the 21 day 

bortezomib treatment cycle. For patients with a response first documented at cycle 6, two additional 

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 to 

next anti-lymphoma treatment (TNT), duration of treatment free interval (TFI), overall response 

rate (ORR) and complete response (CR/CRu) rate, overall survival (OS) and response duration. 
 

The demographic and baseline disease characteristics were generally well balanced between the 

two treatment arms: median patient age was 66 years, 74% were male, 66% were Caucasian and 

32% Asian, 69% of patients had a positive bone marrow aspirate and/or a positive bone marrow 
biopsy for MCL, 54% of patients had an International Prognostic Index (IPI) score of ≥ 3, and 76% 

had Stage 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 received 
by patients in both treatment arms with 14% of subjects in the BR-CAP group and 17% of patients 

in the R-CHOP group receiving 2 additional cycles. The majority of the patients in both groups 

completed treatment, 80% in the BR-CAP group and 82% in the R-CHOP group. Efficacy results 
are presented in table 15: 

 

Table 15: Efficacy results from study LYM-3002 

Efficacy endpoint BR-CAP R-CHOP 
 

n: ITT patients 243 244 

Progression free survival (IRC)
a
 



30 

 

Efficacy endpoint BR-CAP R-CHOP 
 

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

p-valued < 0.001 
Medianc (95% CI) 

(months) 

24.7 (19.8; 31.8) 14.4 (12; 16.9) 

Response rate 

n: response-evaluable 

patients 

229 228 
 

Overall complete 

response 

(CR+CRu)f n(%) 

122 (53.3%) 95 (41.7%) ORe (95% CI)=1.688 

(1.148; 2.481) 

p-valueg=0.007 

Overall response 

(CR+CRu+PR)h n(%) 

211 (92.1%) 204 (89.5%) ORe (95% CI)=1.428 

(0.749; 2.722) 
p-valueg=0.275 

a 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 of 

disease 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 stratification 

factors. 
h Include all radiological CR+CRu+PR by IRC regardless the verification by bone marrow and LDH. 

CR=Complete Response; CRu=Complete Response unconfirmed; PR=Partial Response; CI=Confidence 
Interval, HR=Hazard Ratio; OR=Odds Ratio; ITT=Intent to Treat 

 

Median PFS by investigator assessment was 30.7 months in the BR-CAP group and 16.1 months in 

the 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 (median 

40.6 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 response 

was 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-CHOP 

group (HR=0.66; p=0.001). The observed final median difference in the OS between the 2 

treatment 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 efficacy 

of bortezomib in patients with previously treated light-chain (AL) Amyloidosis. No new safety 
concerns were observed during the study, and in particular bortezomib did not exacerbate target 

organ damage (heart, kidney and liver). In an exploratory efficacy analysis, a 67.3% response rate 

(including a 28.6% CR rate) as measured by hematologic response (M-protein) was reported in 49 

evaluable patients treated with the maximum allowed doses of 1.6 mg/m2 weekly and 1.3 mg/m2 
twice-weekly. For these dose cohorts, the combined 1-year survival rate was 88.1%. 

 

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

bortezomib in all subsets of the paediatric population in multiple myeloma and in mantle cell 

lymphoma (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 induction 



31 

 

chemotherapy in paediatric and young adult patients with lymphoid malignancies (pre-B cell acute 

lymphoblastic leukemia [ALL], T-cell ALL, and T-cell lymphoblastic lymphoma [LL]). An 
effective reinduction multiagent chemotherapy regimen was administered in 3 blocks. Bortezomib 

was administered only in Blocks 1 and 2 to avoid potential overlapping toxicities with 

coadministered drugs in Block 3. 
 

Complete response (CR) was evaluated at the end of Block 1. In B-ALL patients with relapse 

within 18 months of diagnosis (n=27) the CR rate was 67% (95% CI: 46, 84); the 4-month event 

free survival rate was 44% (95% CI: 26, 62). In B-ALL patients with relapse 18-36 months from 
diagnosis (n=33) the CR rate was 79% (95% CI: 61, 91) and the 4-month event free survival rate 

was 73% (95% CI: 54, 85). The CR rate in first-relapsed T-cell ALL patients (n=22) was 68% 

(95% CI: 45, 86) and the 4-month event free survival rate was 67% (95% CI: 42, 83). The reported 
efficacy data are considered inconclusive (see section 4.2). 

 

There were 140 patients with ALL or LL enrolled and evaluated for safety; median age was 10 

years (range 1 to 26). No new safety concerns were observed when bortezomib was added to the 
standard 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 as 

compared 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 were 

available 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) and 

hyponatraemia (12% versus 5% in Block 1 and 4% versus 0 in Block 2). 

 
5.2 Pharmacokinetic properties 

 

Absorption 
Following intravenous bolus administration of a 1.0 mg/m2 and 1.3 mg/m2 dose to 11 patients with 

multiple myeloma and creatinine clearance values greater than 50 ml/min, the mean first-dose 

maximum plasma concentrations of bortezomib were 57 and 112 ng/ml, respectively. In subsequent 
doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/ml for the 

1.0 mg/m2 dose and 89 to 120 ng/ml for the 1.3 mg/m2 dose. 

 

Distribution 
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 multiple 

myeloma. This suggests that bortezomib distributes widely to peripheral tissues. Over a bortezomib 
concentration range of 0.01 to 1.0 μg/ml, the in vitro protein binding averaged 82.9% in human 

plasma. The fraction of bortezomib bound to plasma proteins was not concentration-dependent. 

 

Biotransformation 
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 

isozymes indicate that bortezomib is primarily oxidatively metabolised via cytochrome P450 

enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form two 
deboronated metabolites that subsequently undergo hydroxylation to several metabolites. 

Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors. 

 
Elimination 

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/m2 
and 1.3 mg/m2, respectively, and ranged from 15 to 32 l/h and 18 to 32 l/h following subsequent 

doses for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively. 

 



32 

 

Special populations 

Hepatic impairment 
The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in a Phase I 

study during the first treatment cycle, including 61 patients primarily with solid tumors and varying 

degrees 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 alter 

dose-normalised bortezomib AUC. However, the dose-normalised mean AUC values were 

increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower 
starting dose is recommended in patients with moderate or severe hepatic impairment, and those 

patients should be closely monitored (see section 4.2, table 6). 

 
Renal impairment 

A pharmacokinetic study was conducted in patients with various degrees of renal impairment who 

were 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 of 

dialysis patients who were dosed after dialysis was also included in the study (n=8). Patients were 

administered intravenous doses of 0.7 to 1.3 mg/m2 of bortezomib twice weekly. Exposure of 
bortezomib (dose-normalised AUC and Cmax) was comparable among all the groups (see 

section 4.2). 

 
Age 

The pharmacokinetics of bortezomib were characterized following twice weekly intravenous bolus 

administration of 1.3 mg/m2 doses to 104 pediatric patients (2-16 years old) with acute 

lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Based on a population 
pharmacokinetic analysis, clearance of bortezomib increased with increasing body surface area 

(BSA). Geometric mean (%CV) clearance was 7.79 (25%) L/hr/m2, volume of distribution at 

steady-state was 834 (39%) L/m2, and the elimination half-life was 100 (44%) hours. After 
correcting for the BSA effect, other demographics such as age, body weight and sex did not have 

clinically significant effects on bortezomib clearance. BSA-normalized clearance of bortezomib in 

pediatric patients was similar to that observed in adults. 
 

5.3 Preclinical safety data 

 

Bortezomib was positive for clastogenic activity (structural chromosomal aberrations) in the 

in vitro chromosomal aberration assay using Chinese hamster ovary (CHO) cells at concentrations 
as low as 3.125 μg/ml, which was the lowest concentration evaluated. Bortezomib was not 

genotoxic when tested in the in vitro mutagenicity assay (Ames assay) and in vivo micronucleus 

assay in mice. 
 

Developmental toxicity studies in the rat and rabbit have shown embryo-fetal lethality at maternally 

toxic doses, but no direct embryo-foetal toxicity below maternally toxic doses. Fertility studies 
were not performed but evaluation of reproductive tissues has been performed in the general 

toxicity studies. In the 6-month rat study, degenerative effects in both the testes and the ovary have 

been observed. It is, therefore, likely that bortezomib could have a potential effect on either male or 

female fertility. Peri- and postnatal development studies were not conducted. 
 

In multi-cycle general toxicity studies conducted in the rat and monkey, the principal target organs 

included the gastrointestinal tract, resulting in vomiting and/or diarrhoea; haematopoietic and 
lymphatic tissues, resulting in peripheral blood cytopenias, lymphoid tissue atrophy and 

haematopoietic bone marrow hypocellularity; peripheral neuropathy (observed in monkeys, mice 

and dogs) involving sensory nerve axons; and mild changes in the kidneys. All these target organs 
have shown partial to full recovery following discontinuation of treatment. 

Based on animal studies, the penetration of bortezomib through the blood-brain barrier appears to 

be limited, if any and the relevance to humans is unknown. 



33 

 

 

Cardiovascular safety pharmacology studies in monkeys and dogs show that intravenous doses 
approximately two to three times the recommended clinical dose on a mg/m2 basis are associated 

with increases in heart rate, decreases in contractility, hypotension and death. In dogs, the 

decreased cardiac contractility and hypotension responded to acute intervention with positive 
inotropic or pressor agents. Moreover, in dog studies, a slight increase in the corrected QT interval 

was observed. 
 
 
6 PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 
Mannitol (E 421) 
 

6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial 
2 years 
 
Reconstituted solution 
The chemical and physical in-use stability of the reconstituted solution has been demonstrated at 
concentrations of 1 mg/ml  for 96 hours at 25°C and 8 days at 2-8°C, when stored in the original 
vial and/or a syringe.  
 
From a microbiological point of view, the reconstituted solution should be used immediately after 
preparation. If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user. The total storage time for the reconstituted medicinal product should not 
exceed 96 hours (if stored at 25°C) and 8 days (if stored at 2-8 °C) prior to administration. 
 

6.4 Special precautions for storage 
 

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. 

 
6.5 Nature and contents of container 
 

5 ml clear Type I glass vial with grey chlorobutyl rubber stopper and green aluminium flip-off over 
seal, containing 1 mg bortezomib. 
 

The vial is placed in a tray with a lid. Each pack contains 1 single-use vial. 

 

6.6 Special precautions for disposal and other handling 
 
General precautions 

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

of 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 it 

contains no preservative. 



34 

 

 

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 mg and 3.5 mg powder for solution for injection is for intravenous 

or subcutaneous use. Bortezomib should not be administered intrathecally. 

Instructions for reconstitution 
Bortezomib must be reconstituted by a healthcare professional. 

 

Each 5 ml vial of Bortezomib Fresenius Kabi 1 mg powder for solution for injection must be 
carefully reconstituted with 1 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, by 

using a syringe of the appropriate size, without removing the vial stopper. Dissolution of the 

lyophilised powder is completed in less than 2 minutes.  

 

After reconstitution, each ml solution contains 1 mg bortezomib. The reconstituted solution is clear 

and colourless, with a final pH of 4 to 7. The reconstituted solution must be inspected visually for 
particulate matter and discolouration prior to administration. If any discolouration or particulate 

matter is observed, the reconstituted solution must be discarded.  

 

Disposal 
Bortezomib is for single use only. Any unused medicinal product or waste material should be 

disposed of in accordance with local requirements. 
 
 
7 MARKETING AUTHORISATION HOLDER 
 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 
 
 
8 MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1397/003 
 
 
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
 
10 DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of European Medicinal 
Agency http://www.ema.europa.eu 

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


35 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection 
Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

 

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. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for solution for injection. 
 
White to off-white lyophilized powder or cake. 
 
 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Bortezomib as monotherapy or in combination with pegylated liposomal doxorubicin or 
dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma 

who have received at least 1 prior therapy and who have already undergone or are unsuitable for 

haematopoietic stem cell transplantation. 

 
Bortezomib in combination with melphalan and prednisone is indicated for the treatment of adult 

patients with previously untreated multiple myeloma who are not eligible for high-dose 

chemotherapy with haematopoietic stem cell transplantation. 
 

Bortezomib in combination with dexamethasone, or with dexamethasone and thalidomide, is 

indicated for the induction treatment of adult patients with previously untreated multiple myeloma 
who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation. 

 

Bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone is 

indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who 
are unsuitable for haematopoietic stem cell transplantation. 

 

4.2 Posology and method of administration 
 
Bortezomib treatment must be initiated under supervision of a physician experienced in the 

treatment of cancer patients, however bortezomib may be administered by a healthcare professional 

experienced in use of chemotherapeutic agents. Bortezomib must be reconstituted by a healthcare 

professional (see section 6.6). 



36 

 

 

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

Monotherapy 

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg powder for solution for injection is administered via 
intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area 

twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period 

is considered a treatment cycle. It is recommended that patients receive 2 cycles of bortezomib 

following a confirmation of a complete response. It is also recommended that responding patients 
who do not achieve a complete remission receive a total of 8 cycles of bortezomib therapy. At least 

72 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 any 

grade 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 a 
25% reduced dose (1.3 mg/m2 reduced to 1.0 mg/m2; 1.0 mg/m2 reduced to 0.7 mg/m2). If the 

toxicity is not resolved or if it recurs at the lowest dose, discontinuation of bortezomib must be 

considered 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 to 
be managed as presented in table 1 (see section 4.4). Patients with pre-existing severe neuropathy 

may 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 

reflexes or paresthesia) with no pain or loss of 

function 

None 

Grade 1 with pain or grade 2 (moderate 

symptoms; limiting instrumental Activities of 

Daily Living (ADL)**) 

Reduce bortezomib to 1.0 mg/m2 

or 

Change bortezomib treatment schedule to 

1.3 mg/m2 once per week. 

Grade 2 with pain or grade 3 (severe symptoms; 

limiting self care ADL***) 

Withhold bortezomib treatment until symptoms 

of toxicity have resolved. When toxicity resolves 

re-initiate bortezomib treatment and reduce dose 

to 0.7 mg/m2 once per week 

Grade 4 (life-threatening consequences; urgent 

intervention indicated)  

and/or severe autonomic neuropathy 

Discontinue bortezomib 

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

experience. 

Grading based on NCI Common Toxicity Criteria CTCAE v 4.0. 

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

money, etc; 

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

products, 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 via 

intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area 

twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period 

is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of 

bortezomib. 



37 

 

Pegylated liposomal doxorubicin is administered at 30 mg/m2 on day 4 of the bortezomib treatment 

cycle 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 not 

progressed and tolerate treatment. Patients achieving a complete response can continue treatment 

for at least 2 cycles after the first evidence of complete response, even if this requires treatment for 

more than 8 cycles. Patients whose levels of paraprotein continue to decrease after 8 cycles can also 

continue 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 via 

intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area 

twice weekly for two weeks on days 1, 4, 8, and 11 in a 21 day treatment cycle. This 3-week period 

is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of 

bortezomib. 

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

bortezomib treatment cycle. 

Patients achieving a response or a stable disease after 4 cycles of this combination therapy can 

continue 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 guidelines 

described under monotherapy above. 

 

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

cell transplantation 

Combination therapy with melphalan and prednisone 

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg powder for solution for injection is administered via 

intravenous or subcutaneous injection in combination with oral melphalan and oral prednisone as 

shown in table 2. A 6-week period is considered a treatment cycle. In cycles 1-4, bortezomib is 

administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In cycles 5-9, bortezomib is 

administered once weekly on days 1, 8, 22 and 29. At least 72 hours should elapse between 

consecutive doses of bortezomib. 

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

each 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 
(1.3 mg/m2) 

Day 
1 

-- -- Day 
4 

Day 
8 

Day 
11 

rest 
period 

Day 
22 

Day 
25 

Day 
29 

Day 
32 

rest 
period 

M (9 mg/m2) 
P (60 mg/m2) 

Day 
1 

Day 
2 

Day 
3 

Day 
4 

-- -- rest 
period 

-- -- -- -- rest 
period 

Once weekly bortezomib (cycles 5-9) 

Week 1 2 3 4 5 6 

B 

(1.3 mg/m2) 

Day 

1 

-- -- -- Day 

8 

rest 

period 

Day 

22 

Day 

29 

rest 

period 

M (9 mg/m2) 

P (60 mg/m2) 

Day 

1 

Day 

2 

Day 

3 

Day 

4 

-- rest 

period 

-- 
 

rest 

period 



38 

 

B=bortezomib; M=melphalan, P=prednisone 

 

Dose adjustments during treatment and re-initiation of treatment for combination therapy with 
melphalan 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 in 

 combination with melphalan and prednisone 

 

Toxicity Posology modification or delay 

Haematological toxicity during a cycle 
 

• If prolonged grade 4 neutropenia or 
thrombocytopenia, or thrombocytopenia with 

bleeding is observed in the previous cycle 

Consider reduction of the melphalan dose by 

25% in the next cycle. 

