Bortezomib Sun

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Bortezomib SUN 3.5 mg powder for solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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 SUN 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 SUN 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 SUN 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 SUN 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 SUN treatment must be initiated under supervision of a physician experienced in the 
treatment of cancer patients, however Bortezomib SUN may be administered by a healthcare 
professional experienced in use of chemotherapeutic agents. Bortezomib SUN must be reconstituted 
by a healthcare professional (see section 6.6). 



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Posology for treatment of progressive multiple myeloma (patients who have received at least one 
prior therapy) 
 
Monotherapy 
Bortezomib SUN 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 SUN 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 SUN therapy. At least 72 hours should elapse between consecutive doses of 
Bortezomib SUN. 
 
Dose adjustments during treatment and re-initiation of treatment for monotherapy 
Bortezomib SUN 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 SUN 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 SUN 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 SUN 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 SUN to 1.0 mg/m2 
or 

Change Bortezomib SUN 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 SUN treatment until 
symptoms of toxicity have resolved. When 
toxicity resolves re-initiate Bortezomib SUN 
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 SUN 

* 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 SUN 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 SUN. 



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Pegylated liposomal doxorubicin is administered at 30 mg/m2 on day 4 of the Bortezomib SUN 
treatment cycle as a 1 hour intravenous infusion administered after the Bortezomib SUN 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 SUN 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 SUN. 
Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the Bortezomib 
SUN 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 SUN 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 SUN 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 SUN is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. 
In Cycles 5-9, Bortezomib SUN is administered once weekly on days 1, 8, 22 and 29. At least 
72 hours should elapse between consecutive doses of Bortezomib SUN. 
Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each 
Bortezomib SUN treatment cycle. 
Nine treatment cycles of this combination therapy are administered. 
 
Table 2: Recommended posology for Bortezomib SUN in combination with melphalan and prednisone 

Twice weekly Bortezomib SUN (cycles 1-4) 
Week 1 2 3 4 5 6 
Bzmb 

(1.3 mg/m2) 
Day     --       --     Day 

1                         4 
Day    Day 

8       11 
Rest 

period 
Day    Day  
22       25 

Day    Day 
29      32 

Rest 
period 

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

Day    Day    Day    Day  
1        2        3        4 

 

--       -- Rest 
period 

--        -- --         -- Rest 
period 

Once weekly Bortezomib SUN (cycles 5-9) 
Week 1 2 3 4 5 6 
Bzmb 

(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    Day    Day    Day  
1        2        3        4 

 

-- Rest 
period 

--  Rest 
period 

Bzmb=Bortezomib SUN; M=melphalan, P=prednisone 
 



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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 SUN 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 SUN dosing 
day (other than day 1) 

Bortezomib SUN therapy should be withheld 

- If several Bortezomib SUN doses in a cycle 
are withheld (≥ 3 doses during twice 
weekly administration or ≥ 2 doses during 
weekly administration) 

Bortezomib SUN 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 SUN therapy should be withheld 
until symptoms of the toxicity have resolved to 
Grade 1 or baseline. Then, Bortezomib SUN 
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 SUN 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 SUN 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 SUN. 
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the Bortezomib 
SUN treatment cycle. 
Four treatment cycles of this combination therapy are administered. 
 
Combination therapy with dexamethasone and thalidomide 
Bortezomib SUN 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 SUN. 



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Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the Bortezomib 
SUN 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 SUN combination therapy for patients with previously untreated 
multiple myeloma eligible for haematopoietic stem cell transplantation 
 
Bzmb+ Dx Cycles 1 to 4 

Week 1 2 3 
Bzmb (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 - 

Bzmb+Dx+T Cycle 1 
Week 1 2 3 4 
Bzmb (1.3 mg/m2) Day 1, 4 Day 8, 11 Rest period  Rest period 
T 50 mg Daily Daily - - 
T 100 mga - - Daily Daily 
Dx 40 mg Day 1, 2, 3, 4 Day 8, 9, 10, 11 - - 

Cycles 2 to 4b 
Bzmb (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 - - 

Bzmb=Bortezomib SUN; 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 SUN dosage adjustments, dose modification guidelines described for monotherapy 
should be followed. 
In addition, when Bortezomib SUN 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 (BzmbR-CAP) 
Bortezomib SUN 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 
SUN cycles are recommended, although for patients with a response first documented at cycle 6, two 
additional Bortezomib SUN cycles may be given. At least 72 hours should elapse between 
consecutive doses of Bortezomib SUN. 
 
