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BORTEZOMIB KOANAA 3.5 MG POWDER FOR SOLUTION FOR INJECTION

Active substance(s): BORTEZOMIB / BORTEZOMIB

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Bortezomib Koanaa 3.5 mg powder for solution for injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 3.5mg bortezomib (as a mannitol boronic ester).
After reconstitution with 1.4 ml, 1 ml of solution for subcutaneous injection contains
2.5 mg bortezomib.
After reconstitution with 3.5 ml, 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 cake or powder.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Bortezomib as monotherapy or in combination with pegylated liposomal doxorubicin
or dexamethasone is indicated for the treatment of adult patients with progressive
multiple myeloma who have received at least 1 prior therapy and who have already
undergone or are unsuitable for haematopoietic stem cell transplantation.
Bortezomib in combination with melphalan and prednisone is indicated for the
treatment of adult patients with previously untreated multiple myeloma who are not
eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.

Bortezomib in combination with dexamethasone, or with dexamethasone and
thalidomide, is indicated for the induction treatment of adult patients with previously
untreated multiple myeloma who are eligible for high-dose chemotherapy with
haematopoietic stem cell transplantation.
Bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and
prednisone is indicated for the treatment of adult patients with previously untreated
mantle cell lymphoma who are unsuitable for haematopoietic stem cell
transplantation.

4.2

Posology and method of administration
Treatment must be initiated and administered under the supervision of a physician
qualified and experienced in the use of chemotherapeutic agents. Bortezomib must be
reconstituted by a healthcare professional.
Posology for treatment of progressive multiple myeloma (patients who have received
at least one prior therapy)
Monotherapy
Bortezomib 3.5 mg powder for solution for injection is administered via intravenous
or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area
twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This
3-week period is considered a treatment cycle. It is recommended that patients
receive 2 cycles of bortezomib following a confirmation of a complete response. It is
also recommended that responding patients who do not achieve a complete remission
receive a total of 8 cycles of bortezomib therapy. At least 72 hours should elapse
between consecutive doses of bortezomib.
Dose adjustments during treatment and re-initiation of treatment for monotherapy
Bortezomib treatment must be withheld at the onset of any Grade 3 nonhaematological or any Grade 4 haematological toxicities, excluding neuropathy as
discussed below (see also section 4.4). Once the symptoms of the toxicity have
resolved, bortezomib treatment may be re-initiated at a 25% reduced dose (1.3 mg/m2
reduced to 1.0 mg/m2; 1.0 mg/m2 reduced to 0.7 mg/m2). If the toxicity is not resolved
or if it recurs at the lowest dose, discontinuation of Bortezomib must be considered
unless the benefit of treatment clearly outweighs the risk.
Neuropathic pain and/or peripheral neuropathy
Patients who experience bortezomib-related neuropathic pain and/or peripheral
neuropathy are to be managed as presented in Table 1 (see section 4.4). Patients with
pre-existing severe neuropathy may be treated with bortezomib only after careful
risk/benefit assessment.
Table 1: Recommended* posology modifications for bortezomib-related neuropathy

Severity of neuropathy
Grade 1 (asymptomatic; loss of deep tendon
reflexes or paresthesia) with no pain or loss of

Posology modification
None

function
Grade 1 with pain or Grade 2 (moderate
symptoms; limiting instrumental Activities of
Daily Living (ADL)**)
Grade 2 with pain or Grade 3 (severe symptoms;
limiting self-care ADL***)

Reduce bortezomib to 1.0 mg/m2
or Change bortezomib treatment schedule
to 1.3 mg/m2 once per week
Withhold bortezomib treatment until
symptoms of toxicity have resolved.
When toxicity resolves re-initiate
bortezomib treatment and reduce dose to
0.7 mg/m2 once per week
Discontinue bortezomib

Grade 4 (life-threatening consequences; urgent
intervention indicated) and/or severe autonomic
neuropathy
*
Based on posology modifications in Phase II and III multiple myeloma studies and
post- marketing experience. Grading based on NCI Common Toxicity Criteria
CTCAE v 4.0.
**

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

Self care ADL: refers to bathing, dressing and undressing, feeding self, using the
toilet, taking medicinal products, and not bedridden.
Combination therapy with pegylated liposomal doxorubicin
Bortezomib 3.5 mg powder for solution for injection is administered via intravenous
or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area
twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This
3-week period is considered a treatment cycle. At least 72 hours should elapse
between consecutive doses of bortezomib.
Pegylated liposomal doxorubicin is administered at 30 mg/m² on day 4 of the
bortezomib treatment cycle as a 1 hour intravenous infusion administered after the
bortezomib injection.
Up to 8 cycles of this combination therapy can be administered as long as patients
have not progressed and tolerate treatment. Patients achieving a complete response
can continue treatment for at least 2 cycles after the first evidence of complete
response, even if this requires treatment for more than 8 cycles. Patients whose levels
of paraprotein continue to decrease after 8 cycles can also continue for as long as
treatment is tolerated and they continue to respond.
For additional information concerning pegylated liposomal doxorubicin, see the
corresponding Summary of Product Characteristics.
Combination with dexamethasone
Bortezomib 3.5 mg powder for solution for injection is administered via intravenous
or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area
twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This
3-week period is considered a treatment cycle. At least 72 hours should elapse
between consecutive doses of bortezomib.
Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of
the bortezomib treatment cycle.

Patients achieving a response or a stable disease after 4 cycles of this combination
therapy can continue to receive the same combination for a maximum of 4 additional
cycles.
For additional information concerning dexamethasone, see the corresponding
Summary of Product Characteristics.

Dose adjustments for combination therapy for patients with progressive multiple
myeloma
For bortezomib dosage adjustments for combination therapy follow dose modification
guidelines described under monotherapy above.
Posology for previously untreated multiple myeloma patients not eligible for
haematopoietic stem cell transplantation
Combination therapy with melphalan and prednisone
Bortezomib 3.5 mg powder for solution for injection is administered via intravenous
or subcutaneous injection in combination with oral melphalan and oral prednisone as
shown in Table 2. A 6-week period is considered a treatment cycle. In Cycles 1-4,
Bortezomib is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In
Cycles 5-9, bortezomib is administered once weekly on days 1, 8, 22 and 29. At least
72 hours should elapse between consecutive doses of bortezomib.
Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the
first week of each bortezomib treatment cycle.
Nine treatment cycles of this combination therapy are administered.
Table 2: Recommended posology for Bortezomib in combination with melphalan
and prednisone
Twice weekly Bortezomib (cycles 1-4)
Week
1
2
3
Vc
Day
Day Day Day rest
--(1.3
1
4
8
11
period
2
mg/m )
M (9
Day Day Day Day
rest
mg/m2)
--P (60
1
2
3
4
period
mg/m2)
Once weekly Bortezomib (cycles 5-9)
Week
1
2
3
Vc
Day
rest
---Day 8
(1.3
1
period
2
mg/m )
M (9
Day Day Day Day
rest
mg/m2)
-P (60
1
2
3
4
period
mg/m2)
Vc= Bortezomib; M=melphalan, P=prednisone

4

5

6

Day Day Day Day rest
22
25
29
32
period

--

--

4
Day 22

--

--

--

5
Day 29

rest
period

6
rest
period
rest
period

Dose adjustments during treatment and re-initiation of treatment for combination
therapy with melphalan and prednisone
Prior to initiating a new cycle of therapy:


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



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

Table 3: Posology modifications during subsequent cycles of bortezomib therapy in
combination with melphalan and Prednisone
Toxicity
Haematological toxicity during a cycle
• If prolonged Grade 4 neutropenia or
thrombocytopenia, or thrombocytopenia
with bleeding is observed in the previous
cycle
• If platelet counts ≤ 30 x 109/l or ANC ≤
0.75 x 109/l on a Bortezomib dosing day
(other than day 1)
• If several bortezomib doses in a cycle
are withheld (≥ 3 doses during twice
weekly administration or ≥ 2 doses
during weekly administration)
Grade ≥ 3 non-haematological toxicities

Posology modification or delay
Consider reduction of the melphalan dose by
25% in the next cycle.