• If platelet counts ≤ 30 x 109/l or ANC 
≤ 0.75 x 109/l on a bortezomib dosing day 

(other than day 1) 

Bortezomib therapy should be withheld 

• If several bortezomib doses in a cycle are 
withheld (≥ 3 doses during twice weekly 

administration or ≥ 2 doses during weekly 

administration) 

Bortezomib dose should be reduced by 1 dose 

level (from 1.3 mg/m2 to 1 mg/m2, or from 

1 mg/m2 to 0.7 mg/m2) 

Grade ≥ 3 non-haematological toxicities Bortezomib therapy should be withheld until 

symptoms of the toxicity have resolved to 
grade 1 or baseline. Then, bortezomib may be 

reinitiated with one dose level reduction (from 

1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 
0.7 mg/m2). For bortezomib-related neuropathic 

pain and/or peripheral neuropathy, hold and/or 

modify bortezomib as outlined in table 1. 

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

of Product Characteristics. 

 

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

Combination therapy with dexamethasone 

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg powder for solution for injection is administered via 
intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area 

twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period 

is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of 

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

treatment 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 via 
intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area 

twice weekly for two weeks on days 1, 4, 8, and 11 in a 28-day treatment cycle. This 4-week period 

is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of 

bortezomib. 



39 

 

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

treatment cycle. 
Thalidomide is administered orally at 50 mg daily on days 1-14 and if tolerated the dose is 

increased to 100 mg on days 15-28, and thereafter may be further increased to 200 mg daily from 

cycle 2 (see table 4). 
Four treatment cycles of this combination are administered. It is recommended that patients with at 

least partial response receive 2 additional cycles. 

 

Table 4:  Posology for bortezomib combination therapy for patients with previously untreated 
multiple 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 - - 

Cycles 2 to 4
b
 

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=thalidomide 
a Thalidomide dose is increased to 100 mg from week 3 of cycle 1 only if 50 mg is tolerated and to 200 mg 

from 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 monotherapy 

should be followed. 
In addition, when bortezomib is given in combination with other chemotherapeutic medicinal 

products, appropriate dose reductions for these products should be considered in the event of 

toxicities 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 via 

intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area 

twice weekly for two weeks on days 1, 4, 8, and 11, followed by a 10-day rest period on days 

12-21. This 3-week period is considered a treatment cycle. Six bortezomib cycles are 
recommended, although for patients with a response first documented at cycle 6, two additional 

bortezomib cycles may be given. At least 72 hours should elapse between consecutive doses of 

bortezomib. 
 

The following medicinal products are administered on day 1 of each bortezomib 3 week treatment 

cycle as intravenous infusions: rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2 and 

doxorubicin at 50 mg/m2. 
Prednisone is administered orally at 100 mg/m2 on days 1, 2, 3, 4 and 5 of each bortezomib 

treatment cycle. 

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



40 

 

Prior to initiating a new cycle of therapy: 

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

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

- 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 -related 
non-haematological toxicities (excluding neuropathy) or ≥ grade 3 haematological toxicities (see 

also section 4.4). For dose adjustments, see table 5 below. 

Granulocyte colony stimulating factors may be administered for haematologic toxicity according to 
local standard practice. Prophylactic use of granulocyte colony stimulating factors should be 

considered in case of repeated delays in cycle administration. Platelet transfusion for the treatment 

of thrombocytopenia should be considered when clinically appropriate. 

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

  lymphoma 

 

Toxicity Posology modification or delay 

Haematological toxicity 

- ≥ Grade 3 neutropenia with fever, grade 4 
neutropenia lasting more than 7 days, a 

platelet count < 10,000 cells/μL 

Bortezomib therapy should be withheld for up to 

2 weeks until the patient has an ANC 

≥ 750 cells/μL and a platelet count 
≥ 25,000 cells/μL. 

- If, after bortezomib has been held, the 
toxicity 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 be 
reinitiated at a dose reduced by one dose 

level (from 1.3 mg/m2 to 1 mg/m2, or from 

1 mg/m2 to 0.7 mg/m2). 

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

Bortezomib therapy should be withheld 

Grade ≥ 3 non-haematological toxicities 
considered to be related to bortezomib  

Bortezomib therapy should be withheld until 
symptoms of the toxicity have resolved to 

grade 2 or better. Then, bortezomib may be 

reinitiated at a dose reduced by one dose level 
(from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 

0.7 mg/m2). For bortezomib-related neuropathic 

pain and/or peripheral neuropathy, hold and/or 

modify bortezomib as outlined in table 1. 

 
In addition, when bortezomib is given in combination with other chemotherapeutic medicinal 

products, appropriate dose reductions for these medicinal products should be considered in the 

event of toxicities, according to the recommendations in the respective Summary of Product 
Characteristics. 

 

Special populations 

 
Elderly 



41 

 

There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age 

with multiple myeloma or with mantle cell lymphoma. 
There are no studies on the use of bortezomib in elderly patients with previously untreated multiple 

myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell 

transplantation. Therefore no dose recommendations can be made in this population. 
In a study in previously untreated mantle cell lymphoma patients, 42.9% and 10.4% of patients 

exposed to bortezomib were in the range 65-74 years and ≥ 75 years of age, respectively. In 

patients aged ≥ 75 years, both regimens, BR-CAP as well as R-CHOP, were less tolerated (see 

section 4.8). 
 

Hepatic impairment 

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

bortezomib at a reduced dose of 0.7 mg/m2 per injection during the first treatment cycle, and a 

subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered 

based on patient tolerability (see table 6 and sections 4.4 and 5.2). 
 

Table 6:  Recommended starting dose modification for bortezomib in patients with hepatic 

impairment 

Grade of hepatic 

impairment* 
Bilirubin level SGOT (AST) 

levels 
Modification of starting 

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 to 

0.7 mg/m2 in the first 

treatment cycle. Consider 
dose escalation to 1.0 mg/m2 

or further dose reduction to 

0.5 mg/m2 in subsequent 
cycles based on patient 

tolerability. 

Severe > 3 x ULN Any 

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). 

 

Renal impairment 
The pharmacokinetics of bortezomib are not influenced in patients with mild to moderate renal 

impairment (Creatinine Clearance [CrCL] > 20 ml/min/1.73 m2); therefore, dose adjustments are 

not necessary for these patients. It is unknown if the pharmacokinetics of bortezomib are influenced 
in 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 the 

dialysis procedure (see section 5.2). 
 

Paediatric population 

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 no 
recommendation on a posology can be made. 

 

Method of administration 
 

Bortezomib Fresenius Kabi 1 mg powder for solution for injection is available for intravenous 

administration only.  

 
Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection is available for intravenous or 



42 

 

subcutaneous administration. 

 
Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection is available for intravenous or 

subcutaneous 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 injection 
through a peripheral or central intravenous catheter followed by a flush with sodium chloride 

9 mg/ml (0.9%) solution for injection. At least 72 hours should elapse between consecutive doses 

of bortezomib. 
 

Subcutaneous injection 

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 less 
concentrated 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. 

 

4.3 Contraindications 
 

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 Summaries 

of Product Characteristics for additional contraindications. 
 

4.4 Special warnings and precautions for use 

 

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 treatment 

with bortezomib. When thalidomide is used, particular attention to pregnancy testing and 

prevention 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 or 

subcutaneous use. Bortezomib should not be administered intrathecally. 

 
Gastrointestinal toxicity 

Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common 

with bortezomib treatment. Cases of ileus have been uncommonly reported (see section 4.8). 

Therefore, patients who experience constipation should be closely monitored. 
 

Haematological toxicity 

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

myeloma treated with bortezomib and in patients with previously untreated MCL treated with 

bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone 



43 

 

(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 to 
baseline by the next cycle. There was no evidence of cumulative thrombocytopenia. The mean 

platelet count nadir measured was approximately 40% of baseline in the single-agent multiple 

myeloma studies and 50% in the MCL study. In patients with advanced myeloma the severity of 
thrombocytopenia 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 a 

count ≤ 25,000/μl during the study. 
 

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

grade ≥ 3 thrombocytopenia in the bortezomib treatment group (BR-CAP) as compared to the 
non-bortezomib treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and 

prednisone [R-CHOP]). The two treatment groups were similar with regard to the overall incidence 

of all-grade bleeding events (6.3% in the BR-CAP group and 5.0% in the R-CHOP group) as well 

as grade 3 and higher bleeding events (BR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). In 
the BR-CAP group, 22.5% of patients received platelet transfusions compared to 2.9% of patients 

in the R-CHOP group. 

 
Gastrointestinal and intracerebral haemorrhage, have been reported in association with bortezomib 

treatment. 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 of 
combination with melphalan and prednisone, when the platelet count is ≤ 30,000/μl (see 

section 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 frequently 

monitored throughout treatment with bortezomib. Platelet transfusion should be considered when 

clinically appropriate (see section 4.2). 
 

In patients with MCL, transient neutropenia that was reversible between cycles was observed, with 

no evidence of cumulative neutropenia. Neutrophils were lowest at Day 11 of each cycle of 
bortezomib 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% of 

patients 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. Granulocyte 
colony stimulating factors may be administered for haematologic toxicity according to local 

standard practice. Prophylactic use of granulocyte colony stimulating factors should be considered 

in 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 incidence 
of 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 be 

performed in patients at risk of infection with HBV before initiation of treatment. Carriers of 

hepatitis B and patients with a history of hepatitis B must be closely monitored for clinical and 
laboratory signs of active HBV infection during and following rituximab combination treatment 

with bortezomib. Antiviral prophylaxis should be considered. Refer to the Summary of Product 

Characteristics of rituximab for more information. 



44 

 

 

Progressive multifocal leukoencephalopathy (PML) 
Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML 

and death, have been reported in patients treated with bortezomib. Patients diagnosed with PML 

had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 
12 months of their first dose of bortezomib. Patients should be monitored at regular intervals for 

any new or worsening neurological symptoms or signs that may be suggestive of PML as part of 

the differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be 

referred to a specialist in PML and appropriate diagnostic measures for PML should be initiated. 
Discontinue bortezomib if PML is diagnosed. 

 

Peripheral neuropathy 
Treatment with bortezomib is very commonly associated with peripheral neuropathy, which is 

predominantly sensory. However, cases of severe motor neuropathy with or without sensory 

peripheral neuropathy have been reported. The incidence of peripheral neuropathy increases early 

in 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 a 

burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or 
weakness. 

 

In the Phase III study comparing bortezomib administered intravenously versus subcutaneously, the 
incidence of grade ≥ 2 peripheral neuropathy events was 24% for the subcutaneous injection group 

and 41% for the intravenous injection group (p=0.0124). Grade ≥ 3 peripheral neuropathy occurred 

in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous 

treatment group (p=0.0264). The incidence of all grade peripheral neuropathy with bortezomib 
administered intravenously was lower in the historical studies with bortezomib administered 

intravenously than in study MMY-3021. 

 
Patients experiencing new or worsening peripheral neuropathy should undergo neurological 

evaluation and may require a change in the dose, schedule or route of administration to 

subcutaneous (see section 4.2). Neuropathy has been managed with supportive care and other 
therapies. 

 

Early and regular monitoring for symptoms of treatment-emergent neuropathy with neurological 

evaluation should be considered in patients receiving bortezomib in combination with medicinal 
products known to be associated with neuropathy (e.g. thalidomide) and appropriate dose reduction 

or treatment discontinuation should be considered. 

 
In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to some 

adverse reactions such as postural hypotension and severe constipation with ileus. Information on 

autonomic neuropathy and its contribution to these undesirable effects is limited. 

 
Seizures 

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

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

Hypotension 

Bortezomib treatment is commonly associated with orthostatic/postural hypotension. Most adverse 
reactions are mild to moderate in nature and are observed throughout treatment. Patients who 

developed orthostatic hypotension on bortezomib (injected intravenously) did not have evidence of 

orthostatic hypotension prior to treatment with bortezomib. Most patients required treatment for 

their orthostatic hypotension. A minority of patients with orthostatic hypotension experienced 
syncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion of 

bortezomib. The mechanism of this event is unknown although a component may be due to 

autonomic neuropathy. Autonomic neuropathy may be related to bortezomib or bortezomib may 



45 

 

aggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advised 

when treating patients with a history of syncope receiving medicinal products known to be 
associated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting. 

Management of orthostatic/postural hypotension may include adjustment of antihypertensive 

medicinal products, rehydration or administration of mineralocorticosteroids and/or 
sympathomimetics. Patients should be instructed to seek medical advice if they experience 

symptoms of dizziness, light-headedness or fainting spells. 

 

Posterior Reversible Encephalopathy Syndrome (PRES) 
There have been reports of PRES in patients receiving 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 patients 

developing PRES, bortezomib should be discontinued. 

 

Heart failure 
Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left 

ventricular ejection fraction has been reported during bortezomib treatment. Fluid retention may be 

a predisposing factor for signs and symptoms of heart failure. Patients with risk factors for or 
existing heart disease should be closely monitored. 

 

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

been established. 

 

Pulmonary disorders 
There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology 

such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress 

syndrome (ARDS) in patients receiving bortezomib (see section 4.8). Some of these events have 
been fatal. A pre-treatment chest radiograph is recommended to serve as a baseline for potential 

post-treatment pulmonary changes. 

 
In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt 

diagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratio 

should 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 continuous 

infusion over 24 hours with daunorubicin and bortezomib for relapsed acute myelogenous 

leukaemia 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 impairment 
Renal complications are frequent in patients with multiple myeloma. Patients with renal 

impairment should be monitored closely (see sections 4.2 and 5.2). 

 
Hepatic impairment 

Bortezomib is metabolised by liver enzymes. Bortezomib exposure is increased in patients with 

moderate or severe hepatic impairment; these patients should be treated with bortezomib at reduced 
doses and closely monitored for toxicities (see sections 4.2 and 5.2). 

 

Hepatic reactions 

Rare cases of hepatic failure have been reported in patients receiving bortezomib and concomitant 
medicinal products and with serious underlying medical conditions. Other reported hepatic 

reactions include increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may 

be reversible upon discontinuation of bortezomib (see section 4.8). 



46 

 

 

Tumour lysis syndrome 
Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells and MCL cells, 

the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis 

syndrome are those with high tumour burden prior to treatment. These patients should be monitored 
closely and appropriate precautions taken. 

 

Concomitant medicinal products 

Patients should be closely monitored when given bortezomib in combination with potent 
CYP3A4-inhibitors. Caution should be exercised when bortezomib is combined with CYP3A4- or 

CYP2C19 substrates (see section 4.5). 

 
Normal liver function should be confirmed and caution should be exercised in patients receiving 

oral hypoglycemics (see section 4.5). 

 

Potentially immunocomplex-mediated reactions 
Potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis 

with rash and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should 

be discontinued if serious reactions occur. 
 
4.5 Interaction with other medicinal products and other forms of interaction 

 

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 to 
the metabolism of bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affect 

the overall disposition of bortezomib. 

A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on 
the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC 

increase of 35% (CI90% [1.032 to 1.772]) based on data from 12 patients. Therefore, patients should 

be 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, on 

the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the 
pharmacokinetics of bortezomib based on data from 17 patients. 

 

A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the 

pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC 
reduction of 45% based on data from 6 patients. Therefore, the concomitant use of bortezomib with 

strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's 

Wort) is not recommended, as efficacy may be reduced. 
 

In the same drug-drug interaction study assessing the effect of dexamethasone, a weaker CYP3A4 

inducer, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant 
effect on the pharmacokinetics of bortezomib based on data from 7 patients. 

 

A drug-drug interaction study assessing the effect of melphalan-prednisone on the 

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

 

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

bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of 

the dose of their antidiabetics. 
 

 



47 

 

4.6 Fertility, pregnancy and lactation 

 
Contraception in males and females 

Male and female patients of childbearing potential must use effective contraceptive measures 

during and for 3 months following treatment. 
 

Pregnancy 

No clinical data are available for bortezomib with regard to exposure during pregnancy. The 

teratogenic potential of bortezomib has not been fully investigated. 
 

In non-clinical studies, bortezomib had no effects on embryonal/foetal development in rats and 

rabbits at the highest maternally tolerated doses. Animal studies to determine the effects of 
bortezomib 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 woman 

requires treatment with bortezomib. 

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

 

Thalidomide is a known human teratogenic active substance that causes severe life-threatening 
birth defects. Thalidomide is contraindicated during pregnancy and in women of childbearing 

potential unless all the conditions of the thalidomide pregnancy prevention programme are met. 

Patients receiving bortezomib in combination with thalidomide should adhere to the pregnancy 
prevention programme of thalidomide. Refer to the Summary of Product Characteristics of 

thalidomide for additional information. 

 

Breast-feeding 
It is not known whether bortezomib is excreted in human milk. Because of the potential for serious 

adverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with 

bortezomib. 
 

Fertility 

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

 
4.7 Effects on ability to drive and use machines 

 

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

Bortezomib may be associated with fatigue very commonly, dizziness commonly, syncope 
uncommonly 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 or 

operate machinery if they experience these symptoms (see section 4.8). 
 

4.8 Undesirable effects 

 

Summary of the safety profile 

Serious adverse reactions uncommonly reported during treatment with bortezomib include cardiac 
failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy 

syndrome, 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. 