The following medicinal products are administered on day 1 of each Bortezomib SUN 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 SUN 
treatment cycle. 
 
Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma 
Prior to initiating a new cycle of therapy: 



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- 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 SUN 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). 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 SUN 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 SUN has been held, the 

toxicity does not resolve, as defined above, 
then Bortezomib SUN must be discontinued. 

- If toxicity resolves i.e. patient has an ANC 
≥ 750 cells/μl and a platelet count 
≥ 25,000 cells/μl, Bortezomib SUN 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 SUN dosing 
day (other than Day 1 of each cycle) 

Bortezomib SUN therapy should be withheld 

Grade ≥ 3 non-haematological toxicities 
considered to be related to Bortezomib SUN 

Bortezomib SUN therapy should be withheld 
until symptoms of the toxicity have resolved to 
Grade 2 or better. Then, Bortezomib SUN 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 SUN as outlined in Table 1. 

 
In addition, when Bortezomib SUN 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. 



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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, BzmbR-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 SUN 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 SUN 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 SUN 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 SUN 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 SUN is available for intravenous or subcutaneous administration. 
 
Bortezomib SUN should not be given by other routes. Intrathecal administration has resulted in death. 
 
Intravenous injection 
Bortezomib SUN 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 



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(0.9%) solution for injection. At least 72 hours should elapse between consecutive doses of 
Bortezomib SUN. 
 
Subcutaneous injection 
Bortezomib SUN 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 SUN subcutaneous injection, either a less 
concentrated Bortezomib SUN solution (bortezomib 3.5 mg 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 SUN 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 SUN 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 SUN 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 SUN. 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 SUN 
is for intravenous or subcutaneous use. Bortezomib SUN 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 (BzmbR-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.  
 



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



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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 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) 



12 

 

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). 
 
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. 
 



13 

 

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. 
 
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. 



14 

 

 
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 summary 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. 



15 

 

 
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 (inc 
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*, 



16 

 

System Organ 
Class 

Incidence Adverse reaction 

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)* 

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 



17 

 

System Organ 
Class 

Incidence Adverse reaction 

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 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 



18 

 

System Organ 
Class 

Incidence Adverse reaction 

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* 
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*, 



19 

 

System Organ 
Class 

Incidence Adverse reaction 

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. 
# Post-marketing 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 (BzmbR-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 (BzmbR-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 
BzmbR-CAP arm and with at least a possible or probable causal relationship to the components of the 
BzmbR-CAP arm, are listed in Table 8 below. Also included are adverse drug reactions identified in 
the BzmbR-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 BzmbR-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 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* 



21 

 

System Organ 
Class 

Incidence Adverse reaction 

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 Bzmb+M+P arm. The incidence 
of herpes zoster among patients in the Bzmb+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 BzmbR-CAP arm. The 
incidence of herpes zoster among patients in the BzmbR-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 (BzmbR-CAP). The overall incidence of hepatitis B infections was 
similar in patients treated with BzmbR-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) 

BzmbDx 
(N=239) 

TDx 
(N=126) 

BzmbTDx 
(N=130) 

Incidence of PN (%)     
All GradePN 3 15 12 45 
≥ Grade 2 PN 1 10 2 31 
≥ Grade 3 PN <1 5 0 5 

Discontinuation due to 
PN (%) 

<1 2 1 5 



22 

 

VDDx=vincristine, doxorubicin, dexamethasone; BzmbDx=bortezomib, dexamethasone; TDx=thalidomide, dexamethasone; 
BzmbTDx=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 (R-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 
 
 BzmbR-CAP 

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

Incidence of PN (%)   
All GradePN 30 29 
≥ Grade 2 PN 18 9 
≥ Grade 3 PN 8 4 

Discontinuation due to PN (%) 2 < 1 
BzmbR-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 BzmbR-CAP arm were in the range 65-74 years and ≥ 75 years of 
age, respectively. Although in patients aged ≥ 75 years, both BzmbR-CAP and R-CHOP were less 
tolerated, the serious adverse event rate in the BzmbR-CAP groups was 68%, compared to 42% in the 
R-CHOP group. 
 