Bortezomib therapy should be with-held

Bortezomib dose should be reduced by 1
dose level (from 1.3 mg/m2 to 1 mg/m2, or
from 1 mg/m2 to 0.7 mg/m2)
Bortezomib therapy should be withheld until
symptoms of the toxicity have resolved to
Grade 1 or baseline. Then, bortezomib may
be reinitiated with one dose level
reduction (from 1.3 mg/m2 to 1 mg/m2, or
from 1 mg/m2 to 0.7 mg/m2). For bortezomib
-related neuropathic pain and/or peripheral
neuropathy, hold and/or modify bortezomib
as outlined in Table 1.

For additional information concerning melphalan and prednisone, see the
corresponding Summary of Product Characteristics.
Posology for previously untreated multiple myeloma patients eligible for
haematopoietic stem cell transplantation (induction therapy)
Combination therapy with dexamethasone
Bortezomib 3.5 mg powder for solution for injection is administered via intravenous
or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area
twice weekly for two weeks on days 1, 4, 8, and 11 in a 21- day treatment cycle. This
3-week period is considered a treatment cycle. At least 72 hours should elapse
between consecutive doses of bortezomib.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of
the bortezomib treatment cycle.
Four treatment cycles of this combination therapy are administered.

Combination therapy with dexamethasone and thalidomide
Bortezomib 3.5 mg powder for solution for injection is administered via intravenous
or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area
twice weekly for two weeks on days 1, 4, 8, and 11 in a 28- day treatment cycle. This
4-week period is considered a treatment cycle. At least 72 hours should elapse
between consecutive doses of bortezomib.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of
the bortezomib treatment cycle.
Thalidomide is administered orally at 50 mg daily on days 1-14 and if tolerated the
dose is increased to 100 mg on days 15-28, and thereafter may be further increased to
200 mg daily from cycle 2 (see Table 4).
Four treatment cycles of this combination are administered. It is recommended that
patients with at least partial response receive 2 additional cycles.
Table 4: Posology for bortezomib combination therapy for patients with previously
untreated multiple myeloma eligible for haematopoietic stem cell transplantation
Vc+Dx

Cycles 1 to 4
Week
1
2
Vc
Day 1, 4
Day 8, 11
2
(1.3 mg/m )
Dx 40 mg
Day 1, 2, 3, 4
Day 8, 9, 10, 11
Vc+Dx+T Cycle 1
Week
1
2
Vc
Day 1, 4
Day 8, 11
(1.3 mg/m2)
T 50 mg
Daily
Daily
T 100 mga
Dx 40 mg
Day 1,2,3,4
Day8,9,10,11
Cycles 2 to 4b
Day 1, 4
Day 8, 11
Vc
2
(1.3 mg/m )
T 200 mga
Daily
Daily
Dx 40 mg
Day 1, 2, 3, 4
Day 8, 9, 10, 11
Vc= Bortezomib; Dx=dexamethasone; T=thalidomide

3
Rest Period
-3
Rest
Period
Daily
-

4
Rest
Period
Daily
-

Rest
Period
Daily
-

Rest
Period
Daily
-

a

Thalidomide dose is increased to 100 mg from week 3 of Cycle 1 only if 50 mg is
tolerated and to 200 mg from cycle 2 onwards if 100 mg is tolerated.

b

Up to 6 cycles may be given to patients who achieve at least a partial response after
4 cycles.
Dosage adjustments for transplant eligible patients
For bortezomib dosage adjustments, dose modification guidelines described for

monotherapy should be followed.
In addition, when bortezomib is given in combination with other chemotherapeutic
medicinal products, appropriate dose reductions for these products should be
considered in the event of toxicities according to the recommendations in the
Summary of Product Characteristics.

Posology for patients with previously untreated mantle cell lymphoma (MCL)
Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone
(VcR-CAP)
Bortezomib 3.5 mg powder for solution for injection is administered via intravenous
or subcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area
twice weekly for two weeks on days 1, 4, 8, and 11, followed by a 10-day rest period
on days 12-21. This 3-week period is considered a treatment cycle. Six bortezomib
cycles are recommended, although for patients with a response first documented at
cycle 6, two additional bortezomib cycles may be given. At least 72 hours should
elapse between consecutive doses of bortezomib.
The following medicinal products are administered on day 1 of each bortezomib 3
week treatment cycle as intravenous infusions: rituximab at 375 mg/m2,
cyclophosphamide at 750 mg/m2 and doxorubicin at 50 mg/m2.
Prednisone is administered orally at 100 mg/m2 on days 1, 2, 3, 4 and 5 of each
bortezomib treatment cycle.
Dose adjustments during treatment for patients with previously untreated mantle cell
lymphoma
Prior to initiating a new cycle of therapy:


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



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



Haemoglobin ≥ 8 g/dL



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

Bortezomib treatment must be withheld at the onset of any ≥ Grade 3 bortezomib related non-haematological toxicities (excluding neuropathy) or ≥ Grade 3
haematological toxicities (see also section 4.4). For dose adjustments, see Table 5
below.
Granulocyte colony stimulating factors may be administered for haematologic
toxicity according to local standard practice. Prophylactic use of granulocyte colony
stimulating factors should be considered in case of repeated delays in cycle
administration. Platelet transfusion for the treatment of thrombocytopenia should be
considered when clinically appropriate.
Table 5: Dose adjustments during treatment for patients with previously untreated
mantle cell lymphoma
Toxicity
Haematological toxicity
• ≥ Grade 3 neutropenia with fever, Grade 4
neutropenia lasting more than 7 days, a
platelet count < 10,000 cells/μL

Posology modification or delay
Bortezomib therapy should be withheld for
up to 2 weeks until the patient has an ANC ≥
750 cells/μL and a platelet count ≥ 25,000
cells/μL.
• If, after bortezomib has been held, the

• If platelet counts < 25,000 cells/μL. or
ANC < 750 cells/μL on a bortezomib
dosing day (other than Day 1 of each
cycle)
Grade ≥ 3 non-haematological toxicities
considered to be related to bortezomib

toxicity does not resolve, as defined
above, then bortezomib must be
discontinued.
• If toxicity resolves i.e. patient has an ANC
≥ 750 cells/μL and a platelet count ≥
25,000 cells/μL, bortezomib may be
reinitiated at a dose reduced by one dose
level (from 1.3 mg/m2 to 1 mg/m2, or from
1 mg/m2 to 0.7 mg/m2).
Bortezomib therapy should be withheld

Bortezomib therapy should be withheld until
symptoms of the toxicity have resolved to
Grade 2 or better. Then, bortezomib may be
reinitiated at a dose reduced by one dose
level (from 1.3 mg/m2 to 1 mg/m2, or from 1
mg/m2to 0.7 mg/m2). For bortezomib -related
neuropathic pain and/or peripheral
neuropathy, hold and/or modify bortezomib
as outlined in Table 1.