 
Tabulated list of adverse reactions 

Multiple myeloma 

Undesirable effects in table 7 were considered by the investigators to have at least a possible or 
probable causal relationship to bortezomib. These adverse reactions are based on an integrated data 



48 

 

set of 5,476 patients of whom 3,996 were treated with bortezomib at 1.3 mg/m2 and included in 

table 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 are 
defined as: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to 

< 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated 

from the available data). Within each frequency grouping, undesirable effects are presented in order 

of 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 in 
clinical 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*, Meningoencephalitis 

herpetic#, Bacteraemia (inc staphylococcal), 
Hordeolum, Influenza, Cellulitis, Device related 

infection, Skin infection*, Ear infection*, 

Staphylococcal infection, Tooth infection* 

Rare Meningitis (inc bacterial), Epstein-Barr virus 

infection, Genital herpes, Tonsillitis, Mastoiditis, 
Post viral fatigue syndrome 

Neoplasms benign, 
malignant and unspecified 

(incl cysts and polyps) 

Rare Neoplasm malignant, Leukaemia plasmacytic, 
Renal cell carcinoma, Mass, Mycosis fungoides, 

Neoplasm benign* 

Blood and lymphatic system 

disorders 

Very common Thrombocytopenia*, Neutropenia*, Anaemia* 

Common Leukopenia*, Lymphopenia* 

Uncommon Pancytopenia*, Febrile neutropenia, 

Coagulopathy*, Leukocytosis*, 
Lymphadenopathy, Haemolytic anaemia# 

Rare Disseminated intravascular coagulation, 
Thrombocytosis*, Hyperviscosity syndrome, 

Platelet disorder NOS, Thrombotic 

microangiopathy (including thrombocytopenic 
purpura)#, Blood disorder NOS, Haemorrhagic 

diathesis, Lymphocytic infiltration 

Immune system disorders Uncommon Angioedema#, Hypersensitivity* 

Rare Anaphylactic shock, Amyloidosis, Type III 
immune complex mediated reaction 

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

Rare Hypothyroidism 

Metabolism and nutrition 

disorders 

Very common Decreased appetite 

Common Dehydration, Hypokalaemia*, Hyponatraemia*, 

Blood glucose abnormal*, Hypocalcaemia*, 

Enzyme abnormality* 

Uncommon Tumour lysis syndrome, Failure to thrive*, 



49 

 

System Organ Class Incidence Adverse reaction 

Hypomagnesaemia*, Hypophosphataemia*, 
Hyperkalaemia*, Hypercalcaemia*, 

Hypernatraemia*, Uric acid abnormal*, Diabetes 

mellitus*, Fluid retention 

Rare Hypermagnesaemia*, Acidosis, Electrolyte 

imbalance*, Fluid overload, Hypochloraemia*, 
Hypovolaemia, Hyperchloraemia*, 

Hyperphosphataemia*, Metabolic disorder, 

Vitamin B complex deficiency, Vitamin B12 
deficiency, Gout, Increased appetite, Alcohol 

intolerance 

Psychiatric disorders Common Mood disorders and disturbances*, Anxiety 

disorder*, Sleep disorders and disturbances* 

Uncommon Mental disorder*, Hallucination*, Psychotic 

disorder*, 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 (inc 

syncope), Dizziness*, Dysgeusia*, Lethargy, 

Headache* 

Uncommon Tremor, Peripheral sensorimotor neuropathy, 

Dyskinesia*, Cerebellar coordination and balance 

disturbances*, Memory loss (exc dementia)*, 
Encephalopathy*, Posterior Reversible 

Encephalopathy Syndrome#, Neurotoxicity, 

Seizure disorders*, Post herpetic neuralgia, Speech 
disorder*, Restless legs syndrome, Migraine, 

Sciatica, Disturbance in attention, Reflexes 

abnormal*, Parosmia 

Rare Cerebral haemorrhage*, Haemorrhage intracranial 

(inc subarachnoid)*, Brain oedema, Transient 
ischaemic attack, Coma, Autonomic nervous 

system imbalance, Autonomic neuropathy, Cranial 

palsy*, Paralysis*, Paresis*, Presyncope, Brain 

stem syndrome, Cerebrovascular disorder, Nerve 
root lesion, Psychomotor hyperactivity, Spinal cord 

compression, Cognitive disorder NOS, Motor 

dysfunction, Nervous system disorder NOS, 
Radiculitis, Drooling, Hypotonia 

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

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

Blepharitis#, Eye inflammation*, Diplopia, Dry 
eye*, Eye irritation*, Eye pain, Lacrimation 

increased, Eye discharge 

Rare Corneal lesion*, Exophthalmos, Retinitis, 

Scotoma, Eye disorder (inc. eyelid) NOS, 

Dacryoadenitis acquired, Photophobia, Photopsia, 
Optic neuropathy#, Different degrees of visual 

impairment (up to blindness)* 



50 

 

System Organ Class Incidence Adverse reaction 

Ear and labyrinth disorders Common Vertigo* 

Uncommon Dysacusis (inc tinnitus)*,Hearing impaired (up to 

and inc deafness), Ear discomfort* 

Rare Ear haemorrhage, Vestibular neuronitis, Ear 

disorder NOS 

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

Cardiac fibrillation (inc atrial), Cardiac failure (inc 
left 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, Vein 

discolouration, Venous insufficiency 

Respiratory, thoracic and 

mediastinal disorders 

Common Dyspnoea*, Epistaxis, Upper/lower respiratory 

tract infection*, Cough* 

Uncommon Pulmonary embolism, Pleural effusion, Pulmonary 

oedema (inc acute), Pulmonary alveolar 
haemorrhage#, Bronchospasm, Chronic obstructive 

pulmonary disease*, Hypoxaemia*, Respiratory 

tract congestion*, Hypoxia, Pleurisy*, Hiccups, 
Rhinorrhoea, Dysphonia, Wheezing 

Rare Respiratory failure, Acute respiratory distress 
syndrome, Apnoea, Pneumothorax, Atelectasis, 

Pulmonary hypertension, Haemoptysis, 

Hyperventilation, Orthopnoea, Pneumonitis, 

Respiratory alkalosis, Tachypnoea, Pulmonary 
fibrosis, Bronchial disorder*, Hypocapnia*, 

Interstitial lung disease, Lung infiltration, Throat 

tightness, Dry throat, Increased upper airway 
secretion, Throat irritation, Upper-airway cough 

syndrome 

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

Constipation 

Common Gastrointestinal haemorrhage (inc mucosal)*, 

Dyspepsia, Stomatitis*, Abdominal distension, 

Oropharyngeal pain*, Abdominal pain (inc 



51 

 

System Organ Class Incidence Adverse reaction 

gastrointestinal and splenic pain)*, Oral disorder*, 
Flatulence 

Uncommon Pancreatitis (inc chronic)*, Haematemesis, Lip 
swelling*, Gastrointestinal obstruction (inc small 

intestinal obstruction, ileus)*, Abdominal 

discomfort, Oral ulceration*, Enteritis*, Gastritis*, 
Gingival bleeding, Gastrooesophageal reflux 

disease*, Colitis (inc clostridium difficile)*, Colitis 

ischaemic#, Gastrointestinal inflammation*, 
Dysphagia, Irritable bowel syndrome, 

Gastrointestinal disorder NOS, Tongue coated, 

Gastrointestinal motility disorder*, Salivary gland 

disorder* 

Rare Pancreatitis acute, Peritonitis*, Tongue oedema*, 

Ascites, Oesophagitis, Cheilitis, Faecal 
incontinence, Anal sphincter atony, Faecaloma*, 

Gastrointestinal ulceration and perforation*, 

Gingival hypertrophy, Megacolon, Rectal 
discharge, 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-Chiari 

syndrome, Cytomegalovirus hepatitis, Hepatic 

haemorrhage, Cholelithiasis 

Skin and subcutaneous tissue 

disorders 

Common Rash*, Pruritus*, Erythema, Dry skin 

Uncommon Erythema multiforme, Urticaria, Acute febrile 

neutrophilic dermatosis, Toxic skin eruption, Toxic 

epidermal necrolysis#, Stevens-Johnson syndrome#, 
Dermatitis*, Hair disorder*, Petechiae, 

Ecchymosis, Skin lesion, Purpura, Skin mass*, 

Psoriasis, Hyperhidrosis, Night sweats, Decubitus 

ulcer#, Acne*, Blister*, Pigmentation disorder* 

Rare Skin reaction, Jessner's lymphocytic infiltration, 

Palmar-plantar erythrodysaesthesia syndrome, 
Haemorrhage subcutaneous, Livedo reticularis, 

Skin induration, Papule, Photosensitivity reaction, 

Seborrhoea, Cold sweat, Skin disorder NOS, 
Erythrosis, Skin ulcer, Nail disorder 

Musculoskeletal and 
connective tissue disorders 

Very common Musculoskeletal pain* 

Common Muscle spasms*, Pain in extremity, Muscular 

weakness 

Uncommon Muscle twitching, Joint swelling, Arthritis*, Joint 

stiffness, Myopathies*,Sensation of heaviness 

Rare Rhabdomyolysis, Temporomandibular joint 

syndrome, Fistula, Joint effusion, Pain in jaw, 
Bone disorder, Musculoskeletal and connective 

tissue infections and inflammations*, Synovial cyst 

Renal and urinary disorders Common Renal impairment* 



52 

 

System Organ Class Incidence Adverse reaction 

Uncommon Renal failure acute, Renal failure chronic*, Urinary 
tract infection*, Urinary tract signs and 

symptoms*, Haematuria*, Urinary retention, 

Micturition disorder*, Proteinuria, Azotaemia, 
Oliguria*, Pollakiuria 

Rare Bladder irritation 

Reproductive system and 

breast disorders 

Uncommon Vaginal haemorrhage, Genital pain*, Erectile 

dysfunction, 

Rare Testicular disorder*, Prostatitis, Breast disorder 

female, Epididymal tenderness, Epididymitis, 
Pelvic pain, Vulval ulceration 

Congenital, familial and 
genetic disorders 

Rare Aplasia, Gastrointestinal malformation, Ichthyosis 

General disorders and 
administration site 

conditions 

Very common Pyrexia*, Fatigue, Asthenia 

Common Oedema (inc peripheral), Chills, Pain*, Malaise* 

Uncommon General physical health deterioration*, Face 

oedema*, Injection site reaction*, Mucosal 

disorder*, Chest pain, Gait disturbance, Feeling 
cold, Extravasation*, Catheter related 

complication*, Change in thirst*, Chest 

discomfort, Feeling of body temperature change*, 
Injection site pain* 

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

healing*, Inflammation, Injection site phlebitis*, 

Tenderness, Ulcer, Irritability, Non-cardiac chest 

pain, Catheter site pain, Sensation of foreign body 

Investigations Common Weight decreased 

Uncommon Hyperbilirubinaemia*, Protein analyses abnormal*, 

Weight increased, Blood test abnormal*,C-reactive 

protein increased 

Rare Blood gases abnormal*, Electrocardiogram 

abnormalities (inc QT prolongation)*, International 
normalised ratio abnormal*, Gastric pH decreased, 

Platelet aggregation increased, Troponin I 

increased, Virus identification and serology*, 
Urine analysis abnormal* 

Injury, poisoning and 
procedural complications 

Uncommon Fall, Contusion 

Rare Transfusion reaction, Fractures*, Rigors*, Face 

injury, Joint injury*, Burns, Laceration, Procedural 
pain, Radiation injuries* 

Surgical and medical 
procedures 

Rare Macrophage activation 

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 in 

combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BR-CAP) versus 

242 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 



53 

 

[R-CHOP] was relatively consistent to that observed in patients with multiple myeloma with main 

differences described below. Additional adverse drug reactions identified associated with the use of 
the 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 adverse 

drug reactions are not attributable to bortezomib alone. Notable differences in the MCL patient 
population as compared to patients in the multiple myeloma studies were a ≥ 5% higher incidence 

of the haematological adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, 

lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and 

hair 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 causal 

relationship to bortezomib based on historical data in the multiple myeloma studies. 

 

Adverse reactions are listed below by system organ class and frequency grouping. Frequencies are 
defined as: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to 

< 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated 

from the available data). Within each frequency grouping, undesirable effects are presented in order 
of 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 a 
clinical trial 

System Organ Class Incidence Adverse reaction 

Infections and infestations Very common Pneumonia* 

Common Sepsis (inc septic shock)*, Herpes zoster (inc 

disseminated & ophthalmic), Herpes virus 
infection*, Bacterial infections*, Upper/lower 

respiratory tract infection*, Fungal infection*, 

Herpes simplex* 

Uncommon Hepatitis B, Infection*, Bronchopneumonia 

Blood and lymphatic system 

disorders 

Very common Thrombocytopenia*, Febrile neutropenia, 

Neutropenia*, Leukopenia*, Anaemia*, 

Lymphopenia* 

Uncommon Pancytopenia* 

Immune system disorders Common Hypersensitivity* 

Uncommon Anaphylactic reaction 

Metabolism and nutrition 

disorders 

Very common Decreased appetite 

Common Hypokalaemia*, Blood glucose abnormal*, 

Hyponatraemia*, Diabetes mellitus*, Fluid 

retention 

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 of 
consciousness (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)* 



54 

 

System Organ Class Incidence Adverse reaction 

Uncommon Vertigo*, Hearing impaired (up to and inc 
deafness) 

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

Myocardial ischaemia, Ventricular dysfunction* 

Uncommon Cardiovascular disorder (inc cardiogenic shock) 

Vascular disorders Common Hypertension*, Hypotension*, Orthostatic 
hypotension 

Respiratory, thoracic and 
mediastinal disorders 

Common Dyspnoea*, Cough*, Hiccups 

Uncommon Acute respiratory distress syndrome, Pulmonary 

embolism, Pneumonitis, Pulmonary hypertension, 
Pulmonary oedema (inc acute) 

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

Common Gastrointestinal haemorrhage (inc mucosal)*, 
Abdominal distension, Dyspepsia, Oropharyngeal 

pain*, Gastritis*, Oral ulceration*, Abdominal 

discomfort, Dysphagia, Gastrointestinal 
inflammation*, Abdominal pain (inc 

gastrointestinal and splenic pain)*, Oral disorder* 

Uncommon Colitis (inc clostridium difficile)* 

Hepatobiliary disorders Common Hepatotoxicity (inc liver disorder) 

Uncommon Hepatic failure 

Skin and subcutaneous tissue 

disorders 

Very common Hair disorder* 

Common Pruritus*, Dermatitis*, Rash* 

Musculoskeletal and 
connective tissue disorders 

Common Muscle spasms*, Musculoskeletal pain*, Pain in 
extremity 

Renal and urinary disorders Common Urinary tract infection* 

General disorders and 

administration site 
conditions 

Very common Pyrexia*, Fatigue, Asthenia 

Common Oedema (inc peripheral), Chills, Injection site 

reaction*, Malaise* 

Investigations Common Hyperbilirubinaemia*, Protein analyses abnormal*, 

Weight decreased, Weight increased 

* Grouping of more than one MedDRA preferred term. 
Description of selected adverse reactions 

Herpes zoster virus reactivation 
Multiple myeloma 

Antiviral prophylaxis was administered to 26% of the patients in the B+M+P arm. The incidence of 

herpes zoster among patients in the B+M+P treatment group was 17% for patients not administered 
antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis. 

 

Mantle cell lymphoma 

Antiviral prophylaxis was administered to 137 of 240 patients (57%) in the BR-CAP arm. The 
incidence of herpes zoster among patients in the BR-CAP arm was 10.7% for patients not 

administered antiviral prophylaxis compared to 3.6% for patients administered antiviral 

prophylaxis (see section 4.4). 
 

Hepatitis B virus (HBV) reactivation and infection 

Mantle cell lymphoma 



55 

 

HBV infection with fatal outcomes occurred in 0.8% (n=2) of patients in the non-bortezomib 

treatment 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 B 

infections was similar in patients treated with BR-CAP or with R-CHOP (0.8% vs 1.2% 
respectively). 

 

Peripheral neuropathy in combination regimens 

Multiple myeloma 
In trials in which bortezomib was administered as induction treatment in combination with 

dexamethasone (study IFM-2005-01), and dexamethasone-thalidomide (study MMY-3010), the 

incidence of peripheral neuropathy in the combination regimens is presented in the table below: 
 

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

  treatment discontinuation due to peripheral neuropathy  
IFM-2005-01 MMY-3010 

 
VDDx 

(N=239) 

BDx 

(N=239) 

TDx 

(N=126) 

BTDx 

(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 motor 

neuropathy, peripheral sensory neuropathy, and polyneuropathy. 

 
Mantle cell lymphoma 

In study LYM-3002 in which bortezomib was administered with rituximab, cyclophosphamide, 

doxorubicin, and prednisone (BR-CAP), the incidence of peripheral neuropathy in the combination 
regimens is presented in the table below: 

 

Table 10:  Incidence of peripheral neuropathy in study LYM-3002 by toxicity and treatment  

  discontinuation due to peripheral neuropathy  
BR-CAP 
(N=240) 

R-CHOP 
(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 patients 

42.9% and 10.4% of patients in the BR-CAP arm were in the range 65-74 years and ≥ 75 years of 
age, respectively. Although in patients aged ≥ 75 years, both BR-CAP and R-CHOP were less 

tolerated, the serious adverse event rate in the BR-CAP groups was 68%, compared to 42% in the 

R-CHOP group. 
 