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 



23 

 

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. 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. 
 

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


24 

 

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 Bzmb+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 Bzmb+M+P treatment group was observed 
(HR=0.695; p=0.00043) despite subsequent therapies including bortezomib-based regimens. Median 
survival for the Bzmb+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 Bzmb+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) 



25 

 

Efficacy endpoint Bzmb+M+P 
n=344 

M+P 
n=338 

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 
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 [BzmbDx, n=240] was compared to 
vincristine- doxorubicin-dexamethasone [VDDx, n=242]. Patients in the BzmbDx 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 BzmbDx groups respectively; the majority of patients underwent one single transplant 
procedure. Patient demographic and baseline disease characteristics 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 BzmbDx group. The median number of cycles received for both groups 



26 

 

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 BzmbDx VDDx OR; 95% CI; P valuea 
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; 
Bzmb=bortezomib; BzmbDx=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 BzmbDx 
group and 52/242 [21%] in VDDx group). 
Note: An OR > 1 indicates an advantage for Bzmb-containing induction therapy. 
 
In study MMY-3010 induction treatment with bortezomib combined with thalidomide and 
dexamethasone [BzmbTDx, n=130] was compared to thalidomide-dexamethasone [TDx, n=127]. 
Patients in the BzmbTDx group received six 4-week cycles, each consisting of bortezmib (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 BzmbTDx and TDx groups, respectively. Patient demographic and baseline disease 
characteristics were similar between the treatment groups. Patients in the BzmbTDx 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 BzmbTDx 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 BzmbTDx TDx OR; 95% CI; P valuea 
MMY-3010 N=130 (ITT 

population) 
N=127 (ITT 
population) 

 

*RR (Post-induction) 
CR+nCR 

49.2 (40.4, 58.1) 
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 



27 

 

CR+nCR+PR% (95% 
CI) 
*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; 
Bzmb=bortezomib; BzmbTDx=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 Bzmb-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 
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 

Bzmb 
n=333a 

Dex 
n=336a 

Bzmb 
n=132a 

Dex 
n=119a 

Bzmb 
n=200a 

Dex 
n=217a 

Bzmb 
n=202a 



28 

 

 Phase III Phase III Phase III Phase II 
 All patients 1 prior line of therapy 

> 1 prior line of 
therapy 

≥ 2 prior 
lines  

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 

(%) 
Bzmb 
n=315c 

Dex 
n=312c 

Bzmb 
n=128 

Dex 
n=110 

Bzmb 
n=187 

Dex 
n=202 

Bzmb 
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+M

R 
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 
Bzmb=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. 
 
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. 
 



29 

 

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 0.839 (0.564, 1.249) 
p-valued 0.38657 
Progression Free Survival, months 8.0 10.2 
(95% CI) (6.7, 9.8) (8.1, 10.8) 
Hazard ratio (95% CI)c 0.824 (0.574, 1.183) 
p-valued 0.295 
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. 
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; 



30 

 

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).  
 
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 
(BzmbR-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 BzmbR-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 



31 

 

comparable in both treatment arms. A median of 6 cycles was received by patients in both treatment 
arms with 14% of subjects in the BzmbR-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 BzmbR-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 BzmbR-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 BzmbR-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 BzmbR-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 BzmbR-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 BzmbR-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 BzmbR-CAP 
group compared with 18 months in the R-CHOP group. The duration of overall response was 
21.4 months longer in the BzmbR-CAP group (median 36.5 months versus 15.1 months in the 
R-CHOP group). With a median duration of follow-up of 40 months, median OS (56.3 months in the 
R-CHOP group, and not reached in the BzmbR-CAP group) favoured the BzmbR-CAP group, 
(estimated HR=0.80; p=0.173). There was a trend towards prolonged overall survival favouring the 
BzmbR-CAP group; the estimated 4-year survival rate was 53.9% in the R-CHOP group and 64.4% in 
the BzmbR-CAP group. 
 