In addition, when bortezomib is given in combination with other chemotherapeutic
medicinal products, appropriate dose reductions for these medicinal products should
be considered in the event of toxicities, according to the recommendations in the
respective Summary of Product Characteristics.
Special populations
Elderly
There is no evidence to suggest that dose adjustments are necessary in patients over
65 years of age with multiple myeloma or with mantle cell lymphoma.
There are no studies on the use of bortezomib in elderly patients with previously
untreated multiple myeloma who are eligible for high-dose chemotherapy with
haematopoietic stem cell transplantation. Therefore no dose recommendations can be
made in this population.
In a study in previously untreated mantle cell lymphoma patients, 42.9% and 10.4%
of patients exposed to bortezomib were in the range 65-74 years and ≥ 75 years of
age, respectively. In patients aged ≥ 75 years, both regimens, VcR-CAP as well as RCHOP, were less tolerated (see section 4.8).
Hepatic impairment
Patients with mild hepatic impairment do not require a dose adjustment and should be
treated per the recommended dose. Patients with moderate or severe hepatic
impairment should be started on bortezomib at a reduced dose of 0.7 mg/m2 per
injection during the first treatment cycle, and a subsequent dose escalation to 1.0
mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on patient
tolerability (see Table 6 and sections 4.4 and 5.2).

Table 6: Recommended starting dose modification for Bortezomib in patients with
hepatic impairment
Grade of
hepatic
impairment*
Mild

Bilirubin level

≤ 1.0 x ULN
> 1.0 x −1.5 x
ULN
> 1.5 x −3 x ULN
> 3 x ULN

SGOT
(AST)
levels
> ULN
Any

Modification of starting dose
None
None

Reduce bortezomib to 0.7 mg/m2 in the
first treatment cycle. Consider dose
escalation to 1.0 mg/m2 or further dose
reduction to 0.5 mg/m2 in subsequent
cycles based on patient tolerability.
Abbreviations: SGOT=serum glutamic oxaloacetic transaminase;

Moderate
Severe

Any
Any

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

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

The pharmacokinetics of bortezomib are not influenced in patients with mild to
moderate renal impairment (Creatinine Clearance [CrCL] > 20 ml/min/1.73 m2);
therefore, dose adjustments are not necessary for these patients. It is unknown if the
pharmacokinetics of bortezomib are influenced in patients with severe renal
impairment not undergoing dialysis (CrCL < 20 ml/min/1.73 m2). Since dialysis may
reduce Bortezomib concentrations, bortezomib should be administered after the
dialysis procedure (see section 5.2).
Paediatric population
The safety and efficacy of bortezomib in children below 18 years of age have not
been established (see sections 5.1 and 5.2). Currently available data are described
in section 5.1 but no recommendation on a posology can be made.
Method of administration
Bortezomib 3.5 mg powder for solution for injection is available for intravenous or
subcutaneous administration.
Bortezomib 1 mg powder for solution for injection is available for intravenous
administration only.
Bortezomib should not be given by other routes. Intrathecal administration has
resulted in death.
Intravenous injection
Bortezomib 3.5 mg reconstituted solution is administered as a 3-5 second bolus
intravenous injection through a peripheral or central intravenous catheter followed by
a flush with sodium chloride 9 mg/ml (0.9%) solution for injection. At least 72 hours
should elapse between consecutive doses of bortezomib.

Subcutaneous injection
Bortezomib 3.5 mg reconstituted solution is administered subcutaneously through the
thighs (right or left) or abdomen (right or left). The solution should be injected
subcutaneously, at a 45-90° angle. Injection sites should be rotated for successive
injections.
If local injection site reactions occur following bortezomib subcutaneous injection,
either a less concentrated bortezomib solution (bortezomib 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 is given in combination with other medicinal products, refer to the
Summary of Product Characteristics of these products for instructions for
administration.

4.3

Contraindications
Hypersensitivity to the active substance, to boron or to any of the excipients listed in
section 6.1.
Acute diffuse infiltrative pulmonary and pericardial disease.
When bortezomib is given in combination with other medicinal products, refer to
their Summaries of Product Characteristics for additional contraindications.

4.4

Special warnings and precautions for use
When bortezomib is given in combination with other medicinal products, the
Summary of Product Characteristics of these other medicinal products must be
consulted prior to initiation of treatment with bortezomib. When thalidomide is used,
particular attention to pregnancy testing and prevention requirements is needed (see
section 4.6).
Intrathecal administration
There have been fatal cases of inadvertent intrathecal administration of bortezomib.
Bortezomib 1 mg powder for solution for injection is for intravenous use only, while
bortezomib 3.5 mg powder for solution for injection is for intravenous or
subcutaneous use. Bortezomib should not be administered intrathecally.
Gastrointestinal toxicity
Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are
very common with bortezomib treatment. Cases of ileus have been uncommonly
reported (see section 4.8). Therefore, patients who experience constipation should be
closely monitored.
Haematological toxicity
Bortezomib treatment is very commonly associated with haematological toxicities
(thrombocytopenia, neutropenia and anaemia). In studies in patients with relapsed
multiple myeloma treated with bortezomib and in patients with previously untreated
MCL treated with bortezomib in combination with rituximab, cyclophosphamide,

doxorubicin, and prednisone (VcR-CAP), one of the most common haematologic
toxicity was transient thrombocytopenia. Platelets were lowest at Day 11 of each
cycle of bortezomib treatment and typically recovered to baseline by the next cycle.
There was no evidence of cumulative thrombocytopenia. The mean platelet count
nadir measured was approximately 40% of baseline in the single-agent multiple
myeloma studies and 50% in the MCL study. In patients with advanced myeloma the
severity of thrombocytopenia was related to pre-treatment platelet count: for baseline
platelet counts < 75,000/μl, 90% of 21 patients had a count ≤ 25,000/μl during the
study, including 14% < 10,000/μl; in contrast, with a baseline platelet count >
75,000/μl, only 14% of 309 patients had a count ≤ 25,000/μl during the study.
In patients with MCL (study LYM-3002), there was a higher incidence (56.7% versus
5.8%) of Grade ≥ 3 thrombocytopenia in the bortezomib treatment group (VcR-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
VcR-CAP group and 5.0% in the R-CHOP group) as well as Grade 3 and higher
bleeding events (VcR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). In the
VcR-CAP group, 22.5% of patients received platelet transfusions compared to 2.9%
of patients in the R-CHOP group.
Gastrointestinal and intracerebral haemorrhage, have been reported in association
with bortezomib treatment. Therefore, platelet counts should be monitored prior to
each dose of bortezomib. Bortezomib therapy should be withheld when the platelet
count is < 25,000/μl or, in the case of combination with melphalan and prednisone,
when the platelet count is ≤ 30,000/μl (see section 4.2). Potential benefit of the
treatment should be carefully weighed against the risks, particularly in case of
moderate to severe thrombocytopenia and risk factors for bleeding.
Complete blood counts (CBC) with differential and including platelet counts should
be frequently monitored throughout treatment with bortezomib. Platelet transfusion
should be considered when clinically appropriate (see section 4.2).
In patients with MCL, transient neutropenia that was reversible between cycles was
observed, with no evidence of cumulative neutropenia. Neutrophils were lowest at
Day 11 of each cycle of bortezomib treatment and typically recovered to baseline by
the next cycle. In study LYM-3002, colony stimulating factor support was given to
78% of patients in the VcR-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 VcR-CAP arm and 1.2% in the R-CHOP arm (see section 4.8).