56 

 

Notable differences in the safety profile of bortezomib administered subcutaneously versus 

intravenously as single agent 
In the Phase III study patients who received bortezomib subcutaneously compared to intravenous 

administration had 13% lower overall incidence of treatment emergent adverse reactions that were 

grade 3 or higher in toxicity, and a 5% lower incidence of discontinuation of bortezomib. The 
overall incidence of diarrhoea, gastrointestinal and abdominal pain, asthenic conditions, upper 

respiratory tract infections and peripheral neuropathies were 12%-15% lower in the subcutaneous 

group than in the intravenous group. In addition, the incidence of grade 3 or higher peripheral 

neuropathies was 10% lower, and the discontinuation rate due to peripheral neuropathies 8% lower 
for the subcutaneous group as compared to the intravenous group. 

 

Six percent of patients had an adverse local reaction to subcutaneous administration, mostly 
redness. 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 the 
intravenous treatment group. Incidence of death from “Progressive disease” was 18% in the 

subcutaneous 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 multiple 

myeloma, who previously had at least partial response on a bortezomib-containing regimen, the 
most common all-grade adverse events occurring in at least 25% of patients were 

thrombocytopenia (55%), neuropathy (40%), anaemia (37%), diarrhoea (35%), and constipation 

(28%). All grade peripheral neuropathy and grade ≥ 3 peripheral neuropathy were observed in 40% 

and 8.5% of patients, respectively. 
 

Reporting of suspected adverse reactions 

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. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 
 

4.9 Overdose 
 

In patients, overdose more than twice the recommended dose has been associated with the acute 

onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. For preclinical 
cardiovascular safety pharmacology studies, see section 5.3. 

 

There is no known specific antidote for bortezomib overdose. In the event of an overdose, the 
patient's vital signs should be monitored and appropriate supportive care given to maintain blood 

pressure (such as fluids, pressors, and/or inotropic agents) and body temperature (see sections 4.2 

and 4.4). 
 
 

5 PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: 
L01XX32. 

 

Mechanism of action 
Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-like 

activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex 

that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in 

regulating the turnover of specific proteins, thereby maintaining homeostasis within cells. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
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57 

 

Inhibition of the 26S proteasome prevents this targeted proteolysis and affects multiple signalling 

cascades within the cell, ultimately resulting in cancer cell death. 
 

Bortezomib is highly selective for the proteasome. At 10 μM concentrations, bortezomib does not 

inhibit any of a wide variety of receptors and proteases screened and is more than 1,500-fold more 
selective for the proteasome than for its next preferable enzyme. The kinetics of proteasome 

inhibition were evaluated in vitro, and bortezomib was shown to dissociate from the proteasome 

with 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, but 

not limited to, altering regulatory proteins, which control cell cycle progression and nuclear factor 

kappa B (NF-kB) activation. Inhibition of the proteasome results in cell cycle arrest and apoptosis. 
NF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis, 

including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma, 

bortezomib affects the ability of myeloma cells to interact with the bone marrow 

microenvironment. 
 

Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types and 

that cancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than 
normal cells. Bortezomib causes reduction of tumour growth in vivo in many preclinical tumour 

models, including multiple myeloma. 

 
Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast 

differentiation and activity and inhibits osteoclast function. These effects have been observed in 

patients with multiple myeloma affected by an advanced osteolytic disease and treated with 

bortezomib. 
 

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 injected 

intravenously) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in 

improvement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone 
(60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered 

for a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease 

progression 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 the 
patients was 80. Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median 

hemoglobin of 105 g/l, and a median platelet count of 221.5 x 109/l. Similar proportions of patients 

had creatinine clearance ≤ 30 ml/min (3% in each arm). 
At the time of a pre-specified interim analysis, the primary endpoint, time to progression, was met 

and 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. A 

statistically 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+P 

treatment 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 

n=344 

M+P 

n=338 

Time to progression 

Events n (%) 

 

101 (29) 

 

152 (45) 

Mediana (95% CI) 20.7 mo 

(17.6, 24,7) 

15.0 mo 

(14.1, 17.9) 

Hazard ratiob 0.54 



58 

 

Efficacy endpoint B+M+P 

n=344 

M+P 

n=338 

(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 

(16.6, 21.7) 

14.0 mo 

(11.1, 15.0) 

Hazard ratiob 

(95% CI) 

0.61 

(0.49, 0.76) 

p-valuec 0.00001 

Overall survival* 

Events (deaths) n (%) 

 

176 (51.2) 

 

211 (62.4) 

Mediana 

(95% CI) 

56.4 mo 

(52.8, 60.9) 

43.1 mo 

(35.3, 48.3) 

Hazard ratiob 

(95% CI) 

0.695 

(0.567, 0.852) 

p-valuec 0.00043 

Response rate 

populatione n=668 

n=337 n=331 

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 

populationg n=667 

n=336 n=331 

≥90% n (%) 151 (45) 34 (10) 

Time to first response in CR + PR 
 

Median 1.4 mo 4.2 mo 

Mediana response duration 
 

CRf 24.0 mo 12.8 mo 

CR+PRf 19.9 mo 13.1 mo 

Time to next therapy 
Events n (%) 

 
224 (65.1) 

 
260 (76.9) 

Mediana 
(95% CI) 

27.0 mo 
(24.7, 31.1) 

19.2 mo 
(17.0, 21.0) 

Hazard ratiob 

(95% CI) 

0.557 

(0.462, 0.671) 

p-valuec < 0.000001 
a Kaplan-Meier estimate 
b 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 VMP 
c Nominal p-value based on the stratified log-rank test adjusted for stratification factors: β2-microglobulin, 

albumin, and region 
d p-value for Response Rate (CR+PR) from the Cochran Mantel-Haenszel chi-square test adjusted for the 

stratification factors 
e Response population includes patients who had measurable disease at baseline 
f CR=Complete Response; PR=Partial Response. EBMT criteria 



59 

 

g All randomised patients with secretory disease 

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

mo: months 

CI=Confidence Interval 

 
Patients eligible for stem cell transplantation 

Two randomised, open-label, multicenter Phase III trials (IFM-2005-01, MMY-3010) were 

conducted to demonstrate the safety and efficacy of bortezomib in dual and triple combinations 
with other chemotherapeutic agents, as induction therapy prior to stem cell transplantation in 

patients with previously untreated multiple myeloma. 

 

In study IFM-2005-01 bortezomib combined with dexamethasone [BDx, n=240] was compared to 
vincristine-doxorubicin-dexamethasone [VDDx, n=242]. Patients in the BDx group received four 

21 day cycles, each consisting of bortezomib (1.3 mg/m2 administered intravenously twice weekly 

on days 1, 4, 8, and 11), and oral dexamethasone (40 mg/day on days 1 to 4 and days 9 to 12, in 
cycles 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 in 

the VDDx and BDx groups respectively; the majority of patients underwent one single transplant 
procedure. Patient demographic and baseline disease charateristics were similar between the 

treatment groups. Median age of the patients in the study was 57 years, 55% were male and 48% of 

patients had high-risk cytogenetics. The median duration of treatment was 13 weeks for the VDDx 

group and 11 weeks for the BDx group. The median number of cycles received for both groups was 
4 cycles. 

The primary efficacy endpoint of the study was post-induction response rate (CR+nCR). A 

statistically significant difference in CR+nCR was observed in favour of the bortezomib combined 
with dexamethasone group. Secondary efficacy endpoints included post-transplant response rates 

(CR+nCR, CR+nCR+VGPR+PR), Progression Free Survival and Overall Survival. Main efficacy 

results are presented in table 12. 
 

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

Endpoints BDx VDDx OR; 95% CI; P value
a
 

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

RR (Post-induction) 

*CR+nCR 
CR+nCR+VGPR+PR 

% (95% CI) 

 

14.6 (10.4, 19.7) 
77.1 (71.2, 82.2) 

 

6.2 (3.5, 10.0) 
60.7 (54.3, 66.9) 

 

2.58 (1.37, 4.85); 0.003 
2.18 (1.46, 3.24); < 0.001 

RR (Post-transplant)b 

CR+nCR 

CR+nCR+VGPR+PR 
% (95% CI) 

 

37.5 (31.4, 44.0) 

79.6 (73.9, 84.5) 

 

23.1 (18.0, 29.0) 

74.4 (68.4, 79.8) 

 

1.98 (1.33, 2.95); 0.001 

1.34 (0.87, 2.05); 0.179 

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 endpoint 
a 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 and 

dexamethasone [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/m2 
administered twice weekly days 1, 4, 8, and 11, followed by a 17-day rest period from day 12 to 

day 28), dexamethasone (40 mg administered orally on days 1 to 4 and days 8 to 11), and 



60 

 

thalidomide (administered orally at 50 mg daily on days 1-14, increased to 100 mg on days 15-28 

and 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 disease 

characteristics were similar between the treatment groups. Patients in the BTDx and TDx groups 
respectively 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 cytogenetically 

classified as high risk versus 16% of patients in the TDx group. The median duration of treatment 

was 24.0 weeks and the median number of treatment cycles received was 6.0, and was consistent 
across treatment groups.  

The primary efficacy endpoints of the study were post-induction and post-transplant response rates 

(CR+nCR). A statistically significant difference in CR+nCR was observed in favour of the 
bortezomib combined with dexamethasone and thalidomide group. Secondary efficacy endpoints 

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

table 13. 

 
Table 13:  Efficacy results from study MMY-3010 

Endpoints BTDx TDx OR; 95% CI; P value
a
 

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

*RR (Post-induction) 

CR+nCR 
 

CR+nCR+PR 

% (95% CI) 

 

49.2 (40.4, 58.1) 
 

84.6 (77.2, 90.3) 

 

17.3 (11.2, 25.0) 
 

61.4 (52.4, 69.9) 

 

4.63 (2.61, 8.22); 
< 0.001a 

3.46 (1.90, 6.27); 

< 0.001a 

*RR (Post-transplant) 

CR+nCR 
CR+nCR+PR 

% (95% CI) 

 

55.4 (46.4, 64.1) 
77.7 (69.6, 84.5) 

 

34.6 (26.4, 43.6) 
56.7 (47.6, 65.5) 

 

2.34 (1.42, 3.87); 0.001a 
2.66 (1.55, 4.57); 

< 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 endpoint 
a 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 the 

recommended dose of 1.3 mg/m2: a Phase III randomised, comparative study (APEX), versus 
dexamethasone (Dex), of 669 patients with relapsed or refractory multiple myeloma who had 

received 1-3 prior lines of therapy, and a Phase II single-arm study of 202 patients with relapsed 

and refractory multiple myeloma, who had received at least 2 prior lines of treatment and who were 
progressing on their most recent treatment. 

 

In the Phase III study, treatment with bortezomib led to a significantly longer time to progression, a 

significantly prolonged survival and a significantly higher response rate, compared to treatment 
with dexamethasone (see table 14), in all patients as well as in patients who have received 1 prior 

line of therapy. As a result of a pre-planned interim analysis, the dexamethasone arm was halted at 

the recommendation of the data monitoring committee and all patients randomised to 
dexamethasone were then offered bortezomib, regardless of disease status. Due to this early 

crossover, the median duration of follow-up for surviving patients is 8.3 months. Both in patients 

who were refractory to their last prior therapy and those who were not refractory, overall survival 
was 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 well 

as TTP remained significantly better for bortezomib independently of age. Regardless of 



61 

 

β2-microglobulin levels at baseline, all efficacy parameters (time to progression and overall 

survival, 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 independent 

review 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). This 

survival was greater than the six-to-nine month median survival anticipated by consultant clinical 

investigators for a similar patient population. By multivariate analysis, the response rate was 

independent of myeloma type, performance status, chromosome 13 deletion status, or the number 
or type of previous therapies. Patients who had received 2 to 3 prior therapeutic regimens had a 

response rate of 32% (10/32) and patients who received greater than 7 prior therapeutic regimens 

had 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 

therapy 

> 1 prior line of 

therapy 

≥ 2 prior 

lines 

Time related 

events 

B 

n=333
a
 

Dex 

n=336
a
 

B 

n=132
a
 

Dex 

n=119
a
 

B 

n=200
a
 

Dex 

n=217
a
 

B 

n=202
a
 

TTP, days 

[95% CI] 

189b 

[148, 211] 

106b 

[86, 128] 

212d 

[188, 267] 

169d 

[105, 191] 

148b 

[129, 192] 

87b 

[84, 107] 

210 

[154, 281] 

1 year survival, % 

[95% CI] 

 

80d 

[74,85] 

 

66d 

[59,72] 

 

89d 

[82,95] 

 

72d 

[62,83] 

 

73 

[64,82] 

 

62 

[53,71] 

 

 

60 

Best response 

(%) 

B 

n=315c 

Dex 

n=312c 

B 

n=128 

Dex 

n=110 

B 

n=187 

Dex 

n=202 

B 

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 

Days (months) 

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

Time to response 

CR+PR (days) 

43 43 44 46 41 27 38* 

a Intent to Treat (ITT) population 
b p-value from the stratified log-rank test; analysis by line of therapy excludes stratification for therapeutic 

history; p < 0.0001 
c Response population includes patients who had measurable disease at baseline and received at least 1 dose 

of study medicinal product. 
d p-value from the Cochran Mantel-Haenszel chi-square test adjusted for the stratification factors; analysis by 

line 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 bortezomib 

alone were able to receive high-dose dexamethasone in conjunction with bortezomib. The protocol 

allowed patients to receive dexamethasone if they had had a less than optimal response to 

bortezomib alone. A total of 74 evaluable patients were administered dexamethasone in 



62 

 

combination 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 with 

relapsed/refractory multiple myeloma 
An open label, randomised, Phase III non-inferiority study compared the efficacy and safety of the 

subcutaneous administration of bortezomib versus the intravenous administration. This study 

included 222 patients with relapsed/refractory multiple myeloma, who were randomised in a 2:1 

ratio to receive 1.3 mg/m2 of bortezomib by either the subcutaneous or intravenous route for 
8 cycles. Patients who did not obtain an optimal response (less than Complete Response [CR]) to 

therapy with bortezomib alone after 4 cycles were allowed to receive dexamethasone 20 mg daily 

on the day of and after bortezomib administration. Patients with baseline grade ≥ 2 peripheral 
neuropathy or platelet counts < 50,000/µl were excluded. A total of 218 patients were evaluable for 

response. 

 

This study met its primary objective of non-inferiority for response rate (CR+PR) after 4 cycles of 
single agent bortezomib for both the subcutaneous and intravenous routes, 42% in both groups. In 

addition, secondary response-related and time to event related efficacy endpoints showed consistent 

results for subcutaneous and intravenous administration (table 15). 
 

Table 15: Summary of efficacy analyses comparing subcutaneous and intravenous   

  administrations of bortezomib 
  

Bortezomib intravenous 

arm 

Bortezomib subcutaneous 

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) 

Intent to Treat Populationb 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 

p-valued 

0.839 (0.564, 1.249) 

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 

p-valued 

0.824 (0.574, 1.183) 

0.295 

1-year Overall Survival (%)e 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. 



63 

 

b 222 subjects were enrolled into the study; 221 subjects were treated with bortezomib 
c Hazards ratio estimate is based on a Cox model adjusted for stratification factors: ISS staging and number of 

prior 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 in 646 
patients comparing the safety and efficacy of bortezomib plus pegylated liposomal doxorubicin 

versus bortezomib monotherapy in patients with multiple myeloma who had received at least 1 

prior therapy and who did not progress while receiving anthracycline-based therapy. The primary 
efficacy 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 termination 

for 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 liposomal 

doxorubicin. The median TTP was 6.5 months for the bortezomib monotherapy patients compared 

with 9.3 months for the bortezomib plus pegylated liposomal doxorubicin combination therapy 
patients. These results, though not mature, constituted the protocol defined final analysis. 

The final analysis for OS performed after a median follow-up of 8.6 years showed no significant 

difference 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; 28.9-37.1 

months) 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 with 
dexamethasone in patients with progressive multiple myeloma, a statistical matched-pair analysis 

was conducted to compare results from the non randomised arm of bortezomib in combination with 

dexamethasone (Phase II open-label study MMY-2045), with results obtained in the bortezomib 
monotherapy 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 study 

subjects. This minimises the effects of observed confounders when estimating treatment effects 

using non-randomised data. 
One hundred and twenty seven matched pairs of patients were identified. The analysis 

demonstrated 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 determine 
the efficacy and safety of retreatment with bortezomib. One hundred and thirty patients (≥ 18 years 

of age) with multiple myeloma who previously had at least partial response on a 

bortezomib-containing regimen were retreated upon progression. At least 6 months after prior 
therapy, 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 single 

agent 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 an 

additional 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). 

 

 
 



64 

 

Clinical efficacy in previously untreated mantle cell lymphoma (MCL) 

Study LYM-3002 was a Phase III, randomised, open-label study comparing the efficacy and safety 
of 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 in 
the BR-CAP treatment arm received bortezomib (1.3 mg/m2; on days 1, 4, 8, 11, rest period days 

12-21), rituximab 375 mg/m2 IV on day 1; cyclophosphamide 750 mg/m2 IV on day 1; doxorubicin 

50 mg/m2 IV on day 1; and prednisone 100 mg/m2 orally on day 1 through day 5 of the 21 day 

bortezomib treatment cycle. For patients with a response first documented at cycle 6, two additional 
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 to 
next anti-lymphoma treatment (TNT), duration of treatment free interval (TFI), overall response 

rate (ORR) and complete response (CR/CRu) rate, overall survival (OS) and response duration. 