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%. 
 



32 

 

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 
paediatric 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. 
 
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%. 
 



33 

 

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 
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 paediatric 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 paediatric patients was similar to that observed in adults. 
 



34 

 

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 (E421) 
 
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 
18 months. 
 
Reconstituted solution 
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. However, the chemical and physical in-use stability of the reconstituted 
solution has been demonstrated for 8 hours at 25°C stored in the original vial and/or a syringe. The 



35 

 

total storage time for the reconstituted medicinal product should not exceed 8 hours prior to 
administration. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
 
Keep the vial in the outer carton in order to protect from light. 
 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
10 ml Type 1 tubular colourless glass vial with a grey bromobutyl rubber stopper, sealed with a light 
green flip off aluminium seal containing 3.5 mg bortezomib. 
The vial is contained in a transparent blister pack consisting of 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 SUN. Use of gloves and other protective clothing to prevent skin contact is 
recommended. 
 
Aseptic technique must be strictly observed throughout the handling of Bortezomib SUN, since it 
contains no preservative. 
 
There have been fatal cases of inadvertent intrathecal administration of bortezomib. Bortezomib SUN 
is for intravenous or subcutaneous use. Bortezomib SUN should not be administered intrathecally. 
 
Instructions for reconstitution 
Bortezomib SUN must be reconstituted by a healthcare professional. 
 
Intravenous injection 
Each 10 ml vial of Bortezomib SUN 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 
Each 10 ml vial of Bortezomib SUN 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. 
 



36 

 

Disposal 
Bortezomib SUN 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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/16/1102/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorization: 22 July 2016 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



37 

 

 

 

 

 

 

 

 

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 

 



38 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer responsible for batch release 

Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132JH HOOFDDORP 
NETHERLANDS 

 

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  
 

The requirements for submission of periodic safety update reports 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 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.  

 

 



39 

 

• Additional risk minimisation measures 
 

In each Member State, the Marketing Authorisation Holder (MAH) shall agree the content and format 
of the educational material with the national competent authority. 

The MAH shall ensure that all healthcare professionals involved in the prescribing, dispensing, 
handling or administration of Bortezomib SUN are provided with educational materials. 

The educational material shall consist of the following: 

• SmPC 

• Reconstitution, dosing and administration booklet 

• Reconstitution poster 

• Dosing Slide Rule 

• Induction Transplant Regimens Graph 

The Reconstitution, dosing and administration booklet shall contain the following key elements: 

• Bortezomib SUN 3.5 mg can be administered both intravenously and subcutaneously  

• different reconstitution requirements for intravenous (IV) or subcutaneous (SC) use 

• dosing instructions and examples: how to calculate the body surface area of a patient and the 
volume of reconstituted Bortezomib SUN (both IV and SC use) required for different body 
surface areas (cross reference to Dosing Slide Rule) 

• advice on method of administration for both IV and SC use, including the need to rotate 
injection sites for SC use 

• storage precautions for reconstituted solution 

• potential risks of administration errors including overdosing, underdosing and that 
inadvertent intrathecal administration has resulted in death 

• to report any adverse event, or medication error experienced with the administration of 
Bortezomib SUN 3.5 mg. 

The Reconstitution poster shall contain the following key elements: 

• different reconstitution requirements for Bortezomib SUN 3.5 mg IV or SC use 

• need to handling the medicinal product in sterile setting 

• storage precautions for reconstituted solution 

• advice on how to reduce the risk of mix-up of IV and SC reconstituted syringes 

• that Bortezomib SUN is to be given only by IV or SC injections; no other route of 
administration is  allowed 

• to report any adverse event, or medication error experienced with the administration of 
Bortezomib SUN 3.5 mg. 