Hepatitis B Virus (HBV) reactivation and infection
When rituximab is used in combination with bortezomib, HBV screening must
always be performed in patients at risk of infection with HBV before initiation of
treatment. Carriers of hepatitis B and patients with a history of hepatitis B must be
closely monitored for clinical and laboratory signs of active HBV infection during
and following rituximab combination treatment with bortezomib. Antiviral
prophylaxis should be considered. Refer to the Summary of Product Characteristics of
rituximab for more information.

Progressive multifocal leukoencephalopathy (PML)
Very rare cases with unknown causality of John Cunningham (JC) virus infection,
resulting in PML and death, have been reported in patients treated with bortezomib.
Patients diagnosed with PML had prior or concurrent immunosuppressive therapy.
Most cases of PML were diagnosed within 12 months of their first dose of
bortezomib. Patients should be monitored at regular intervals for any new or
worsening neurological symptoms or signs that may be suggestive of PML as part of
the differential diagnosis of CNS problems. If a diagnosis of PML is suspected,
patients should be referred to a specialist in PML and appropriate diagnostic measures
for PML should be initiated. Discontinue bortezomib if PML is diagnosed.
Peripheral neuropathy
Treatment with bortezomib is very commonly associated with peripheral neuropathy,
which is predominantly sensory. However, cases of severe motor neuropathy with or
without sensory peripheral neuropathy have been reported. The incidence of
peripheral neuropathy increases early in the treatment and has been observed to peak
during cycle 5.
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)
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.
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.
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 lifethreatening 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 (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.
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 as single agent or in combination
System Organ Class
Incidence
Infections
and Common
infestations
Uncommon

Rare

Neoplasms
benign, Rare
malignant
and
unspecified (incl cysts
and polyps)
Blood and lymphatic Very
system disorders
Common

Adverse reaction
Herpes zoster (inc disseminated &
ophthalmic), Pneumonia*, Herpes
simplex*, Fungal infection*
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*
Meningitis (inc bacterial), Epstein-Barr
virus infection, Genital herpes, Tonsillitis,
Mastoiditis, Post viral fatigue syndrome
Neoplasm malignant, Leukaemia
plasmacytic, Renal cell carcinoma, Mass,
Mycosis fungoides, Neoplasm benign*
Thrombocytopenia*, Neutropenia*,
Anaemia*

Common
Uncommon

Rare

Immune
disorders

system Uncommon
Rare

Endocrine disorders

Uncommon

Rare
Metabolism
and Very
nutrition disorders
Common
Common

Uncommon

Rare

Psychiatric disorders

Common

Uncommon

Rare
Nervous
disorders

system Very
Common
Common

Leukopenia*, Lymphopenia*
Pancytopenia*, Febrile neutropenia,
Coagulopathy*, Leukocytosis*,
Lymphadenopathy, Haemolytic anaemia#
Disseminated intravascular coagulation,
Thrombocytosis*, Hyperviscosity
syndrome, Platelet disorder NOS,
Thrombocytopenic purpura, Blood disorder
NOS, Haemorrhagic diathesis,
Lymphocytic infiltration
Angioedema#, Hypersensitivity*
Anaphylactic shock, Amyloidosis, Type III
immune complex mediated reaction
Cushing's syndrome*, Hyperthyroidism*,
Inappropriate antidiuretic hormone
secretion
Hypothyroidism
Decreased appetite
Dehydration, Hypokalaemia*,
Hyponatraemia*, Blood glucose
abnormal*, Hypocalcaemia*, Enzyme
abnormality*
Tumour lysis syndrome, Failure to thrive*,
Hypomagnesaemia*,
Hypophosphataemia*, Hyperkalaemia*,
Hypercalcaemia*, Hypernatraemia*, Uric
acid abnormal*, Diabetes mellitus*, Fluid
retention
Hypermagnesaemia*, Acidosis, Electrolyte
imbalance*, Fluid overload,
Hypochloraemia*, Hypovolaemia,
Hyperchloraemia*, Hyperphosphataemia*,
Metabolic disorder, Vitamin B complex
deficiency, Vitamin B12 deficiency, Gout,
Increased appetite, Alcohol intolerance
Mood disorders and disturbances*, Anxiety
disorder*,
Sleep
disorders
and
disturbances*
Mental
disorder*,
Hallucination*,
Psychotic
disorder*,
Confusion*,
Restlessness
Suicidal ideation*, Adjustment disorder,
Delirium, Libido decreased
Neuropathies*,
Peripheral
sensory
neuropathy, Dysaesthesia*, Neuralgia*
Motor neuropathy*, Loss of consciousness
(inc syncope), Dizziness*, Dysgeusia*,
Lethargy, Headache*

Uncommon

Rare

Eye disorders

Common
Uncommon

Rare

Ear
and
disorders

labyrinth Common
Uncommon
Rare

Cardiac disorders

Uncommon

Rare

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
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 swelling*, Vision abnormal*,
Conjunctivitis*
Eye haemorrhage*, Eyelid infection*, Eye
inflammation*, Diplopia, Dry eye*, Eye
irritation*, Eye pain, Lacrimation
increased, Eye discharge
Corneal lesion*, Exophthalmos, Retinitis,
Scotoma, Eye disorder (inc. eyelid) NOS,
Dacryoadenitis acquired, Photophobia,
Photopsia, Optic neuropathy#, Different
degrees of visual impairment (up to
blindness)*
Vertigo*
Dysacusis (inc tinnitus)*,Hearing impaired
(up to and inc deafness), Ear discomfort*
Ear haemorrhage, Vestibular neuronitis,
Ear disorder NOS
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
Atrial flutter, Myocardial infarction*,
Atrioventricular block*, Cardiovascular
disorder (inc cardiogenic shock), Torsade

Vascular disorders

Common
Uncommon

Rare

Respiratory,
thoracic Common
and
mediastinal
disorders
Uncommon

Rare

Gastrointestinal
disorders

Very
Common
Common

Uncommon

de pointes, Angina unstable, Cardiac valve
disorders*, Coronary artery insufficiency,
Sinus arrest
Hypotension*, Orthostatic hypotension,
Hypertension*
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)*
Peripheral embolism, Lymphoedema,
Pallor, Erythromelalgia, Vasodilatation,
Vein discolouration, Venous insufficiency
Dyspnoea*, Epistaxis, Upper/lower
respiratory tract infection*, Cough*
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
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
Nausea and vomiting symptoms*,
Diarrhoea*, Constipation
Gastrointestinal haemorrhage (inc
mucosal)*, Dyspepsia, Stomatitis*,
Abdominal distension, Oropharyngeal
pain*, Abdominal pain (inc gastrointestinal
and splenic pain)*, Oral disorder*,
Flatulence
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

Rare

Hepatobiliary disorders

Common
Uncommon
Rare

Skin and subcutaneous Common
tissue disorders
Uncommon

Rare

Musculoskeletal
and Very
connective
tissue Common
disorders
Common
Uncommon

Rare

(inc clostridium difficile)*, Colitis
ischaemic#, Gastrointestinal inflammation*,
Dysphagia, Irritable bowel syndrome,
Gastrointestinal disorder NOS, Tongue
coated, Gastrointestinal motility disorder*,
Salivary gland disorder*
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
Hepatic enzyme abnormality*
Hepatotoxicity (inc liver disorder),
Hepatitis*, Cholestasis
Hepatic failure, Hepatomegaly, BuddChiari syndrome, Cytomegalovirus
hepatitis, Hepatic haemorrhage,
Cholelithiasis
Rash*, Pruritus*, Erythema, Dry skin
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*
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 pain*
Muscle spasms*, Pain in extremity,
Muscular weakness
Muscle twitching, Joint swelling,
Arthritis*, Joint stiffness,
Myopathies*,Sensation of heaviness
Rhabdomyolysis, Temporomandibular joint
syndrome, Fistula, Joint effusion, Pain in
jaw, Bone disorder, Musculoskeletal and