 

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

32% Asian, 69% of patients had a positive bone marrow aspirate and/or a positive bone marrow 

biopsy for MCL, 54% of patients had an International Prognostic Index (IPI) score of ≥ 3, and 76% 
had Stage 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 received 

by patients in both treatment arms with 14% of subjects in the BR-CAP group and 17% of patients 
in the R-CHOP group receiving 2 additional cycles. The majority of the patients in both groups 

completed treatment, 80% in the BR-CAP group and 82% in the R-CHOP group. Efficacy results 

are presented in table 16: 

 
Table 16: Efficacy results from study LYM-3002 

Efficacy endpoint BR-CAP R-CHOP 
 

n: ITT patients 243 244 

Progression free survival (IRC)
a
 

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

(0.50; 0.79) 

p-valued < 0.001 
Medianc (95% CI) 

(months) 

24.7 (19.8; 31.8) 14.4 (12; 16.9) 

Response rate 

n: response-evaluable 
patients 

229 228 
 

Overall complete 
response 

(CR+CRu)f n(%) 

122 (53.3%) 95 (41.7%) ORe (95% CI)=1.688 
(1.148; 2.481) 

p-valueg=0.007 

Overall response 

(CR+CRu+PR)h n(%) 

211 (92.1%) 204 (89.5%) ORe (95% CI)=1.428 

(0.749; 2.722) 

p-valueg=0.275 
a 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 of 

disease 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 stratification 

factors. 
h Include all radiological CR+CRu+PR by IRC regardless the verification by bone marrow and LDH. 

CR=Complete Response; CRu=Complete Response unconfirmed; PR=Partial Response; CI=Confidence 

Interval, HR=Hazard Ratio; OR=Odds Ratio; ITT=Intent to Treat 



65 

 

Median PFS by investigator assessment was 30.7 months in the BR-CAP group and 16.1 months in 

the 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 (median 

40.6 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 response 

was 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-CHOP 
group (HR=0.66; p=0.001). The observed final median difference in the OS between the 2 

treatment 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 efficacy 

of bortezomib in patients with previously treated light-chain (AL) Amyloidosis. No new safety 

concerns were observed during the study, and in particular bortezomib did not exacerbate target 
organ damage (heart, kidney and liver). In an exploratory efficacy analysis, a 67.3% response rate 

(including a 28.6% CR rate) as measured by hematologic response (M-protein) was reported in 49 

evaluable patients treated with the maximum allowed doses of 1.6 mg/m2 weekly and 1.3 mg/m2 
twice-weekly. For these dose cohorts, the combined 1-year survival rate was 88.1%. 

 

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

bortezomib in all subsets of the paediatric population in multiple myeloma and in mantle cell 

lymphoma (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 induction 

chemotherapy in paediatric and young adult patients with lymphoid malignancies (pre-B cell acute 
lymphoblastic leukemia [ALL], T-cell ALL, and T-cell lymphoblastic lymphoma [LL]). An 

effective reinduction multiagent chemotherapy regimen was administered in 3 blocks. Bortezomib 

was administered only in Blocks 1 and 2 to avoid potential overlapping toxicities with 
coadministered drugs in Block 3. 

 

Complete response (CR) was evaluated at the end of Block 1. In B-ALL patients with relapse 

within 18 months of diagnosis (n=27) the CR rate was 67% (95% CI: 46, 84); the 4-month event 
free survival rate was 44% (95% CI: 26, 62). In B-ALL patients with relapse 18-36 months from 

diagnosis (n=33) the CR rate was 79% (95% CI: 61, 91) and the 4-month event free survival rate 

was 73% (95% CI: 54, 85). The CR rate in first-relapsed T-cell ALL patients (n=22) was 68% 
(95% CI: 45, 86) and the 4-month event free survival rate was 67% (95% CI: 42, 83). The reported 

efficacy data are considered inconclusive (see section 4.2). 

 

There were 140 patients with ALL or LL enrolled and evaluated for safety; median age was 10 
years (range 1 to 26). No new safety concerns were observed when bortezomib was added to the 

standard 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 as 
compared 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 were 
available 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) and 

hyponatraemia (12% versus 5% in Block 1 and 4% versus 0 in Block 2). 
 

 

 



66 

 

5.2 Pharmacokinetic properties 

 
Absorption 

Following intravenous bolus administration of a 1.0 mg/m2 and 1.3 mg/m2 dose to 11 patients with 

multiple myeloma and creatinine clearance values greater than 50 ml/min, the mean first-dose 
maximum plasma concentrations of bortezomib were 57 and 112 ng/ml, respectively. In subsequent 

doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/ml for the 

1.0 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 with 

multiple myeloma (n=14 in the intravenous group, n=17 in the subcutaneous group), the total 

systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and 
intravenous administrations. The Cmax after subcutaneous administration (20.4 ng/ml) was lower 

than intravenous (223 ng/ml). The AUClast geometric mean ratio was 0.99 and 90% confidence 

intervals were 80.18%-122.80%. 

 
Distribution 

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 multiple 
myeloma. This suggests that bortezomib distributes widely to peripheral tissues. Over a bortezomib 

concentration range of 0.01 to 1.0 μg/ml, the in vitro protein binding averaged 82.9% in human 

plasma. The fraction of bortezomib bound to plasma proteins was not concentration-dependent. 
 

Biotransformation 

In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 

isozymes indicate that bortezomib is primarily oxidatively metabolised via cytochrome P450 
enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form two 

deboronated metabolites that subsequently undergo hydroxylation to several metabolites. 

Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors. 
 

Elimination 

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/m2 

and 1.3 mg/m2, respectively, and ranged from 15 to 32 l/h and 18 to 32 l/h following subsequent 

doses for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively. 
 

Special populations 

Hepatic impairment 
The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in a Phase I 

study during the first treatment cycle, including 61 patients primarily with solid tumors and varying 

degrees 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 alter 

dose-normalised bortezomib AUC. However, the dose-normalised mean AUC values were 

increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower 
starting dose is recommended in patients with moderate or severe hepatic impairment, and those 

patients should be closely monitored (see section 4.2, table 6). 

 
Renal impairment 

A pharmacokinetic study was conducted in patients with various degrees of renal impairment who 

were 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 of 

dialysis patients who were dosed after dialysis was also included in the study (n=8). Patients were 

administered intravenous doses of 0.7 to 1.3 mg/m2 of bortezomib twice weekly. Exposure of 



67 

 

bortezomib (dose-normalised AUC and Cmax) was comparable among all the groups (see 

section 4.2). 
Age 

The pharmacokinetics of bortezomib were characterized following twice weekly intravenous bolus 

administration of 1.3 mg/m2 doses to 104 pediatric patients (2-16 years old) with acute 
lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Based on a population 

pharmacokinetic analysis, clearance of bortezomib increased with increasing body surface area 

(BSA). Geometric mean (%CV) clearance was 7.79 (25%) L/hr/m2, volume of distribution at 

steady-state was 834 (39%) L/m2, and the elimination half-life was 100 (44%) hours. After 
correcting for the BSA effect, other demographics such as age, body weight and sex did not have 

clinically significant effects on bortezomib clearance. BSA-normalized clearance of bortezomib in 

pediatric patients was similar to that observed in adults. 
 

5.3 Preclinical safety data 

 

Bortezomib was positive for clastogenic activity (structural chromosomal aberrations) in the 
in vitro chromosomal aberration assay using Chinese hamster ovary (CHO) cells at concentrations 

as low as 3.125 μg/ml, which was the lowest concentration evaluated. Bortezomib was not 

genotoxic when tested in the in vitro mutagenicity assay (Ames assay) and in vivo micronucleus 

assay in mice. 
 

Developmental toxicity studies in the rat and rabbit have shown embryo-fetal lethality at maternally 

toxic doses, but no direct embryo-foetal toxicity below maternally toxic doses. Fertility studies 
were not performed but evaluation of reproductive tissues has been performed in the general 

toxicity studies. In the 6-month rat study, degenerative effects in both the testes and the ovary have 

been observed. It is, therefore, likely that bortezomib could have a potential effect on either male or 
female fertility. Peri- and postnatal development studies were not conducted. 

 

In multi-cycle general toxicity studies conducted in the rat and monkey, the principal target organs 

included the gastrointestinal tract, resulting in vomiting and/or diarrhoea; haematopoietic and 
lymphatic tissues, resulting in peripheral blood cytopenias, lymphoid tissue atrophy and 

haematopoietic bone marrow hypocellularity; peripheral neuropathy (observed in monkeys, mice 

and dogs) involving sensory nerve axons; and mild changes in the kidneys. All these target organs 
have shown partial to full recovery following discontinuation of treatment. 

Based on animal studies, the penetration of bortezomib through the blood-brain barrier appears to 

be limited, if any and the relevance to humans is unknown. 

 
Cardiovascular safety pharmacology studies in monkeys and dogs show that intravenous doses 

approximately two to three times the recommended clinical dose on a mg/m2 basis are associated 

with increases in heart rate, decreases in contractility, hypotension and death. In dogs, the 
decreased cardiac contractility and hypotension responded to acute intervention with positive 

inotropic or pressor agents. Moreover, in dog studies, a slight increase in the corrected QT interval 

was observed. 
 
 
6 PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 
Mannitol (E 421) 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
 



68 

 

6.3 Shelf life 
 
Unopened vial 
2 years 
 
Reconstituted solution 
The chemical and physical in-use stability of the reconstituted solution has been demonstrated at 
concentrations of 1 mg/ml and 2.5 mg/ml for 96 hours at 25°C and 8 days at 2-8°C, when stored in 
the original vial and/or a syringe.  
 
From a microbiological point of view, the reconstituted solution should be used immediately after 
preparation. If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user. The total storage time for the reconstituted medicinal product should not 
exceed 96 hours (if stored at 25°C) and 8 days (if stored at 2-8 °C) prior to administration. 
 

6.4 Special precautions for storage 
 

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. 

 

6.5 Nature and contents of container 
 

 
Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection 

10 ml clear Type I glass vial with grey chlorobutyl rubber stopper and yellow aluminium flip-off 
over seal, containing 2.5 mg bortezomib. 
 

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection 

10 ml clear Type I glass vial with grey chlorobutyl rubber stopper and blue aluminium flip-off over 
seal, containing 3.5 mg bortezomib. 

 

The vial is placed in a tray with a lid. Each pack contains 1 single-use vial. 

 
6.6 Special precautions for disposal and other handling 
 

General precautions 

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

subcutaneous use. Bortezomib should not be administered intrathecally. 

 
Instructions for reconstitution 

Bortezomib must be reconstituted by a healthcare professional. 

 
Intravenous injection 

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection  



69 

 

Each 10 ml vial of Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection must be 

carefully reconstituted with 2.5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, by 
using a syringe of the appropriate size, without removing the vial stopper. Dissolution of the 

lyophilised powder is completed in less than 2 minutes.  

 
After reconstitution, each ml solution contains 1 mg bortezomib. The reconstituted solution is clear 

and colourless, with a final pH of 4 to 7. The reconstituted solution must be inspected visually for 

particulate matter and discolouration prior to administration. If any discolouration or particulate 

matter 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 be 
carefully reconstituted with 3.5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, by 

using a syringe of the appropriate size, without removing the vial stopper. Dissolution of the 

lyophilised powder is completed in less than 2 minutes. 

 
After reconstitution, each ml solution contains 1 mg bortezomib. The reconstituted solution is clear 

and colourless, with a final pH of 4 to 7. 

 
The reconstituted solution must be inspected visually for particulate matter and discolouration prior 

to administration. If any discolouration or particulate matter is observed, the reconstituted solution 

must be discarded. 
 

Subcutaneous 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 

be carefully reconstituted with 1 ml of sodium chloride 9 mg/ml (0.9%) solution for 

injection, by using a syringe of the appropriate size, without removing the vial stopper. 

Dissolution of the lyophilised powder is completed in less than 2 minutes.  

 

After reconstitution, each ml solution contains 2.5 mg bortezomib. The reconstituted 

solution is clear and colourless, with a final pH of 4 to 7. The reconstituted solution must 

be inspected visually for particulate matter and discolouration prior to administration. If 

any discolouration or particulate matter 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 chloride 
9 mg/ml (0.9%) solution for injection, by using a syringe of the appropriate size, without removing 

the vial stopper. Dissolution of the lyophilised powder is completed in less than 2 minutes. 

After reconstitution, each ml solution contains 2.5 mg bortezomib. The reconstituted solution is 

clear and colourless, with a final pH of 4 to 7. The reconstituted solution must be inspected visually 
for particulate matter and discolouration prior to administration. If any discolouration or particulate 

matter is observed, the reconstituted solution must be discarded. 

 
Disposal 

Bortezomib is for single use only. Any unused medicinal product or waste material should be 

disposed of in accordance with local requirements. 
 
7 MARKETING AUTHORISATION HOLDER 
 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 



70 

 

8 MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1397/002 
EU/1/19/1397/001 
 
 
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 14 November 2019 
 
 
10 DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of European Medicinal 
Agency http://www.ema.europa.eu 

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


71 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
 AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
 EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



72 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 

Fresenius Kabi Deutschland GmbH  

Pfingstweide 53  
61169 Friedberg,  

Germany  

 
or 

Fresenius Kabi Oncology Plc, 

Lion Court, Farnham Road, 

Bordon, Hampshire, GU35 0NF, 
United Kingdom 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
 AUTHORISATION 
 

• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 
any subsequent updates published on the European medicines web-portal.> 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
 EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 

• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 



73 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III  
 

LABELLING AND PACKAGE LEAFLET 



74 

 

 
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



75 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON  
 
 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bortezomib Fresenius Kabi 1 mg powder for solution for injection 

bortezomib 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

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

3. LIST OF EXCIPIENTS 

 
Mannitol (E421) 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for solution for injection 
1 vial 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

For intravenous use after reconstitution. 
For single use. 

May be fatal if given by other routes. 
Intravenous use: Add 1 ml sodium chloride 0.9% to make 1 mg/ml final concentration. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 
Cytotoxic 
Handle with care 
 
 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 



76 

 

 

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

 

 

10, SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 
Germany 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/19/1397/003 
 
 
 

13. BATCH NUMBER 

 

Lot 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 
 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 
Justification for not including Braille accepted 

 

 

17. UNIQUE IDENTIFIER-2D BARCODE  

 
2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER-HUMAN READABLE DATA  

 
PC 

SN 

NN 
 



77 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING 

UNITS 

 

LABEL 
 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Bortezomib Fresenius Kabi 1 mg powder for solution for injection 

bortezomib 
IV 
 

2. METHOD OF ADMINISTRATION 
 
 

3. EXPIRY DATE 

 
EXP 
 
 

4. BATCH NUMBER 

 
Lot 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

1 mg 
 
 

6. OTHER 
 

Cytotoxic  

May be fatal if given by other routes  



78 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON  
 
 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection 

bortezomib 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

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

3. LIST OF EXCIPIENTS 

 
Mannitol (E421) 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for solution for injection 
1 vial 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

For subcutaneous or intravenous use after reconstitution  
For single use. 

May be fatal if given by other routes. 

Subcutaneous use: Add 1 ml sodium chloride 0.9% to make 2.5 mg/ml final concentration. 
Intravenous use: Add 2.5 ml sodium chloride 0.9%  to make 1 mg/ml final concentration. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 
Cytotoxic 
Handle with care 
 
 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 



79 

 

 

 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 
Germany 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/19/1397/002 
 
 
 

13. BATCH NUMBER 

 

Lot 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 
 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 
Justification for not including Braille accepted 

 

 

17. UNIQUE IDENTIFIER-2D BARCODE  

 
2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER-HUMAN READABLE DATA  

 
PC 

SN 

NN 
 



80 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING 

UNITS 

 

LABEL 
 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection 

bortezomib 
SC or IV 
 

2. METHOD OF ADMINISTRATION 
 
 

3. EXPIRY DATE 

 
EXP 
 
 

4. BATCH NUMBER 

 
Lot 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

2.5 mg 
 
 

6. OTHER 
 

Cytotoxic  

May be fatal if given by other routes  



81 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON  

 
 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection 

bortezomib 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

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

3. LIST OF EXCIPIENTS 

 
Mannitol (E421) 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for solution for injection 
1 vial 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 
For subcutaneous or intravenous use after reconstitution  

For single use. 

May be fatal if given by other routes. 
Subcutaneous use: Add 1.4 ml sodium chloride 0.9% to make 2.5 mg/ml final concentration. 
Intravenous use: Add 3.5 ml sodium chloride 0.9% to make 1 mg/ml final concentration. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 
Cytotoxic 
Handle with care 
 
 

8. EXPIRY DATE 

 

EXP 

 

 

 



82 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 

PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 

PRODUCTS, IF APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 
Germany 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1397/001 
 
 

13. BATCH NUMBER 

 

Lot 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 
 
 

15. INSTRUCTIONS ON USE 

 
 

 

16. INFORMATION IN BRAILLE 

 
Justification for not including Braille accepted 

 

 

17. UNIQUE IDENTIFIER-2D BARCODE  

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER-HUMAN READABLE DATA  

 
PC 

SN 

NN 



83 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING 

UNITS 

 

LABEL 
 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection 

bortezomib 
SC or IV 
 
 

2. METHOD OF ADMINISTRATION 
 
 
 

3. EXPIRY DATE 

 
EXP 
 
 

4. BATCH NUMBER 

 
Lot 
 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

3.5 mg 
 
 

6. OTHER 
 

Cytotoxic  

May be fatal if given by other routes  



84 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



85 

 

 
Package leaflet: Information for the user 

 

Bortezomib Fresenius Kabi 1 mg powder for solution for injection 

bortezomib 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any side effects 

not listed in this leaflet. See section 4. 