Dosing Slide Rule shall contain the following key elements: 

• a dose-calculation tool that enables prescribers to input a patient’s height and weight in order 
to calculate the body surface area (BSA) and thereby to determine the appropriate 



40 

 

Bortezomib SUN dose. 

• different reconstitution requirements for intravenous (IV) or subcutaneous (SC) use 

• dosing instructions and examples: how to calculate the body surface area of a patient and the 
volume of reconstituted Bortezomib SUN (both IV and SC use) required for different body 
surface areas. 

Induction Transplant Regimens Graph shall contain the following key elements: 

• instructions for prescribing and administration including the cycles’ length and number of 
cycles, to minimise the risk of medication and dispensing errors potentially induced by the 
existence of the two different bortezomib combination regimens in the Transplant Induction 
Setting (Bortezomib SUN plus dexamethasone, and Bortezomib SUN plus dexamethasone 
and thalidomide). 

• to remind that patients receiving Bortezomib SUN in combination with thalidomide should 
adhere to the pregnancy prevention programme of thalidomide, with reference to the SmPC 
of thalidomide for additional information. 

 

 



41 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



42 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



43 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Bortezomib SUN 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 
 
Excipient: 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. 
Subcutaneous or intravenous use only. 
For single use only. 
May be fatal if given by other routes. 
Subcutaneous use: Add 1.4 ml 0.9% sodium chloride to make 2.5 mg/ml final concentration. 
Intravenous use: Add 3.5 ml 0.9% sodium chloride 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. Special handling instructions 
 
 
8. EXPIRY DATE 
 
EXP 



44 

 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
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 

 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sun Pharmaceutical Industries Europe B.V.  
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/16/1102/001 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
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. 
 
 



45 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 



46 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Bortezomib SUN 3.5 mg powder for solution for injection 
bortezomib 
Subcutaneous or intravenous use only. 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
3.5 mg 
 
 
6. OTHER 
 
For single use only. 
May be fatal if given by other routes. 
 
Subcutaneous use: Add 1.4 ml 0.9% sodium chloride to make 2.5 mg/ml final concentration. 
Intravenous use: Add 3.5 ml 0.9% sodium chloride to make 1 mg/ml final concentration. 
 
Do not store above 25°C. Keep the vial in the outer carton in order to protect from light. 
 



47 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET  



48 

 

Package leaflet: Information for the user 
 

Bortezomib SUN 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 SUN is and what it is used for 
2. What you need to know before you are given Bortezomib SUN 
3. How to use Bortezomib SUN 
4. Possible side effects 
5. How to store Bortezomib SUN 
6. Contents of the pack and other information 
 
 
1. What Bortezomib SUN is and what it is used for 
 
Bortezomib SUN 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 SUN 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). 

- 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 are given Bortezomib SUN 
 
You should NOT be given Bortezomib SUN 
- 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. 



49 

 

 
Warnings and precautions 
You should tell your doctor if you have any of the following: 
- low numbers of red or white blood cells 
- bleeding problems and/or low number of platelets in your blood 
- diarrhoea, constipation, nausea or vomiting 
- 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 SUN, to 
check your blood cell counts regularly. 
 
If you have mantle cell lymphoma and are given the medicine rituximab with Bortezomib SUN you 
should tell your doctor: 
- if you think you have hepatitis infection now or have had it in the past. In a few cases, patients 

who have had hepatitis B might have a repeated attack of hepatitis, which can be fatal. If you 
have a history of hepatitis B infection you will be carefully checked by your doctor for signs of 
active hepatitis B. 

 
You must read the package leaflets of all medicinal products to be taken in combination with 
Bortezomib SUN for information related to these medicines before starting treatment with 
Bortezomib SUN. 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 
Bortezomib SUN should not be used in children and adolescents because it is not known how the 
medicine will affect them. 
 
Other medicines and Bortezomib SUN 
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 should not use Bortezomib SUN if you are pregnant, unless clearly necessary. 
 
 



50 

 

You should not breast-feed while using Bortezomib SUN. Discuss with your doctor when it is safe to 
restart breast-feeding after finishing your treatment. 
 