Renal
and
disorders

urinary Common
Uncommon

Rare
Reproductive
system Uncommon
and breast disorders
Rare

Congenital, familial and
genetic disorders
General disorders and
administration
site
conditions

Rare
Very
Common
Common
Uncommon

Rare

Investigations

Common
Uncommon

Rare

Injury, poisoning and Uncommon
procedural
Rare

connective tissue infections and
inflammations*, Synovial cyst
Renal impairment*
Renal failure acute, Renal failure chronic*,
Urinary tract infection*, Urinary tract signs
and symptoms*, Haematuria*, Urinary
retention, Micturition disorder*,
Proteinuria, Azotaemia, Oliguria*,
Pollakiuria
Bladder irritation
Vaginal haemorrhage, Genital pain*,
Erectile dysfunction,
Testicular disorder*, Prostatitis, Breast
disorder female, Epididymal tenderness,
Epididymitis, Pelvic pain, Vulval
ulceration
Aplasia, Gastrointestinal malformation,
Ichthyosis
Pyrexia*, Fatigue, Asthenia
Oedema (inc peripheral), Chills, Pain*,
Malaise*
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*
Death (inc sudden), Multi-organ failure,
Injection site haemorrhage*, Hernia(inc
hiatus)*, Impaired healing*, Inflammation,
Injection site phlebitis*, Tenderness, Ulcer,
Irritability, Non-cardiac chest pain,
Catheter site pain, Sensation of foreign
body
Weight decreased
Hyperbilirubinaemia*, Protein analyses
abnormal*, Weight increased, Blood test
abnormal*,C-reactive protein increased
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*
Fall, Contusion
Transfusion reaction, Fractures*, Rigors*,

complications

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

Surgical and medical
Rare
Macrophage activation
procedures
NOS=not otherwise specified
* Grouping of more than one MedDRA preferred term.
# Postmarketing adverse reaction
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 (VcR-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 (VcR-CAP) were hepatitis B infection (<
1%) and myocardial ischaemia (1.3%). The similar incidences of these events in both
treatment arms, indicated that these 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 VcR-CAP arm and with at
least a possible or probable causal relationship to the components of the VcR-CAP
arm, are listed in Table 8 below. Also included are adverse drug reactions identified
in the VcR-CAP arm that were considered by investigators to have at least a possible
or probable causal relationship to bortezomib based on historical data in the multiple
myeloma studies.
Adverse reactions are listed below by system organ class and frequency grouping.
Frequencies are defined as: Very common (≥ 1/10); common (≥ 1/100 to < 1/10);
uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (<
1/10,000), not known (cannot be estimated from the available data). Within each
frequency grouping, undesirable effects are presented in order of decreasing
seriousness. Table 8 has been generated using Version 16 of the MedDRA.
Table 8 Adverse reactions in patients with Mantle Cell Lymphoma treated with VcRCAP
System Organ Class

Infections and infestations

Blood and lymphatic
system disorders
Immune system disorders

Incidence
Adverse reaction
Very Common Pneumonia*
Sepsis (inc septic shock)*, Herpes zoster (inc
disseminated & ophthalmic), Herpes virus
Common
infection*, Bacterial infections*, Upper/lower
respiratory tract infection*, Fungal infection*,
Herpes simplex*
Uncommon
Hepatitis B, Infection*, Bronchopneumonia
Thrombocytopenia*, Febrile neutropenia,
Very Common Neutropenia*, Leukopenia*, Anaemia*,
Lymphopenia*
Uncommon
Pancytopenia*
Common
Hypersensitivity*

Metabolism and nutrition
disorders
Psychiatric disorders

Nervous system disorders

Eye disorders
Ear and labyrinth
disorders

Cardiac disorders

Vascular disorders
Respiratory, thoracic and
mediastinal disorders

Gastrointestinal disorders

Hepatobiliary disorders
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Renal and urinary
disorders
General disorders and
administration site
conditions
Investigations

Uncommon
Anaphylactic reaction
Very Common Decreased appetite
Hypokalaemia*, Blood glucose abnormal*,
Common
Hyponatraemia*, Diabetes mellitus*, Fluid
retention
Uncommon
Tumour lysis syndrome
Common
Sleep disorders and disturbances*
Peripheral sensory neuropathy, Dysaesthesia*,
Very Common
Neuralgia*
Neuropathies*, Motor neuropathy*, Loss of
consciousness (inc syncope), Encephalopathy*,
Peripheral sensorimotor neuropathy,
Common
Dizziness*, Dysgeusia*, Autonomic
neuropathy
Uncommon
Autonomic nervous system imbalance
Common
Vision abnormal*
Common
Dysacusis (inc tinnitus)*
Vertigo*, Hearing impaired (up to and inc
Uncommon
deafness)
Cardiac fibrillation (inc atrial), Arrhythmia*,
Cardiac failure (inc left and right ventricular)*,
Common
Myocardial ischaemia, Ventricular
dysfunction*
Cardiovascular disorder (inc cardiogenic
Uncommon
shock)
Hypertension*, Hypotension*, Orthostatic
Common
hypotension
Common
Dyspnoea*, Cough*, Hiccups
Acute respiratory distress syndrome,
Uncommon
Pulmonary embolism, Pneumonitis, Pulmonary
hypertension, Pulmonary oedema (inc acute)
Nausea and vomiting symptoms*, Diarrhoea*,
Very Common
Stomatitis*, Constipation
Gastrointestinal haemorrhage (inc mucosal)*,
Abdominal distension, Dyspepsia,
Oropharyngeal pain*, Gastritis*, Oral
Common
ulceration*, Abdominal discomfort, Dysphagia,
Gastrointestinal inflammation*, Abdominal
pain (inc gastrointestinal and splenic pain)*,
Oral disorder*
Uncommon
Colitis (inc clostridium difficile)*
Common
Hepatotoxicity (inc liver disorder)
Uncommon
Hepatic failure
Very Common Hair disorder*
Common
Pruritus*, Dermatitis*, Rash*
Common

Muscle spasms*, Musculoskeletal pain*, Pain
in extremity

Common

Urinary tract infection*

Very Common Pyrexia*, Fatigue, Asthenia
Oedema (inc peripheral), Chills, Injection site
Common
reaction*, Malaise*
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 Vc+M+P arm.
The incidence of herpes zoster among patients in the Vc+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 VcR-CAP
arm. The incidence of herpes zoster among patients in the VcR-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 nonbortezomib 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 (VcRCAP). The overall incidence of hepatitis B infections was similar in patients treated
with VcR-CAP or with R-CHOP (0.8% vs 1.2% respectively).
Peripheral neuropathy in combination regimens
Multiple Myeloma
In trials in which 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
VDDx
VcDx
(N=239)
(N=239)
Incidence of PN (%)
All GradePN
≥ Grade 2 PN
≥ Grade 3 PN
Discontinuation due to
PN (%)