 

 
What is in this leaflet: 

1. What Bortezomib Fresenius Kabi is and what it is used for 

2. What you need to know before you use Bortezomib Fresenius Kabi  

3. How to use Bortezomib Fresenius Kabi  
4. Possible side effects 

5. How to store Bortezomib Fresenius Kabi  

6. Contents of the pack and other information 
 

 

1. What Bortezomib Fresenius Kabi is and what it is used for 

 

This medicine contains the active substance bortezomib, a so-called ‘proteasome inhibitor’. 

Proteasomes play an important role in controlling cell function and growth. By interfering with 

their function, bortezomib can kill cancer cells. 
 

Bortezomib is used for the treatment of multiple myeloma (a cancer of the bone marrow) in patients 

older than 18 years: 
- alone or together with the medicines pegylated liposomal doxorubicin or dexamethasone, for 

patients whose disease is worsening (progressive) after receiving at least one prior treatment 

and for whom blood stem cell transplantation was not successful or is unsuitable. 
- in combination with the medicines melphalan and prednisone, for patients whose disease has 

not been previously treated and are unsuitable for high-dose chemotherapy with blood stem 

cell transplantation. 

- in combination with the medicines dexamethasone or dexamethasone together with 
thalidomide, for patients whose disease has not been previously treated and before receiving 

high-dose chemotherapy with blood stem cell transplantation (induction treatment). 

 
Bortezomib is used for the treatment of mantle cell lymphoma (a type of cancer affecting the lymph 

nodes) in patients 18 years or older in combination with the medicines rituximab, 

cyclophosphamide, doxorubicin and prednisone, for patients whose disease has not been previously 

treated and for whom blood stem cell transplantation is unsuitable. 
 

 

2. What you need to know before you use Bortezomib Fresenius Kabi  

 

Do not use bortezomib  

- if you are allergic to bortezomib, boron or to any of the other ingredients of this medicine 
(listed in section 6) 

- if you have certain severe lung or heart problems. 
 

Warnings and precautions 

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



86 

 

• low numbers of red or white blood cells 

• bleeding problems and/or low number of platelets in your blood 

• diarrhoea, constipation, nausea or vomiting 

• fainting, dizziness or light-headedness in the past 

• kidney problems 

• moderate to severe liver problems 

• numbness, tingling, or pain in the hands or feet (neuropathy) in the past 

• heart or blood pressure problems 

• shortness of breath or cough 

• seizures 

• shingles (localised including around the eyes or spread across the body) 

• symptoms of tumor lysis syndrome such as muscle cramping, muscle weakness, confusion, 
visual loss or disturbances and shortness of breath 

• memory loss, trouble thinking, difficulty with walking or loss of vision. These may be signs 
of a serious brain infection and your doctor may suggest further testing and follow-up. 

 

You will have to take regular blood tests before and during your treatment with bortezomib, to 

check your blood cell counts regularly. 
 

If you have mantle cell lymphoma and are given the medicine rituximab with bortezomib you must 

tell your doctor: 

• if you think you have hepatitis infection now or have had it in the past. In a few cases, 
patients who have had hepatitis B might have a repeated attack of hepatitis, which can be 

fatal. If you have a history of hepatitis B infection you will be carefully checked by your 

doctor for signs of active hepatitis B. 

 
You must read the package leaflets of all medicinal products to be taken in combination with 

bortezomib for information related to these medicines before starting treatment with bortezomib. 

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

 

Children and adolescents 

This medicine must not be used in children and adolescents because it is not known how it will 
affect them. 

 

Other medicines and bortezomib  

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

medicines. 

In particular, tell your doctor if you are using medicines containing any of the following active 
substances: 

- ketoconazole, used to treat fungal infections 
- ritonavir, used to treat HIV infection 
- rifampicin, an antibiotic used to treat bacterial infections 
- carbamazepine, phenytoin or phenobarbital used to treat epilepsy 
- St. John’s Wort (Hypericum perforatum), used for depression or other conditions 
- oral antidiabetics 

 

Pregnancy and breast-feeding 

You must not use this medicine if you are pregnant, unless clearly necessary. 
 

Both men and women receiving bortezomib must use effective contraception during and for up to 3 

months after treatment. If, despite these measures, pregnancy occurs, tell your doctor immediately. 

 
You must not breast-feed while using bortezomib. Discuss with your doctor when it is safe to 

restart breast-feeding after finishing your treatment. 



87 

 

 

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

leaflet for thalidomide). 

 
Driving and using machines 

Bortezomib might cause tiredness, dizziness, fainting, or blurred vision. Do not drive or operate 

tools or machines if you experience such side effects; even if you do not, you must still be cautious. 

 
 

3. How to use Bortezomib Fresenius Kabi  

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

surface area). The usual starting dose of bortezomib is 1.3 mg/m2 body surface area twice a week. 

Your doctor may change the dose and total number of treatment cycles, depending on your 

response to the treatment on the occurrence of certain side effects and on your underlying 
conditions (e.g. liver problems). 

 

Progressive multiple myeloma 
When bortezomib is given alone, you will receive 4 doses of bortezomib intravenously on days 1, 

4, 8 and 11, followed by a 10-day ‘rest period’ without treatment. This 21-day period (3 weeks) 

corresponds to one treatment cycle. You might receive up to 8 cycles (24 weeks). 
 

You may also be given bortezomib together with the medicines pegylated liposomal doxorubicin or 

dexamethasone. 

 
When bortezomib is given together with pegylated liposomal doxorubicin, you will receive 

bortezomib intravenously as a 21-day treatment cycle and pegylated liposomal doxorubicin 

30 mg/m2 is given on day 4 of the bortezomib 21-day treatment cycle as an intravenous infusion 
after the bortezomib injection. 

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

 
When bortezomib is given together with dexamethasone, you will receive bortezomib intravenously 

as a 21-day treatment cycle and dexamethasone 20 mg is given orally on days 1, 2, 4, 5, 8, 9, 11, 

and 12, of the bortezomib, 21-day treatment cycle. 

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

Previously untreated multiple myeloma 

If you have not been treated before for multiple myeloma, and you are not suitable for blood stem 
cell transplantation you will receive bortezomib intravenously together with two other medicines; 

melphalan and prednisone. 

In this case, the duration of a treatment cycle is 42 days (6 weeks). You will receive 9 cycles 

(54 weeks). 

• In cycles 1 to 4, bortezomib is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 
32. 

• In cycles 5 to 9, bortezomib is administered once weekly on days 1, 8, 22 and 29. 
Melphalan (9 mg/m2) and prednisone (60 mg/m2) are both given orally on days 1, 2, 3 and 4 of the 

first week of each cycle. 
 

If you have not been treated before for multiple myeloma, and you are suitable for blood stem cell 

transplantation you will receive bortezomib intravenously together with the medicines 
dexamethasone, or dexamethasone and thalidomide, as induction treatment. 

 

When bortezomib is given together with dexamethasone, you will receive bortezomib intravenously 

as a 21-day treatment cycle and dexamethasone 40 mg is given orally on days 1, 2, 3, 4, 8, 9, 10 
and 11 of the bortezomib 21-day treatment cycle. 



88 

 

You will receive 4 cycles (12 weeks). 

 
When bortezomib is given together with thalidomide and dexamethasone, the duration of a 

treatment cycle is 28 days (4 weeks). 

 
Dexamethasone 40 mg is given orally on days 1, 2, 3, 4, 8, 9, 10 and 11 of the bortezomib 28-day 

treatment cycle and thalidomide is given orally daily at 50 mg up to day 14 of the first cycle, and if 

tolerated the thalidomide dose is increased to 100 mg on days 15-28 and may be further increased 

to 200 mg daily from the second cycle onwards. 
You might receive up to 6 cycles (24 weeks). 

 

Previously untreated mantle cell lymphoma 
If you have not been treated before for mantle cell lymphoma you will receive bortezomib 

intravenously together with the medicines rituximab, cyclophosphamide, doxorubicin and 

prednisone. 

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

(24 weeks). 

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

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

Prednisone is given orally at 100 mg/m2 on days 1, 2, 3, 4 and 5 of the bortezomib treatment cycle. 
 

How bortezomib is given 

This medicine is for intravenous use only. Bortezomib will be administered by a health care 

professional experienced in the use of cytotoxic medicines. 
Bortezomib powder has to be dissolved before administration. This will be done by a healthcare 

professional. The resulting solution is then injected into a vein rapidly, over 3 to 5 seconds.  

 
If you are given too much bortezomib  

As this medicine is being given by your doctor or nurse, it is unlikely that you will be given too 

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

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some 

of these effects may be serious. 
If you are given bortezomib for multiple myeloma or mantle cell lymphoma, tell your doctor 

straight away if you notice any of the following symptoms: 

- muscle cramping, muscle weakness 
- confusion, visual loss or disturbances, blindness, seizures, headaches 
- shortness of breath, swelling of your feet or changes in your heart beat, high blood pressure, 

tiredness, fainting 

- coughing and breathing difficulties or tightness in the chest. 
 

Treatment with bortezomib can very commonly cause a decrease in the numbers of red and white 

blood cells and platelets in your blood. Therefore, you will have to take regular blood tests before 
and during your treatment with bortezomib, to check your blood cell counts regularly. You may 

experience a reduction in the number of: 

- platelets, which may make you be more prone to bruising, or to bleeding without obvious 
injury (e.g., bleeding from your bowels, stomach, mouth and gum or bleeding in the brain or  
bleeding from the liver) 

- red blood cells, which can cause anaemia, with symptoms such as tiredness and paleness 
- white blood cells may make you more prone to infections or flu-like symptoms. 



89 

 

 

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

 

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

• Sensitivity, numbness, tingling or burning sensation of the skin, or pain in the hands or feet, 
due to nerve damage 

• Reduction in the number of red blood cells and or white blood cells (see above) 

• Fever 

• Feeling sick (nausea) or vomiting, loss of appetite 

• Constipation with or without bloating (can be severe) 

• Diarrhoea: if this happens, it is important that you drink more water than usual. Your doctor 
may give you another medicine to control diarrhoea 

• Tiredness (fatigue), feeling weak 

• Muscle pain, bone pain 
 

Common side effects (may affect up to 1 in 10 people) 

• Low blood pressure, sudden fall of blood pressure on standing which may lead to fainting 

• High blood pressure 

• Reduced functioning of your kidneys 

• Headache 

• General ill feeling, pain, vertigo, light-headedness, a feeling of weakness or loss of 
consciousness 

• Shivering 

• Infections, including pneumonia, respiratory infections, bronchitis, fungal infections, 
coughing with phlegm, flu like illness 

• Shingles (localised including around the eyes or spread across the body) 

• Chest pains or shortness of breath with exercise 

• Different types of rash 

• Itching of the skin, lumps on the skin or dry skin 

• Facial blushing or tiny broken capillaries 

• Redness of the skin 

• Dehydration 

• Heartburn, bloating, belching, wind, stomach pain, bleeding from your bowels or stomach 

• Alteration of liver functioning 

• A sore mouth or lip, dry mouth, mouth ulcers or throat pain 

• Weight loss, loss of taste 

• Muscle cramps, muscle spasms, muscle weakness, pain in your limbs 

• Blurred vision 

• Infection of the outermost layer of the eye and the inner surface of the eyelids 
(conjunctivitis) 

• Nose bleeds 

• Difficulty or problems in sleeping, sweating, anxiety, mood swings, depressed mood, 
restlessness or agitation, changes in your mental status, disorientation 

• Swelling of body, to include around eyes and other parts of the body 
 

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

• Heart failure, heart attack, chest pain, chest discomfort, increased or reduced heart rate 

• Failing of your kidneys 

• Inflammation of a vein, blood clots in your veins and lungs 

• Problems with blood clotting 

• Insufficient circulation 

• Inflammation of the lining around your heart or fluid around your heart 

• Infections including urinary tract infections, the flu, herpes virus infections, ear infection and 



90 

 

cellulitis 

• Bloody stools, or bleeding from mucosal membranes, e.g., mouth, vagina 

• Cerebrovascular disorders 

• Paralysis, seizures, falling, movement disorders, abnormal or change in, or reduced sensation 
(feeling, hearing, tasting, smelling), attention disturbance, trembling, twitching 

• Arthritis, including inflammation of the joints in the fingers, toes, and the jaw 

• Disorders that affect your lungs, preventing your body from getting enough oxygen. Some of 
these include difficulty breathing, shortness of breath, shortness of breath without exercise, 

breathing that becomes shallow, difficult or stops, wheezing 

• Hiccups, speech disorders 

• Increased or decreased urine production (due to kidney damage), painful passing of urine or 
blood/proteins in the urine, fluid retention 

• Altered levels of consciousness, confusion, memory impairment or loss 

• Hypersensitivity 

• Hearing loss, deafness or ringing in the ears, ear discomfort 

• Hormone abnormality which may affect salt and water absorption 

• Overactive thyroid gland 

• Inability to produce enough insulin or resistance to normal levels of insulin 

• Irritated or inflamed eyes, excessively wet eyes, painful eyes, dry eyes, eye infections, lump 
in the eyelid (chalazion), red and swollen eyelids, discharge from the eyes, abnormal vision, 

bleeding of the eye 

• Swelling of your lymph glands 

• Joint or muscle stiffness, sense of heaviness, pain in your groin 

• Hair loss and abnormal hair texture 

• Allergic reactions 

• Redness or pain at the injection site 

• Mouth pain 

• Infections or inflammation of the mouth, mouth ulcers, oesophagus, stomach and intestines, 
sometimes associated with pain or bleeding, poor movement of the intestines (including 
blockage), abdominal or oesophageal discomfort, difficulty swallowing, vomiting of blood 

• Skin infections 

• Bacterial and viral infections 

• Tooth infection 

• Inflammation of the pancreas, obstruction of the bile duct 

• Genital pain, problem having an erection 

• Weight increase 

• Thirst 

• Hepatitis 

• Injection site or injection device related disorders 

• Skin reactions and disorders (which may be severe and life threatening), skin ulcers 

• Bruises, falls and injuries 

• Inflammation or haemorrhage of the blood vessels that can appear as small red or purple dots 
(usually on the legs) to large bruise-like patches under the skin or tissue 

• Benign cysts 

• A severe reversible brain condition which includes seizures, high blood pressure, headaches, 
tiredness, confusion, blindness or other vision problems. 