Thalidomide causes birth defects and foetal death. When Bortezomib SUN is given in combination 
with thalidomide you must follow the pregnancy prevention programme for thalidomide (see package 
leaflet for thalidomide). 
 
Contraception 
Both men and women receiving Bortezomib SUN must use effective contraception during and for up 
to 3 months after treatment. If, despite these measures, pregnancy occurs, tell your doctor 
immediately. 
 
Driving and using machines 
Bortezomib SUN might cause tiredness, dizziness, fainting, or blurred vision. Do not drive or operate 
tools or machines if you experience such side effects; even if you do not, you should still be cautious. 
 
 
3. How to use Bortezomib SUN 
 
Your doctor will work out your dose of Bortezomib SUN according to your height and weight (body 
surface area). The usual starting dose of Bortezomib SUN 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 SUN is given alone, you will receive 4 doses of Bortezomib SUN 

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 SUN together with the medicines pegylated liposomal 
doxorubicin or dexamethasone: 
- When Bortezomib SUN is given together with pegylated liposomal doxorubicin, you will 

receive Bortezomib SUN intravenously or subcutaneously as a 21-day treatment cycle. 
Pegylated liposomal doxorubicin 30 mg/m2 is given on day 4 of the Bortezomib SUN 21-day 
treatment cycle as an intravenous infusion after the Bortezomib SUN injection. 
You might receive up to 8 cycles (24 weeks). 

- When Bortezomib SUN is given together with dexamethasone, you will receive Bortezomib 
SUN intravenously or subcutaneously as a 21-day treatment cycle. Dexamethasone 20 mg is 
given orally on days 1, 2, 4, 5, 8, 9, 11, and 12, of the Bortezomib SUN 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 SUN 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 SUN is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 

and 32. 
- In cycles 5 to 9, Bortezomib SUN is administered once weekly on days 1, 8, 22 and 29. 



51 

 

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 SUN intravenously or subcutaneously together with the 
medicines dexamethasone, or dexamethasone and thalidomide, as induction treatment: 
- When Bortezomib SUN is given together with dexamethasone, you will receive Bortezomib 

SUN intravenously or subcutaneously as a 21-day treatment cycle. Dexamethasone 40 mg is 
given orally on days 1, 2, 3, 4, 8, 9, 10 and 11 of the Bortezomib SUN 21-day treatment cycle. 
You will receive 4 cycles (12 weeks). 

- When Bortezomib SUN 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 
SUN 28-day treatment cycle. 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 SUN 
intravenously or subcutaneously together with the medicines rituximab, cyclophosphamide, 
doxorubicin and prednisone.  
Bortezomib SUN 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 SUN 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 SUN treatment 
cycle. 
 
How Bortezomib SUN is given 
This medicine is for intravenous or subcutaneous use. Bortezomib SUN will be administered by a 
health care professional experienced in the use of cytotoxic medicines. 
Bortezomib SUN 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 SUN 
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. 
 
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. 



52 

 

 
Treatment with Bortezomib SUN 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 SUN, 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. 
 
Multiple myeloma 
If you are given Bortezomib SUN 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 



53 

 

- 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 

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 



54 

 

- 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 
- 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. 
 



55 

 

Mantle cell lymphoma 
If you are given Bortezomib SUN 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 
- 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 intestines 
- 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 



56 

 

- swelling of body, to include eyes and other parts of the body 
- shivering 
- redness and pain at injection site 
- general ill feeling 
- weight loss 
- weight increase. 
 
Uncommon side effects (may affect up to 1 in 100 people) 
- hepatitis 
- severe allergic reaction (anaphylactic reaction) signs of which may include difficulty breathing, 

chest pain or chest tightness, and/or feeling dizzy/faint, severe itching of the skin or raised 
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 SUN 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date stated on the vial and the carton after EXP. 
 
Do not store above 25°C. Keep the vial in the outer carton in order to protect from light. 
 