3
1
<1
<1

15
10
5
2

MMY-3010
TDx
VcTDx
(N=126)
(N=130)
12
2
0
1

45
31
5
5

VDDx=vincristine, doxorubicin, dexamethasone; VcDx= Bortezomib,
dexamethasone; TDx=thalidomide, dexamethasone; VcTDx= 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
VcR-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
VcR-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 VcR-CAP arm were in the range 65-74 years and
≥ 75 years of age, respectively. Although in patients aged ≥ 75 years, both VcR-CAP
and R-CHOP were less tolerated, the serious adverse event rate in the VcR-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
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: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

4.9

Overdose
In patients, overdose more than twice the recommended dose has been associated
with the acute onset of symptomatic hypotension and thrombocytopenia with fatal
outcomes. For preclinical cardiovascular safety pharmacology studies, see section
5.3.
There is no known specific antidote for bortezomib overdose. In the event of an
overdose, the patient's vital signs should be monitored and appropriate supportive
care given to maintain blood pressure (such as fluids, pressors, and/or inotropic
agents) and body temperature (see sections 4.2 and 4.4).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC
code: L01XX32.
Mechanism of action

Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the
chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S
proteasome is a large protein complex that degrades ubiquitinated proteins. The
ubiquitin-proteasome pathway plays an essential role in regulating the turnover of
specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S
proteasome prevents this targeted proteolysis and affects multiple signalling cascades
within the cell, ultimately resulting in cancer cell death.
Bortezomib is highly selective for the proteasome. At 10 μM concentrations,
bortezomib does not inhibit any of a wide variety of receptors and proteases screened
and is more than 1,500-fold more selective for the proteasome than for its next
preferable enzyme. The kinetics of proteasome inhibition were evaluated in vitro, and
bortezomib was shown to dissociate from the proteasome with a t½ of 20 minutes,
thus demonstrating that proteasome inhibition by bortezomib is reversible.
Bortezomib mediated proteasome inhibition affects cancer cells in a number of ways,
including, but not limited to, altering regulatory proteins, which control cell cycle
progression and nuclear factor kappa B (NF-kB) activation. Inhibition of the
proteasome results in cell cycle arrest and apoptosis. NF-kB is a transcription factor
whose activation is required for many aspects of tumourigenesis, including cell
growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma,
bortezomib affects the ability of myeloma cells to interact with the bone marrow
microenvironment.
Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer
cell types and that cancer cells are more sensitive to the pro-apoptotic effects of
proteasome inhibition than normal cells. Bortezomib causes reduction of tumour
growth in vivo in many preclinical tumour models, including multiple myeloma.
Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it
increases osteoblast differentiation and activity and inhibits osteoclast function. These
effects have been observed in patients with multiple myeloma affected by an
advanced osteolytic disease and treated with bortezomib.
Clinical efficacy in previously untreated multiple myeloma
A prospective Phase III, international, randomised (1:1), open-label clinical study
(MMY-3002 VISTA) of 682 patients was conducted to determine whether
BORTEZOMIB (1.3 mg/m2 injected intravenously) in combination with melphalan (9
mg/m2) and prednisone (60 mg/m2) resulted in improvement in time to progression
(TTP) when compared to melphalan (9 mg/m2) and prednisone (60 mg/m2) in patients
with previously untreated multiple myeloma. Treatment was administered for a
maximum of 9 cycles (approximately 54 weeks) and was discontinued early for
disease progression or unacceptable toxicity. The median age of the patients in the
study was 71 years, 50% 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 Vc+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 Vc+M+P treatment group was observed (HR=0.695;
p=0.00043) despite subsequent therapies including BORTEZOMIB-based regimens.

Median survival for the Vc+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
Time to progression
Events n (%)
Mediana (95% CI)
Hazard ratiob
(95% CI)
p-valuec
Progression-free survival
Events n (%)
Mediana (95% CI)

Vc+M+P
n=344

M+P
n=338

101 (29)
20.7 mo
(17.6, 24,7)
0.54
(0.42, 0.70)
0.000002

152 (45)
15.0 mo
(14.1, 17.9)

135 (39)
18.3 mo
(16.6, 21.7)
0.61
(0.49, 0.76)
0.00001

190 (56)
14.0 mo
(11.1, 15.0)

Hazard ratiob
(95% CI)
p-value c
Overall survival*
Events (deaths) n (%)
176 (51.2)
211 (62.4)
Mediana
56.4 mo
43.1 mo
(95% CI)
(52.8, 60.9)
(35.3, 48.3)
Hazard ratiob
0.695
(95% CI)
(0.567, 0.852)
p-valuec
0.00043
n=337
n=331
Response rate
populatione n=668
CRf n (%)
102 (30)
12 (4)
PRf n (%)
136 (40)
103 (31)
nCR n (%)
5 (1)
0
CR+PRf n (%)
238 (71)
115 (35)
p-valued
< 10-10
n=336
n=331
Reduction in serum M-protein
populationg n=667
151 (45)
34 (10)
≥90% n (%)
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)
a
Median
27.0 mo
19.2 mo
(95% CI)
(24.7, 31.1)
(17.0, 21.0)
Hazard ratiob
0.557
(95% CI)
(0.462, 0.671)
p-valuec
< 0.000001
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 chisquare 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 [VcDx, n=240]
was compared to vincristine- doxorubicin-dexamethasone [VDDx, n=242]. Patients in
the VcDx 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 VcDx groups respectively; the majority of patients
underwent one single transplant procedure. Patient demographic and baseline disease
charateristics were similar between the treatment groups. Median age of the patients
in the study was 57 years, 55% were male and 48% of patients had high-risk
cytogenetics. The median duration of treatment was 13 weeks for the VDDx group
and 11 weeks for the VcDx group. The median number of cycles received for both
groups was 4 cycles.
The primary efficacy endpoint of the study was post-induction response rate
(CR+nCR). A 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

VcDx

VDDx

IFM-2005-01

N=240 (ITT
population)

N=242 (ITT
population)

RR (Post-induction )
*CR+nCR
14.6 (10.4, 19.7)
CR+nCR+VGPR+PR 77.1 (71.2, 82.2)
% (95% CI)
RR (Post-transplant)b
CR+nCR

37.5 (31.4, 44.0)

OR; 95% CI; P
valuea

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

23.1 (18.0, 29.0)

1.98 (1.33, 2.95);

CR+nCR+VGPR+PR 79.6 (73.9, 84.5)
% (95% CI)

74.4 (68.4, 79.8)

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; Vc=bortezomib; VcDx=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 VcDx group and 52/242 [21%] in VDDx group).
Note: An OR > 1 indicates an advantage for Vc-containing induction therapy.
In study MMY-3010 induction treatment with bortezomib combined with thalidomide
and dexamethasone [VcTDx, n=130] was compared to thalidomide-dexamethasone
[TDx, n=127]. Patients in the VcTDx group received six 4-week cycles, each
consisting of bortezomib (1.3 mg/m2 administered twice weekly days 1, 4, 8, and 11,
followed by a 17-day rest period from day 12 to day 28), dexamethasone (40 mg
administered orally on days 1 to 4 and days 8 to 11), and thalidomide (administered
orally at 50 mg daily on days 1-14, increased to 100 mg on days 15-28 and thereafter
to 200 mg daily).
One single autologous stem cell transplant was received by 105 (81%) patients and 78
(61%) patients in the VcTDx and TDx groups, respectively. Patient demographic and
baseline disease charateristics were similar between the treatment groups. Patients in
the VcTDx 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
VcTDx 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

VcTDx

TDx

MMY-3010

N=130 (ITT
population)