 

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

• Heart problems to include heart attack, angina 

• Flushing 

• Discoloration of the veins 

• Inflammation of the spinal nerve 

• Problems with your ear, bleeding from your ear 

• Underactivity of your thyroid gland 



91 

 

• Budd–Chiari syndrome (the clinical symptoms caused by blockage of the hepatic veins) 

• Changes in or abnormal bowel function 

• Bleeding in the brain 

• Yellow discolouration of eyes and skin (jaundice) 

• Serious allergic reaction (anaphylactic shock) signs of which may include difficulty 
breathing, chest pain or chest tightness, and/or feeling dizzy/faint, severe itching of the skin 

or raised lumps on the skin, swelling of the face, lips, tongue and /or throat, which may cause 
difficulty in swallowing, collapse 

• Breast disorders 

• Vaginal tears 

• Genital swelling 

• Inability to tolerate alcohol consumption 

• Wasting, or loss of body mass 

• Increased appetite 

• Fistula 

• Joint effusion 

• Cysts in the lining of joints (synovial cysts) 

• Fracture 

• Breakdown of muscle fibers leading to other complications 

• Swelling of the liver, bleeding from the liver 

• Cancer of the kidney 

• Psoriasis like skin condition 

• Cancer of the skin 

• Paleness of the skin 

• Increase of platelets or plasma cells (a type of white cell) in the blood 

• Blood clot in small blood vessels (thrombotic microangiopathy) 

• Abnormal reaction to blood transfusions 

• Partial or total loss of vision 

• Decreased sex drive 

• Drooling 

• Bulging eyes 

• Sensitivity to light 

• Rapid breathing 

• Rectal pain 

• Gallstones 

• Hernia 

• Injuries 

• Brittle or weak nails 

• Abnormal protein deposits in your vital organs 

• Coma 

• Intestinal ulcers 

• Multi-organ failure 

• Death 
 

If you are given bortezomib together with other medicines for the treatment of mantle cell 
lymphoma the side effects you may get are listed below: 

 

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

• Pneumonia 

• Loss of appetite 

• Sensitivity, numbness, tingling or burning sensation of the skin, or pain in the hands or feet, 
due to nerve damage 

• Nausea and vomiting 



92 

 

• Diarrhoea 

• Mouth ulcers 

• Constipation 

• Muscle pain, bone pain 

• Hair loss and abnormal hair texture 

• Tiredness, feeling weak 

• Fever 
 

Common side effects (may affect up to 1 in 10 people) 

• Shingles (localized including around the eyes or spread across the body) 

• Herpes virus infections 

• Bacterial and viral infections 

• Respiratory infections, bronchitis, coughing with phlegm, flu like illness 

• Fungal infections 

• Hypersensitivity (allergic reaction) 

• Inability to produce enough insulin or resistance to normal levels of insulin 

• Fluid retention 

• Difficulty or problems in sleeping 

• Loss of consciousness 

• Altered level of consciousness, confusion 

• Feeling dizzy 

• Increased heartbeat, high blood pressure, sweating, 

• Abnormal vision, blurred vision 

• Heart failure, heart attack, chest pain, chest discomfort, increased or reduced heart rate 

• High or low blood pressure 

• Sudden fall of blood pressure upon standing which may lead to fainting 

• Shortness of breath with exercise 

• Cough 

• Hiccups 

• Ringing in the ears, ear discomfort 

• Bleeding from your bowels or stomach 

• Heartburn 

• Stomach pain, bloating 

• Difficulty swallowing 

• Infection or inflammation of the stomach and intestine 

• Stomach pain 

• Sore mouth or lip, throat pain 

• Alteration of liver function 

• Itching of skin 

• Redness of skin 

• Rash 

• Muscle spasms 

• Infection of the urinary tract 

• Pain in limbs 

• Swelling of body, to include eyes and other parts of the body 

• Shivering 

• Redness and pain at injection site 

• General ill feeling 

• Weight loss 

• Weight increase 
 

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

• Hepatitis 



93 

 

• Severe allergic reaction (anaphylactic reaction) signs of which may include difficulty 
breathing, chest pain or chest tightness, and/or feeling dizzy/faint, severe itching of the skin 

or raised lumps on the skin, swelling of the face, lips, tongue and /or throat, which may cause 
difficulty in swallowing, collapse 

• Movement disorders, paralysis, twitching 

• Vertigo 

• Hearing loss, deafness 

• Disorders that affect your lungs, preventing your body from getting enough oxygen. Some of 
these include difficulty breathing, shortness of breath, shortness of breath without exercise, 

breathing that becomes shallow, difficult or stops, wheezing 

• Blood clots in your lungs 

• Yellow discoloration of the eyes and skin (jaundice) 

• Lump in the eyelid (chalazion), red and swollen eyelids 
 

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

• • Blood clot in small blood vessels (thrombotic microangiopathy) 
 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 

 

 
5. How to store Bortezomib Fresenius Kabi  

 

Keep this medicine out of the sight and reach of children. 

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

 

This medicinal product does not require any special temperature storage condition. Keep the vial in 
the outer carton in order to protect from light. 

 

The chemical and physical in-use stability of the reconstituted solution has been demonstrated at 
concentrations of 1 mg/ml  for 96 hours at 25°C and 8 days at 2-8°C, when stored in the original 

vial and/or a syringe.  

 

From a microbiological point of view, the reconstituted solution should be used immediately after 
preparation. If not used immediately, in-use storage times and conditions prior to use are the 

responsibility of the user. The total storage time for the reconstituted medicinal product should not 

exceed 96 hours (if stored at 25°C) and 8 days (if stored at 2-8 °C) prior to administration. 
Bortezomib is for single use only. Any unused product or waste material should be disposed of in 

accordance with local requirements. 

 

 
6. Contents of the pack and other information 

 

What Bortezomib Fresenius Kabi contains 

- The active substance is bortezomib. Each vial contains 1 mg bortezomib (as a mannitol 
boronic ester). After reconstitution, 1 ml of solution for intravenous injection contains 1 mg 

bortezomib. 
- The other ingredients are mannitol (E421). 

 

What Bortezomib Fresenius Kabi looks like and contents of the pack 

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

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


94 

 

Each carton of Bortezomib Fresenius Kabi 1 mg powder for solution for injection contains a 5 ml 

clear glass vial with grey rubber stopper and aluminium green flip-off over seal, containing 1 mg 
bortezomib. 

 

The vial is placed in a tray with a lid. Each pack contains 1 single-use vial. 
 

Marketing Authorisation Holder 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 

 

Manufacturer 

Fresenius Kabi Deutschland GmbH  

Pfingstweide 53  

61169 Friedberg,  
Germany  

 

or 
Fresenius Kabi Oncology Plc, 

Lion Court, Farnham Road, 

Bordon, Hampshire, GU35 0NF, 

United Kingdom 
 

For any information about this medicine, please contact the Marketing Authorisation Holder. 

 
This leaflet was last revised in MM/YYYY 

 

Other sources of information 

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

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


95 

 

The following information is intended for healthcare professionals only: 

 
 

1. RECONSTITUTION FOR INTRAVENOUS INJECTION 

 
Note: Bortezomib is a cytotoxic agent. Therefore, caution must be used during handling and 

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

 

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

 

1.1 Preparation of the 1 mg vial: carefully add 1 ml of sterile, 9 mg/ml (0.9%) sodium 
chloride solution for injection to the vial containing the bortezomib by using a syringe of the 

appropriate size without removing the vial stopper. Dissolution of the lyophilised powder is 

completed in less than 2 minutes.  

 

The concentration of the resulting solution will be 1 mg/ml. The solution will be clear and 

colourless, with a final pH of 4 to 7. You do not need to check the pH of the solution.  

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

If any discolouration or particulate matter is observed, the solution must be discarded 

Confirm concentration on vial to ensure that the correct dose is being given for the 
intravenous route of administration (1 mg/ml). 

 

1.3 The chemical and physical in-use stability of the reconstituted solution has been 

demonstrated at concentrations of 1 mg/ml  for 96 hours at 25°C and 8 days at 2-8°C, when 
stored in the original vial and/or a syringe.  

 

From a microbiological point of view, the reconstituted solution should be used immediately 
after preparation. If not used immediately, in-use storage times and conditions prior to use 

are the responsibility of the user. The total storage time for the reconstituted medicinal 

product should not exceed 96 hours (if stored at 25°C) and 8 days (if stored at 2-8 °C) prior 
to administration. 

 

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

 
 

2. ADMINISTRATION 

 
- Once dissolved, withdraw the appropriate amount of the reconstituted solution according to 

calculated dose based upon the patient´s Body Surface Area. 

- Confirm the dose and concentration in the syringe prior to use (check that the syringe is 
marked as intravenous administration). 

- Inject the solution as a 3-5 second bolus intravenous injection through a peripheral or central 
intravenous catheter into a vein. 

- Flush the peripheral or intravenous catheter with sterile, sodium chloride 9 mg/ml (0.9%) 
solution. 

 

Bortezomib Fresenius Kabi 1 mg IS FOR INTRAVENOUS USE. Do not give by other routes. 

Intrathecal administration has resulted in death. 

 

 

3. DISPOSAL 

 

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

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



96 

 

Package leaflet: Information for the user 

 

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection  

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection 

bortezomib 

 
Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any side effects 

not listed in this leaflet. See section 4. 

 
 

What is in this leaflet: 

1. What Bortezomib Fresenius Kabi is and what it is used for 

2. What you need to know before you use Bortezomib Fresenius Kabi  
3. How to use Bortezomib Fresenius Kabi  

4. Possible side effects 

5. How to store Bortezomib Fresenius Kabi  
6. Contents of the pack and other information 

 

 
1. What Bortezomib Fresenius Kabi is and what it is used for 

 

This medicine contains the active substance bortezomib, a so-called ‘proteasome inhibitor’. 

Proteasomes play an important role in controlling cell function and growth. By interfering with 
their function, bortezomib can kill cancer cells. 

 

Bortezomib is used for the treatment of multiple myeloma (a cancer of the bone marrow) in patients 
older than 18 years: 

- alone or together with the medicines pegylated liposomal doxorubicin or dexamethasone, for 
patients whose disease is worsening (progressive) after receiving at least one prior treatment 
and for whom blood stem cell transplantation was not successful or is unsuitable. 

- in combination with the medicines melphalan and prednisone, for patients whose disease has 
not been previously treated and are unsuitable for high-dose chemotherapy with blood stem 

cell transplantation. 
- in combination with the medicines dexamethasone or dexamethasone together with 

thalidomide, for patients whose disease has not been previously treated and before receiving 

high-dose chemotherapy with blood stem cell transplantation (induction treatment). 
 

Bortezomib is used for the treatment of mantle cell lymphoma (a type of cancer affecting the lymph 

nodes) in patients 18 years or older in combination with the medicines rituximab, 

cyclophosphamide, doxorubicin and prednisone, for patients whose disease has not been previously 
treated and for whom blood stem cell transplantation is unsuitable. 

 

 
2. What you need to know before you use Bortezomib Fresenius Kabi  

 

Do not use bortezomib  

- if you are allergic to bortezomib, boron or to any of the other ingredients of this medicine 
(listed in section 6) 

- if you have certain severe lung or heart problems. 
 
Warnings and precautions 

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



97 

 

• low numbers of red or white blood cells 

• bleeding problems and/or low number of platelets in your blood 

• diarrhoea, constipation, nausea or vomiting 

• fainting, dizziness or light-headedness in the past 

• kidney problems 

• moderate to severe liver problems 

• numbness, tingling, or pain in the hands or feet (neuropathy) in the past 

• heart or blood pressure problems 

• shortness of breath or cough 

• seizures 

• shingles (localised including around the eyes or spread across the body) 

• symptoms of tumor lysis syndrome such as muscle cramping, muscle weakness, confusion, 
visual loss or disturbances and shortness of breath 

• memory loss, trouble thinking, difficulty with walking or loss of vision. These may be signs 
of a serious brain infection and your doctor may suggest further testing and follow-up. 

 

You will have to take regular blood tests before and during your treatment with bortezomib, to 

check your blood cell counts regularly. 
 

If you have mantle cell lymphoma and are given the medicine rituximab with bortezomib you must 

tell your doctor: 

• if you think you have hepatitis infection now or have had it in the past. In a few cases, 
patients who have had hepatitis B might have a repeated attack of hepatitis, which can be 

fatal. If you have a history of hepatitis B infection you will be carefully checked by your 

doctor for signs of active hepatitis B. 

 
You must read the package leaflets of all medicinal products to be taken in combination with 

bortezomib for information related to these medicines before starting treatment with bortezomib. 

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

 

Children and adolescents 

This medicine must not be used in children and adolescents because it is not known how it will 
affect them. 

 

Other medicines and bortezomib  

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

medicines. 

In particular, tell your doctor if you are using medicines containing any of the following active 
substances: 

- ketoconazole, used to treat fungal infections 
- ritonavir, used to treat HIV infection 
- rifampicin, an antibiotic used to treat bacterial infections 
- carbamazepine, phenytoin or phenobarbital used to treat epilepsy 
- St. John’s Wort (Hypericum perforatum), used for depression or other conditions 
- oral antidiabetics 

 

Pregnancy and breast-feeding 

You must not use this medicine if you are pregnant, unless clearly necessary. 
 

Both men and women receiving bortezomib must use effective contraception during and for up to 3 

months after treatment. If, despite these measures, pregnancy occurs, tell your doctor immediately. 

 
You must not breast-feed while using bortezomib. Discuss with your doctor when it is safe to 

restart breast-feeding after finishing your treatment. 



98 

 

 

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

leaflet for thalidomide). 

 
Driving and using machines 

Bortezomib might cause tiredness, dizziness, fainting, or blurred vision. Do not drive or operate 

tools or machines if you experience such side effects; even if you do not, you must still be cautious. 

 
 

3. How to use Bortezomib Fresenius Kabi  

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

surface area). The usual starting dose of bortezomib is 1.3 mg/m2 body surface area twice a week. 

Your doctor may change the dose and total number of treatment cycles, depending on your 

response to the treatment on the occurrence of certain side effects and on your underlying 
conditions (e.g. liver problems). 

 

Progressive multiple myeloma 
When bortezomib is given alone, you will receive 4 doses of bortezomib intravenously or 

subcutaneously on days 1, 4, 8 and 11, followed by a 10-day ‘rest period’ without treatment. This 

21-day period (3 weeks) corresponds to one treatment cycle. You might receive up to 8 cycles (24 
weeks). 

 

You may also be given bortezomib together with the medicines pegylated liposomal doxorubicin or 

dexamethasone. 
 

When bortezomib is given together with pegylated liposomal doxorubicin, you will receive 

bortezomib intravenously or subcutaneously as a 21-day treatment cycle and pegylated liposomal 
doxorubicin 30 mg/m2 is given on day 4 of the bortezomib 21-day treatment cycle as an 

intravenous infusion after the bortezomib injection. 

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

When bortezomib is given together with dexamethasone, you will receive bortezomib intravenously 

or subcutaneously as a 21-day treatment cycle and dexamethasone 20 mg is given orally on days 1, 

2, 4, 5, 8, 9, 11, and 12, of the bortezomib, 21-day treatment cycle. 
You might receive up to 8 cycles (24 weeks). 

 

Previously untreated multiple myeloma 
If you have not been treated before for multiple myeloma, and you are not suitable for blood stem 

cell transplantation you will receive bortezomib together with two other medicines; melphalan and 

prednisone. 

In this case, the duration of a treatment cycle is 42 days (6 weeks). You will receive 9 cycles 
(54 weeks). 

• In cycles 1 to 4, bortezomib is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 
32. 

• In cycles 5 to 9, bortezomib is administered once weekly on days 1, 8, 22 and 29. 
Melphalan (9 mg/m2) and prednisone (60 mg/m2) are both given orally on days 1, 2, 3 and 4 of the 
first week of each cycle. 

 

If you have not been treated before for multiple myeloma, and you are suitable for blood stem cell 
transplantation you will receive bortezomib intravenously or subcutaneously together with the 

medicines dexamethasone, or dexamethasone and thalidomide, as induction treatment. 

 

When bortezomib is given together with dexamethasone, you will receive bortezomib intravenously 
or subcutaneously as a 21-day treatment cycle and dexamethasone 40 mg is given orally on days 1, 



99 

 

2, 3, 4, 8, 9, 10 and 11 of the bortezomib 21-day treatment cycle. 

You will receive 4 cycles (12 weeks). 
 

When bortezomib is given together with thalidomide and dexamethasone, the duration of a 

treatment cycle is 28 days (4 weeks). 
 

Dexamethasone 40 mg is given orally on days 1, 2, 3, 4, 8, 9, 10 and 11 of the bortezomib 28-day 

treatment cycle and thalidomide is given orally daily at 50 mg up to day 14 of the first cycle, and if 

tolerated the thalidomide dose is increased to 100 mg on days 15-28 and may be further increased 
to 200 mg daily from the second cycle onwards. 

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

 
Previously untreated mantle cell lymphoma 

If you have not been treated before for mantle cell lymphoma you will receive bortezomib 

intravenously or subcutaneously together with the medicines rituximab, cyclophosphamide, 

doxorubicin and prednisone. 
Bortezomib is given intravenously or subcutaneously on days 1, 4, 8 and 11, followed by a ‘rest 

period’ without treatment. The duration of a treatment cycle is 21 days (3 weeks). You might 

receive up to 8 cycles (24 weeks). 
The following medicinal products are given on day 1 of each bortezomib  21-day treatment cycle as 

intravenous infusions: 

Rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2 and doxorubicin at 50 mg/m2. 
Prednisone is given orally at 100 mg/m2 on days 1, 2, 3, 4 and 5 of the bortezomib treatment cycle. 

 

How bortezomib is given 

This medicine is for intravenous or subcutaneous use. Bortezomib will be administered by a health 
care professional experienced in the use of cytotoxic medicines. 

Bortezomib powder has to be dissolved before administration. This will be done by a healthcare 

professional. The resulting solution is then either injected into a vein or under the skin. Injection 
into a vein is rapid, taking 3 to 5 seconds. Injection under the skin is in either the thighs or the 

abdomen. 

 
If you are given too much bortezomib  

As this medicine is being given by your doctor or nurse, it is unlikely that you will be given too 

much. 

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

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some 

of these effects may be serious. 

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

- muscle cramping, muscle weakness 
- confusion, visual loss or disturbances, blindness, seizures, headaches 
- shortness of breath, swelling of your feet or changes in your heart beat, high blood pressure, 

tiredness, fainting 

- coughing and breathing difficulties or tightness in the chest. 
 

Treatment with bortezomib can very commonly cause a decrease in the numbers of red and white 

blood cells and platelets in your blood. Therefore, you will have to take regular blood tests before 

and during your treatment with bortezomib, to check your blood cell counts regularly. You may 
experience a reduction in the number of: 

- platelets, which may make you be more prone to bruising, or to bleeding without obvious 
injury 



100 

 

(e.g., bleeding from your bowels, stomach, mouth and gum or bleeding in the brain or  

bleeding from the liver) 
- red blood cells, which can cause anaemia, with symptoms such as tiredness and paleness 
- white blood cells may make you more prone to infections or flu-like symptoms. 