From a microbiological point of view, the reconstituted solution should be used immediately after 
preparation. If the reconstituted solution is not used immediately, in-use storage times and conditions 
prior to use are the responsibility of the user. However, the reconstituted solution is stable for 8 hours 
at 25°C stored in the original vial and/or a syringe, with a total storage time for the reconstituted 
medicine not exceeding 8 hours prior to administration. 
 
Bortezomib SUN 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 
 

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


57 

 

What Bortezomib SUN contains 
- The active substance is bortezomib. Each vial contains 3.5 mg of bortezomib (as a mannitol 

boronic ester). 
- The other ingredient is mannitol (E421). 
 
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 SUN looks like and contents of the pack 
Bortezomib SUN 3.5 mg powder for solution for injection is a white to off-white powder or cake. 
Each carton of Bortezomib SUN 3.5 mg powder for solution for injection contains a clear glass 10 ml 
vial closed with a light green aluminium cap, in a transparent blister pack. 
 
Marketing Authorisation Holder and Manufacturer 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien/България/Česká republika/ 
Danmark/Eesti/Ελλάδα/Hrvatska/Ireland/Ísland/Κύπρος/ 
Latvija/Lietuva/Luxembourg/Luxemburg/Magyarország/ 
Malta/Nederland/Norge/Österreich/Portugal/ 
Slovenija/Slovenská republika/Suomi/Finland/Sverige 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
Nederland/Pays-Bas/Niederlande/Нидерландия/Nizozemsko/ 
Nederlandene/Holland/Ολλανδία/Nizozemska/The Netherlands/Holland/Ολλανδία/ 
Nīderlande/Nyderlandai/Pays-Bas/Niederlande/Hollandia/ 
L-Olanda/Nederland/Nederland/Niederlande/Países Baixos/ 
Nizozemska/Holandsko/Alankomaat/Nederländerna/Nederländerna 
Tel./тел./tlf./τηλ./Sími/τηλ./Tlf./Puh./ 
 +31 (0)23 568 5501 
 
Deutschland 
Sun Pharmaceuticals Germany GmbH 
Hemmelrather Weg 201 
51377 Leverkusen 
Deutschland 
tel. +49 (0) 214 403 99 192 
 
España 
Sun Pharma Laboratorios, S.L. 
Rambla de Catalunya 53-55 
08007 Barcelona 
España 
tel. +34 93 342 78 90 



58 

 

 
France 
Ranbaxy Pharmacie Generiques 
11-15, Quai de Dion Bouton 
92800 Puteaux 
France 
tel. +33 1 41 44 44 50 
 
Italia 
Ranbaxy Italia S.p.A. 
Viale Giulio Richard, 1 
20143 Milano 
Italia 
tel. +39 02 33 49 07 93 
 
Polska 
Ranbaxy (Poland) Sp. Z o. o. 
ul. Kubickiego 11  
02-954 Warszawa  
Polska 
Tel. +48 22 642 07 75 
 
România 
Terapia S.A. 
Str. Fabricii nr 124 
Cluj-Napoca, Judeţul Cluj 
România 
Tel. +40 (264) 501 500 
 
United Kingdom 
Ranbaxy UK Ltd  
a Sun Pharma Company 
Millington Road 11 
Hyde Park, Hayes 3 
5th Floor 
Hayes 
UB3 4AZ HAYES 
United Kingdom 
tel. +44 (0) 208 848 8688 
 
This leaflet was last revised in  
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 

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


59 

 

The following information is intended for healthcare professionals only: 
 
 
1. RECONSTITUTION FOR INTRAVENOUS INJECTION 
 
Note: Bortezomib SUN is a cytotoxic agent. Therefore, caution should be used during handling and 
preparation. Use of gloves and other protective clothing to prevent skin contact is recommended. 
 
ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF 
BORTEZOMIB SUN SINCE NO PRESERVATIVE IS PRESENT. 
 
1.1 Preparation of the 3.5 mg vial: carefully add 3.5 ml of sterile, 9 mg/ml (0.9%) sodium 

chloride solution for injection to the vial containing the Bortezomib SUN 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 should be discarded. Be sure 
that the correct dose is being given for the intravenous route of administration (1 mg/ml). 

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

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

 
It is not necessary to protect the reconstituted medicinal product from light. 
 
 
2. ADMINISTRATION 
 
- Once dissolved, 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, 9 mg/ml (0.9%) sodium chloride 

solution. 
 
Bortezomib SUN 3.5 mg powder for solution for injection IS FOR SUBCUTANEOUS OR 
INTRAVENOUS USE. Do not give by other routes. Intrathecal administration has resulted in 
death. 
 
 
3. DISPOSAL 
 
A vial is for single use only and the remaining solution must be discarded. 
Any unused product or waste material should be disposed of in accordance with local requirements. 



60 

 

The following information is intended for healthcare professionals only: 
 
Only the 3.5 mg vial can be administered subcutaneously, as described below. 
 
 
1. RECONSTITUTION FOR SUBCUTANEOUS INJECTION 
 
Note: Bortezomib SUN is a cytotoxic agent. Therefore, caution should be used during handling and 
preparation. Use of gloves and other protective clothing to prevent skin contact is recommended. 
 
ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF 
BORTEZOMIB SUN SINCE NO PRESERVATIVE IS PRESENT. 
 
1.1 Preparation of the 3.5 mg vial: carefully add 1.4 ml of sterile, 9 mg/ml (0.9%) sodium 

chloride solution for injection to the vial containing the Bortezomib SUN 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 should be discarded. Be sure 
that the correct dose is being given for the subcutaneous route of administration (2.5 mg/ml). 

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

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

 
It is not necessary to protect the reconstituted medicinal product from light. 
 
 
2. ADMINISTRATION 
 
- Once dissolved, withdraw the appropriate amount of the reconstituted solution according to 

calculated dose based upon the patient´s Body Surface Area. 
- Confirm the dose and concentration in the syringe prior to use. (check that the syringe is 

marked as subcutaneous administration). 
- Inject the solution subcutaneously, under a 45-90°angle. 
- The reconstituted solution is administered subcutaneously through the thighs (right or left) or 

abdomen (right or left). 
- Injection sites should be rotated for successive injections. 
- If local injection site reactions occur following Bortezomib SUN injection subcutaneously, 

either a less concentrated Bortezomib SUN solution (1 mg/ml instead of 2.5 mg/ml) may be 
administered subcutaneously or a switch to intravenous injection is recommended. 

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



61 

 

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. 



62 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 



63 

 

Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSUR(s) for bortezomib, the scientific 
conclusions of CHMP are as follows: 
 
Following a review of post-marketing cases and literature reports for the period covered by this 
PSUR, 158 cases of “Lid, lash and lacrimal infections, irritations and inflammations” were retrieved 
in patients who received bortezomib. Of those, 121 cases reported chalazion, blepharitis, 
meibomianitis, and/or Meibomian gland dysfunction. A biological plausibility supports the 
association between bortezomib and chalazion/blepharitis; theoretically, bortezomib-related 
myelosuppression may facilitate viral infections such as herpes zoster thereby promoting chalazia. 
Based on this review, chalazion/blepharitis is considered associated with the use of bortezomib. 
 
In addition, following a search of the worldwide medical and scientific literature carried out for the 
period covered by this PSUSA and a number of papers reporting safety information, 35 cases of 
Thrombotic Microangiopathy (TMA) were retrieved. Overall, the literature results are suggestive of a 
possible causal association between bortezomib (and other proteasome inhibitors) and TMA. 
 
Based on the data presented, the PRAC was of the view that the product information should be varied 
to update Section 4.8 the SmPC and relevant section of the package leaflet to add the following: 
chalazion, blepharitis and Thrombotic Microangiopathy. 
 
The CHMP agrees with the scientific conclusions made by the PRAC. 
 
 
Grounds for the variation to the terms of the marketing authorisation(s) 
 
On the basis of the scientific conclusions for bortezomib the CHMP is of the opinion that the benefit-
risk balance of the medicinal product(s) containing bortezomib is unchanged subject to the proposed 
changes to the product information. 
 
The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 
 
 


	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