N=127 (ITT
population)

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

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

*RR (Post-induction)
CR+nCR
CR+nCR+PR %
(95% CI)
*RR (Posttransplant)
CR+nCR
CR+nCR+PR %
(95% CI)

OR; 95% CI; P
valuea

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

Time related
events

Phase III
All patients

Phase III
1 prior line of
therapy

Phase III
> 1 prior line of
therapy

Vc
n=333a

Vc
n=132a

Vc
n=200a

Dex
n=336a

Dex
n=119a

Dex
n=217a

Phase II
≥2
prior
lines
Vc
n=202a

TTP, days
[95% CI]
1 year
survival, %
[95% CI]
Best
response
(%)
CR
CR+nCR
CR+nCR+PR

189b
[148,
211]
80d
[74,85]

106b
[86,
128]
66d
[59,72]

212d
[188,
267]
89d
[82,95]

169d
[105,
191]
72d
[62,83]

148b
[129,
192]
73
[64,82]

87b
[84,
107]
62
[53,71]

210
[154,
281]

Vc
n=315c

Dex
n=312c

Vc
n=128

Dex
n=110

Vc
n=187

Dex
n=202

Vc
n=193

20 (6)b
41 (13)b
121
(38)b
146 (46)

2 (< 1)b
5 (2)b
56 (18)b

8 (6)
16 (13)
57 (45)d

2 (2)
4 (4)
29 (26)d

12 (6)
25 (13)
64 (34)b

0 (0)
1 (< 1)
27 (13)b

(4)**
(10)**
(27)**

60

CR+nCR+
108 (35) 66 (52)
45 (41)
80 (43)
63 (31)
(35)**
PR+MR
242
169
246
189
238
126
385*
Median
(8.0)
(5.6)
(8.1)
(6.2)
(7.8)
(4.1)
duration
Days
(months)
43
43
44
46
41
27
38*
Time to
response
CR+PR
(days)
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
Vc=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.
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
n=73

Bortezomib
subcutaneous arm
n=145

Response Evaluable Population
Response Rate at 4 cycles n (%)
ORR (CR+PR)
31 (42)
61 (42)
a
p-value
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
9.4
10.4
TTP, months
(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
8.0
10.2
Progression Free Survival,
months
(95% CI)
(6.7, 9.8)
(8.1, 10.8)
c
0.824 (0.574, 1.183)
Hazard ratio (95% CI)
0.295
p-valued
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; 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 openlabel 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 (VcR-CAP; n=243) to that of
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP;
n=244) in adult patients with previously untreated MCL (Stage II, III or IV). Patients
in the VcR-CAP treatment arm received bortezomib (1.3 mg/m2; on days 1, 4, 8, 11,
rest period days 12-21), rituximab 375 mg/m2 IV on day 1; cyclophosphamide 750
mg/m2 IV on day 1; doxorubicin 50 mg/m2 IV on day 1; and prednisone 100
mg/m2 orally on day 1 through day 5 of the 21 day bortezomib treatment cycle. For
patients with a response first documented at cycle 6, two additional treatment cycles
were given.
The primary efficacy endpoint was progression-free survival based on Independent
Review Committee (IRC) assessment. Secondary endpoints included, time to
progression (TTP), time to next anti-lymphoma treatment (TNT), duration of
treatment free interval (TFI), overall response rate (ORR) and complete response
(CR/CRu) rate, overall survival (OS) and response duration.
The demographic and baseline disease characteristics were generally well balanced
between the two treatment arms: median patient age was 66 years, 74% were male,
66% were Caucasian and 32% Asian, 69% of patients had a positive bone marrow
aspirate and/or a positive bone marrow biopsy for MCL, 54% of patients had an
International Prognostic Index (IPI) score of ≥ 3, and 76% had Stage IV disease.
Treatment duration (median=17 weeks) and duration of follow-up (median=40
months) were comparable in both treatment arms. A median of 6 cycles was received
by patients in both treatment arms with 14% of subjects in the VcR-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 VcR-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
VcR-CAP
n: ITT patients
243
Progression free survival (IRC)a
Events n (%)
133 (54.7%)
c
Median (95% CI)
24.7 (19.8; 31.8)
(months)
Response rate
n: response-evaluable
229
patients
Overall complete
response
122 (53.3%)
(CR+CRu)f n(%)
Overall response
211 (92.1%)
(CR+CRu+PR)h n(%)

R-CHOP
244
165 (67.6%)
14.4 (12; 16.9)

HRb (95% CI)=0.63
(0.50; 0.79)
p-valued < 0.001

228
95 (41.7%)
204 (89.5%)

ORe (95% CI)=1.688
(1.148; 2.481)
p-valueg=0.007
ORe (95% CI)=1.428
(0.749; 2.722)

p-valueg=0.275
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 VcR-CAP.
c
Based on Kaplan-Meier product limit estimates.
d
Based on Log rank test stratified with IPI risk and stage of disease.
e
Mantel-Haenszel estimate of the common odds ratio for stratified tables is used, with IPI risk
and stage of disease as stratification factors. An odds ratio (OR) > 1 indicates an advantage
for VcR-CAP.
f
Include all CR+CRu, by IRC, bone marrow and LDH.
g
P-value from the Cochran Mantel-Haenszel chi-square test, with IPI and stage of disease as
stratification factors.
h
Include all radiological CR+CRu+PR by IRC regardless the verification by bone marrow
and LDH.
CR=Complete Response; CRu=Complete Response unconfirmed; PR=Partial Response;
CI=Confidence Interval, HR=Hazard Ratio; OR=Odds Ratio; ITT=Intent to Treat
a

Median PFS by investigator assessment was 30.7 months in the VcR-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 VcR-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 VcR-CAP group
compared with 18 months in the R-CHOP group. The duration of overall response
was 21.4 months longer in the VcR-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 VcR-CAP
group) favoured the VcR-CAP group, (estimated HR=0.80; p=0.173). There was a
trend towards prolonged overall survival favouring the VcR-CAP group; the
estimated 4-year survival rate was 53.9% in the R-CHOP group and 64.4% in the
VcR-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%.
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 Tcell 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).
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).

5.2

Pharmacokinetic properties
Absorption
Following intravenous bolus administration of a 1.0 mg/m2 and 1.3 mg/m2 dose to 11
patients with multiple myeloma and creatinine clearance values greater than 50
ml/min, the mean first-dose maximum plasma concentrations of bortezomib were 57
and 112 ng/ml, respectively. In subsequent doses, mean maximum observed plasma
concentrations ranged from 67 to 106 ng/ml for the 1.0 mg/m2 dose and 89 to 120
ng/ml for the 1.3 mg/m2 dose.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to
patients with multiple myeloma (n=14 in the intravenous group, n=17 in the
subcutaneous group), the total systemic exposure after repeat dose administration
(AUClast) was equivalent for subcutaneous and intravenous administrations. The
Cmax after subcutaneous administration (20.4 ng/ml) was lower than intravenous (223
ng/ml). The AUClast- geometric mean ratio was 0.99 and 90% confidence intervals
were 80.18%-122.80%.
Distribution
The mean distribution volume (Vd) of bortezomib ranged from 1,659 l to 3,294 l
following single- or repeated-dose intravenous administration of 1.0 mg/m2 or 1.3
mg/m2 to patients with multiple myeloma. This suggests that bortezomib distributes
widely to peripheral tissues. Over a bortezomib concentration range of 0.01 to 1.0
μg/ml, the in vitro protein binding averaged 82.9% in human plasma. The fraction of
bortezomib bound to plasma proteins was not concentration-dependent.

Biotransformation
In vitro studies with human liver microsomes and human cDNA-expressed
cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively
metabolised via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. The major
metabolic pathway is deboronation to form two deboronated metabolites that
subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib
metabolites are inactive as 26S proteasome inhibitors.
Elimination
The mean elimination half-life (t1/2) of bortezomib upon multiple dosing ranged from
40-193 hours. Bortezomib is eliminated more rapidly following the first dose
compared to subsequent doses. Mean total body clearances were 102 and 112 l/h
following the first dose for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively, and
ranged from 15 to 32 l/h and 18 to 32 l/h following subsequent doses for doses of 1.0
mg/m2 and 1.3 mg/m2, respectively.
Special populations
Hepatic impairment
The effect of hepatic impairment on the pharmacokinetics of bortezomib was
assessed in a Phase I study during the first treatment cycle, including 61 patients
primarily with solid tumors and varying degrees of hepatic impairment at bortezomib
doses ranging from 0.5 to 1.3 mg/m2.
When compared to patients with normal hepatic function, mild hepatic impairment
did not alter dose-normalised bortezomib AUC. However, the dose-normalised mean
AUC values were increased by approximately 60% in patients with moderate or
severe hepatic impairment. A lower starting dose is recommended in patients with
moderate or severe hepatic impairment, and those patients should be closely
monitored (see section 4.2, Table 6).
Renal impairment
A pharmacokinetic study was conducted in patients with various degrees of renal
impairment who were classified according to their creatinine clearance values (CrCL)
into the following groups: Normal (CrCL ≥ 60 ml/min/1.73 m2, n=12), Mild
(CrCL=40-59 ml/min/1.73 m2, n=10), Moderate (CrCL=20-39 ml/min/1.73 m2, n=9),
and Severe (CrCL < 20 ml/min/1.73 m2, n=3). A group of dialysis patients who were
dosed after dialysis was also included in the study (n=8). Patients were administered
intravenous doses of 0.7 to 1.3 mg/m2 of bortezomib twice weekly. Exposure of
bortezomib (dose-normalised AUC and Cmax) was comparable among all the groups
(see section 4.2).
Age:
The pharmacokinetics of bortezomib were characterized following twice weekly
intravenous bolus administration of 1.3 mg/m2 doses to 104 pediatric patients (2-16
years old) with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia
(AML). Based on a population pharmacokinetic analysis, clearance of bortezomib
increased with increasing body surface area (BSA). Geometric mean (%CV)

clearance was 7.79 (25%) L/hr/m2, volume of distribution at steady-state was 834
(39%) L/m2, and the elimination half-life was 100 (44%) hours. After correcting for
the BSA effect, other demographics such as age, body weight and sex did not have
clinically significant effects on bortezomib clearance. BSA-normalized clearance of
bortezomib in pediatric patients was similar to that observed in adults.

5.3

Preclinical safety data
Bortezomib was positive for clastogenic activity (structural chromosomal aberrations)
in the in vitro chromosomal aberration assay using Chinese hamster ovary (CHO)
cells at concentrations as low as 3.125 μg/ml, which was the lowest concentration
evaluated. Bortezomib was not genotoxic when tested in the in vitro mutagenicity
assay (Ames assay) and in vivo micronucleus assay in mice.
Developmental toxicity studies in the rat and rabbit have shown embryo-fetal lethality
at maternally toxic doses, but no direct embryo-foetal toxicity below maternally toxic
doses. Fertility studies were not performed but evaluation of reproductive tissues has
been performed in the general toxicity studies. In the 6-month rat study, degenerative
effects in both the testes and the ovary have been observed. It is, therefore, likely that
bortezomib could have a potential effect on either male or female fertility. Peri- and
postnatal development studies were not conducted.
In multi-cycle general toxicity studies conducted in the rat and monkey, the principal
target organs included the gastrointestinal tract, resulting in vomiting and/or
diarrhoea; haematopoietic and lymphatic tissues, resulting in peripheral blood
cytopenias, lymphoid tissue atrophy and haematopoietic bone marrow
hypocellularity; peripheral neuropathy (observed in monkeys, mice and dogs)
involving sensory nerve axons; and mild changes in the kidneys. All these target
organs have shown partial to full recovery following discontinuation of treatment.
Based on animal studies, the penetration of bortezomib through the blood-brain
barrier appears to be limited, if any and the relevance to humans is unknown.
Cardiovascular safety pharmacology studies in monkeys and dogs show that
intravenous doses approximately two to three times the recommended clinical dose
on a mg/m2 basis are associated with increases in heart rate, decreases in contractility,
hypotension and death. In dogs, the decreased cardiac contractility and hypotension
responded to acute intervention with positive inotropic or pressor agents. Moreover,
in dog studies, a slight increase in the corrected QT interval was observed.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Mannitol (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
2 years
Intravenous administration
The chemical and physical in-use stability of the reconstituted solution at a
concentration of 1 mg/ml has been demonstrated for 8 hours at 20°C-25°C stored in
the original vial and/or a syringe. From a microbiological point of view, unless the
method of opening/reconstitution/dilution precludes the risk of microbial
contamination, 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.
Subcutaneous administration
The chemical and physical in -use stability of the reconstituted solution of 2.5 mg/ml
has been demonstrated for 8 hours at 20°C-25°C stored in the original vial and/or a
syringe. From a microbiological point of view, unless the method of
opening/reconstitution/dilution precludes the risk of microbial contamination, 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.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.
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
Type 1 glass 10 ml capacity vial with a dark grey bromobutyl stopper and an
aluminium seal, with a light blue cap containing 3.5 mg bortezomib.

Each pack contains 1 single use vial.

6.6

Special precautions for disposal
General precautions
Bortezomib is a cytotoxic agent. Therefore, caution should be used during handling
and preparation of bortezomib. Use of gloves, goggles and other protective clothing
to prevent skin contact is recommended.
Aseptic technique must be strictly observed throughout the handling of Bortezomib,
since it contains no preservative.
There have been fatal cases of inadvertent intrathecal administration of bortezomib.
Bortezomib 3.5 mg powder for solution for injection is for intravenous or
subcutaneous use. Bortezomib should not be administered intrathecally.
Instructions for reconstitution
Bortezomib must be reconstituted by a healthcare professional.
Intravenous injection
Each 10 ml vial of bortezomib must be reconstituted with 3.5 ml of sodium chloride 9
mg/ml (0.9%) solution for injection. 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 should be reconstituted with 1.4 ml of sodium
chloride 9 mg/ml (0.9%) solution for injection. Dissolution of the lyophilised powder
is completed in less than 2 minutes.
After reconstitution, each ml solution contains 2.5 mg bortezomib. The reconstituted
solution is clear and colourless, with a final pH of 4 to 7. The reconstituted solution
must be inspected visually for particulate matter and discolouration prior to
administration. If any discolouration or particulate matter is observed, the
reconstituted solution must be discarded.
Disposal
Bortezomib is for single use only. Any unused medicinal product or waste material
should be disposed of in accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Koanaa Healthcare Limited
4th Floor Cavendish House,
369 Burnt Oak Broadway,
Edgware, HA8 5AW Middlesex
United Kingdom.

8

MARKETING AUTHORISATION NUMBER(S)
PL 44305/0001

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
13/12/2016

10

DATE OF REVISION OF THE TEXT
13/12/2016

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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