 
If you are given bortezomib for the treatment of multiple myeloma the side effects you may get are 

listed below: 

 

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

• Sensitivity, numbness, tingling or burning sensation of the skin, or pain in the hands or feet, 
due to nerve damage 

• Reduction in the number of red blood cells and or white blood cells (see above) 

• Fever 

• Feeling sick (nausea) or vomiting, loss of appetite 

• Constipation with or without bloating (can be severe) 

• Diarrhoea: if this happens, it is important that you drink more water than usual. Your doctor 
may give you another medicine to control diarrhoea 

• Tiredness (fatigue), feeling weak 

• Muscle pain, bone pain 
 
Common side effects (may affect up to 1 in 10 people) 

• Low blood pressure, sudden fall of blood pressure on standing which may lead to fainting 

• High blood pressure 

• Reduced functioning of your kidneys 

• Headache 

• General ill feeling, pain, vertigo, light-headedness, a feeling of weakness or loss of 
consciousness 

• Shivering 

• Infections, including pneumonia, respiratory infections, bronchitis, fungal infections, 
coughing with phlegm, flu like illness 

• Shingles (localised including around the eyes or spread across the body) 

• Chest pains or shortness of breath with exercise 

• Different types of rash 

• Itching of the skin, lumps on the skin or dry skin 

• Facial blushing or tiny broken capillaries 

• Redness of the skin 

• Dehydration 

• Heartburn, bloating, belching, wind, stomach pain, bleeding from your bowels or stomach 

• Alteration of liver functioning 

• A sore mouth or lip, dry mouth, mouth ulcers or throat pain 

• Weight loss, loss of taste 

• Muscle cramps, muscle spasms, muscle weakness, pain in your limbs 

• Blurred vision 

• Infection of the outermost layer of the eye and the inner surface of the eyelids 
(conjunctivitis) 

• Nose bleeds 

• Difficulty or problems in sleeping, sweating, anxiety, mood swings, depressed mood, 
restlessness or agitation, changes in your mental status, disorientation 

• Swelling of body, to include around eyes and other parts of the body 
 
Uncommon side effects (may affect up to 1 in 100 people) 

• Heart failure, heart attack, chest pain, chest discomfort, increased or reduced heart rate 

• Failing of your kidneys 

• Inflammation of a vein, blood clots in your veins and lungs 



101 

 

• Problems with blood clotting 

• Insufficient circulation 

• Inflammation of the lining around your heart or fluid around your heart 

• Infections including urinary tract infections, the flu, herpes virus infections, ear infection and 
cellulitis 

• Bloody stools, or bleeding from mucosal membranes, e.g., mouth, vagina 

• Cerebrovascular disorders 

• Paralysis, seizures, falling, movement disorders, abnormal or change in, or reduced sensation 
(feeling, hearing, tasting, smelling), attention disturbance, trembling, twitching 

• Arthritis, including inflammation of the joints in the fingers, toes, and the jaw 

• Disorders that affect your lungs, preventing your body from getting enough oxygen. Some of 
these include difficulty breathing, shortness of breath, shortness of breath without exercise, 

breathing that becomes shallow, difficult or stops, wheezing 

• Hiccups, speech disorders 

• Increased or decreased urine production (due to kidney damage), painful passing of urine or 
blood/proteins in the urine, fluid retention 

• Altered levels of consciousness, confusion, memory impairment or loss 

• Hypersensitivity 

• Hearing loss, deafness or ringing in the ears, ear discomfort 

• Hormone abnormality which may affect salt and water absorption 

• Overactive thyroid gland 

• Inability to produce enough insulin or resistance to normal levels of insulin 

• Irritated or inflamed eyes, excessively wet eyes, painful eyes, dry eyes, eye infections, lump 
in the eyelid (chalazion), red and swollen eyelids, discharge from the eyes, abnormal vision, 

bleeding of the eye 

• Swelling of your lymph glands 

• Joint or muscle stiffness, sense of heaviness, pain in your groin 

• Hair loss and abnormal hair texture 

• Allergic reactions 

• Redness or pain at the injection site 

• Mouth pain 

• Infections or inflammation of the mouth, mouth ulcers, oesophagus, stomach and intestines, 
sometimes associated with pain or bleeding, poor movement of the intestines (including 
blockage), abdominal or oesophageal discomfort, difficulty swallowing, vomiting of blood 

• Skin infections 

• Bacterial and viral infections 

• Tooth infection 

• Inflammation of the pancreas, obstruction of the bile duct 

• Genital pain, problem having an erection 

• Weight increase 

• Thirst 

• Hepatitis 

• Injection site or injection device related disorders 

• Skin reactions and disorders (which may be severe and life threatening), skin ulcers 

• Bruises, falls and injuries 

• Inflammation or haemorrhage of the blood vessels that can appear as small red or purple dots 
(usually on the legs) to large bruise-like patches under the skin or tissue 

• Benign cysts 

• A severe reversible brain condition which includes seizures, high blood pressure, headaches, 
tiredness, confusion, blindness or other vision problems. 

 

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

• Heart problems to include heart attack, angina 

• Flushing 



102 

 

• Discoloration of the veins 

• Inflammation of the spinal nerve 

• Problems with your ear, bleeding from your ear 

• Underactivity of your thyroid gland 

• Budd–Chiari syndrome (the clinical symptoms caused by blockage of the hepatic veins) 

• Changes in or abnormal bowel function 

• Bleeding in the brain 

• Yellow discolouration of eyes and skin (jaundice) 

• Serious allergic reaction (anaphylactic shock) signs of which may include difficulty 
breathing, chest pain or chest tightness, and/or feeling dizzy/faint, severe itching of the skin 

or raised lumps on the skin, swelling of the face, lips, tongue and /or throat, which may cause 
difficulty in swallowing, collapse 

• Breast disorders 

• Vaginal tears 

• Genital swelling 

• Inability to tolerate alcohol consumption 

• Wasting, or loss of body mass 

• Increased appetite 

• Fistula 

• Joint effusion 

• Cysts in the lining of joints (synovial cysts) 

• Fracture 

• Breakdown of muscle fibers leading to other complications 

• Swelling of the liver, bleeding from the liver 

• Cancer of the kidney 

• Psoriasis like skin condition 

• Cancer of the skin 

• Paleness of the skin 

• Increase of platelets or plasma cells (a type of white cell) in the blood 

• Blood clot in small blood vessels (thrombotic microangiopathy) 

• Abnormal reaction to blood transfusions 

• Partial or total loss of vision 

• Decreased sex drive 

• Drooling 

• Bulging eyes 

• Sensitivity to light 

• Rapid breathing 

• Rectal pain 

• Gallstones 

• Hernia 

• Injuries 

• Brittle or weak nails 

• Abnormal protein deposits in your vital organs 

• Coma 

• Intestinal ulcers 

• Multi-organ failure 

• Death 
 
If you are given bortezomib together with other medicines for the treatment of mantle cell 

lymphoma the side effects you may get are listed below: 

 

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

• Pneumonia 



103 

 

• Loss of appetite 

• Sensitivity, numbness, tingling or burning sensation of the skin, or pain in the hands or feet, 
due to nerve damage 

• Nausea and vomiting 

• Diarrhoea 

• Mouth ulcers 

• Constipation 

• Muscle pain, bone pain 

• Hair loss and abnormal hair texture 

• Tiredness, feeling weak 

• Fever 
 
Common side effects (may affect up to 1 in 10 people) 

• Shingles (localized including around the eyes or spread across the body) 

• Herpes virus infections 

• Bacterial and viral infections 

• Respiratory infections, bronchitis, coughing with phlegm, flu like illness 

• Fungal infections 

• Hypersensitivity (allergic reaction) 

• Inability to produce enough insulin or resistance to normal levels of insulin 

• Fluid retention 

• Difficulty or problems in sleeping 

• Loss of consciousness 

• Altered level of consciousness, confusion 

• Feeling dizzy 

• Increased heartbeat, high blood pressure, sweating, 

• Abnormal vision, blurred vision 

• Heart failure, heart attack, chest pain, chest discomfort, increased or reduced heart rate 

• High or low blood pressure 

• Sudden fall of blood pressure upon standing which may lead to fainting 

• Shortness of breath with exercise 

• Cough 

• Hiccups 

• Ringing in the ears, ear discomfort 

• Bleeding from your bowels or stomach 

• Heartburn 

• Stomach pain, bloating 

• Difficulty swallowing 

• Infection or inflammation of the stomach and intestine 

• Stomach pain 

• Sore mouth or lip, throat pain 

• Alteration of liver function 

• Itching of skin 

• Redness of skin 

• Rash 

• Muscle spasms 

• Infection of the urinary tract 

• Pain in limbs 

• Swelling of body, to include eyes and other parts of the body 

• Shivering 

• Redness and pain at injection site 

• General ill feeling 

• Weight loss 



104 

 

• Weight increase 
 

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

• Hepatitis 

• Severe allergic reaction (anaphylactic reaction) signs of which may include difficulty 
breathing, chest pain or chest tightness, and/or feeling dizzy/faint, severe itching of the skin 

or raised lumps on the skin, swelling of the face, lips, tongue and /or throat, which may cause 

difficulty in swallowing, collapse 

• Movement disorders, paralysis, twitching 

• Vertigo 

• Hearing loss, deafness 

• Disorders that affect your lungs, preventing your body from getting enough oxygen. Some of 
these include difficulty breathing, shortness of breath, shortness of breath without exercise, 

breathing that becomes shallow, difficult or stops, wheezing 

• Blood clots in your lungs 

• Yellow discoloration of the eyes and skin (jaundice) 

• Lump in the eyelid (chalazion), red and swollen eyelids 
 

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

• Blood clot in small blood vessels (thrombotic microangiopathy) 
 

Reporting of side effects 

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

listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 
 

 

5. How to store Bortezomib Fresenius Kabi  

 
Keep this medicine out of the sight and reach of children. 

 

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

This medicinal product does not require any special temperature storage condition. Keep the vial in 

the outer carton in order to protect from light. 
 

The chemical and physical in-use stability of the reconstituted solution has been demonstrated at 

concentrations of 1 mg/ml and 2.5 mg/ml for 96 hours at 25°C and 8 days at 2-8°C, when stored in 

the original vial and/or a syringe.  
 

From a microbiological point of view, the reconstituted solution should be used immediately after 

preparation. If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user. The total storage time for the reconstituted medicinal product should not 

exceed 96 hours (if stored at 25°C) and 8 days (if stored at 2-8 °C) prior to administration. 

Bortezomib is for single use only. Any unused product or waste material should be disposed of in 

accordance with local requirements. 
 

 

6. Contents of the pack and other information 

 

What Bortezomib Fresenius Kabi contains 

- The active substance is bortezomib.  
- The other ingredients are mannitol (E421). 

 Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection  

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

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


105 

 

 

Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection  
Each vial contains 3.5 mg of bortezomib (as a mannitol boronic ester). 

 

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

 

Subcutaneous reconstitution: 

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

What Bortezomib Fresenius Kabi looks like and contents of the pack 

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

 

Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection 

Each carton of Bortezomib Fresenius Kabi 2.5 mg powder for solution for injection contains a 
10 ml clear glass vial with grey rubber stopper and aluminium yellow flip-off over seal, containing 

2.5 mg bortezomib. 

 
Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection 

Each carton of Bortezomib Fresenius Kabi 3.5 mg powder for solution for injection contains a 

10 ml clear glass vial with grey rubber stopper and aluminium blue flip-off over seal, containing 
3.5 mg bortezomib. 

 

 

The vial is placed in a tray with a lid. Each pack contains 1 single-use vial. 
 

Marketing Authorisation Holder 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 

 
Manufacturer 

Fresenius Kabi Deutschland GmbH  

Pfingstweide 53  
61169 Friedberg,  

Germany  

 

orFresenius Kabi Oncology Plc, 
Lion Court, Farnham Road, 

Bordon, Hampshire, GU35 0NF, 

United Kingdom 
 

For any information about this medicine, please contact the Marketing Authorisation Holder. 

 
This leaflet was last revised in MM/YYYY 

 

Other sources of information 

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

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


106 

 

The following information is intended for healthcare professionals only: 

 
 

1. RECONSTITUTION FOR INTRAVENOUS INJECTION 

 
Note: Bortezomib is a cytotoxic agent. Therefore, caution must be used during handling and 

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

 

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

 

  
 

1.1 Preparation of the 2.5 mg vial: carefully add 2.5 ml of sterile, 9 mg/ml (0.9%) sodium 

chloride solution for injection to the vial containing the bortezomib by using a syringe of the 

appropriate size without removing the vial stopper. Dissolution of the lyophilised powder is 

completed in less than 2 minutes. 

 

Preparation of the 3.5 mg vial: carefully add 3.5 ml of sterile, sodium chloride 

9 mg/ml (0.9%) solution for injection to the vial containing the bortezomib powder by using 
a syringe of the appropriate size without removing the vial stopper. Dissolution of the 
lyophilised powder is completed in less than 2 minutes. 

 

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

 

1.2 Before administration, visually inspect the solution for particulate matter and discolouration. 
If any discolouration or particulate matter is observed, the solution must be discarded. Be 

sure that the correct dose is being given for the intravenous route of administration 

(1 mg/ml). 

 
1.3 The chemical and physical in-use stability of the reconstituted solution has been 

demonstrated at concentrations of 1 mg/ml and 2.5 mg/ml for 96 hours at 25°C and 8 days at 

2-8°C, when stored in the original vial and/or a syringe.  
 

From a microbiological point of view, the reconstituted solution should be used immediately 

after preparation. If not used immediately, in-use storage times and conditions prior to use 

are the responsibility of the user. The total storage time for the reconstituted medicinal 
product should not exceed 96 hours (if stored at 25°C) and 8 days (if stored at 2-8 °C) prior 

to administration. 

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

 

 
2. ADMINISTRATION 

 

- Once dissolved, withdraw the appropriate amount of the reconstituted solution according to 
calculated dose based upon the patient´s Body Surface Area. 

- Confirm the dose and concentration in the syringe prior to use (check that the syringe is 
marked as intravenous administration). 

- Inject the solution as a 3-5 second bolus intravenous injection through a peripheral or central 
intravenous catheter into a vein. 

- Flush the peripheral or intravenous catheter with sterile, sodium chloride 9 mg/ml (0.9%) 
solution. 

 



107 

 

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg IS FOR SUBCUTANEOUS OR 

INTRAVENOUS USE. Do not give by other routes. Intrathecal administration has resulted in 

death. 

 

 
3. DISPOSAL 

 

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

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

The following information is intended for healthcare professionals only: 

Only the 2.5 mg and 3.5 mg vial can be administered subcutaneously, as described below. 
 

 

1. RECONSTITUTION FOR SUBCUTANEOUS INJECTION 

 
Note: Bortezomib is a cytotoxic agent. Therefore, caution must be used during handling and 

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

 
ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF 

BORTEZOMIB SINCE NO PRESERVATIVE IS PRESENT. 

 
1.1 Preparation of the 2.5 mg vial: carefully add 1 ml of sterile, 9 mg/ml (0.9%) sodium 

chloride solution for injection to the vial containing the bortezomib by using a syringe of the 

appropriate size without removing the vial stopper. Dissolution of the lyophilised powder is 

completed in less than 2 minutes. 
 

Preparation of the 3.5 mg vial: carefully add 1.4 ml of sterile, sodium chloride 

9 mg/ml (0.9%) solution for injection to the vial containing the bortezomib powder by using 
a syringe of the appropriate size without removing the vial stopper. Dissolution of the 

lyophilised powder is completed in less than 2 minutes. 

 
The concentration of the resulting solution will be 2.5 mg/ml. The solution will be clear and 

colourless, with a final pH of 4 to 7. You do not need to check the pH of the solution. 

 

1.2 Before administration, visually inspect the solution for particulate matter and discolouration. 
If any discolouration or particulate matter is observed, the solution must be discarded. Be 

sure that the correct dose is being given for the subcutaneous route of administration 

(2.5 mg/ml). 
 

1.3 The chemical and physical in-use stability of the reconstituted solution has been 

demonstrated at concentrations of 1 mg/ml and 2.5 mg/ml for 96 hours at 25°C and 8 days at 

2-8°C, when stored in the original vial and/or a syringe.  
 

From a microbiological point of view, the reconstituted solution should be used immediately 

after preparation. If not used immediately, in-use storage times and conditions prior to use 
are the responsibility of the user. The total storage time for the reconstituted medicinal 

product should not exceed 96 hours (if stored at 25°C) and 8 days (if stored at 2-8 °C) prior 

to administration. 
 

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

 

 
 

 

 



108 

 

2. ADMINISTRATION 

 

• Once dissolved, withdraw the appropriate amount of the reconstituted solution according to 
calculated dose based upon the patient´s Body Surface Area. 

• Confirm the dose and concentration in the syringe prior to use. (check that the syringe is 
marked as subcutaneous administration). 

• Inject the solution subcutaneously, under a 45-90°angle. 

• The reconstituted solution is administered subcutaneously through the thighs (right or left) or 
abdomen (right or left). 

• Injection sites must be rotated for successive injections. 

• If local injection site reactions occur following bortezomib injection subcutaneously, either a 
less concentrated bortezomib solution (1 mg/ml instead of 2.5 mg/ml) may be administered 

subcutaneously or a switch to intravenous injection is recommended. 

 

Bortezomib Fresenius Kabi 2.5 mg and 3.5 mg IS FOR SUBCUTANEOUS OR 

INTRAVENOUS USE. Do not give by other routes. Intrathecal administration has resulted in 

death. 

 
 

3. DISPOSAL 

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

 

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

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET