VELCADE 3.5 MG

J-C Health Care Ltd.

Kibbutz Shefayim, 6099000

ISRAEL

Phone: 09-9591111 Fax: 09-9583636

רבמבונ

2018

ה/דבכנ ה/אפור

ת/חקור /דבכנ

ןודנה

ןוכדע

ןולעב

אפורל

לש

םירישכתה

Velcade 3.5 mg

וננוצרב

איבהל

םכתעידיל

רישכתה לש אפורל ןולעל ןוכדע לח יכ

Velcade 3.5 mg

יוותהה תו

מושרה תו

:ץראב

1.1

Multiple Myeloma

with

of patients

(bortezomib) for Injection is indicated for the treatment

VELCADE

multiple myeloma.

1.2

Mantle Cell Lymphoma

(bortezomib) for Injection is indicated for the treatment of patients with

®

CADE

mantle cell

Lymphoma who have received at least one prior therapy.

VELCADE 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.

:ףיעסב ןוקית לח

Neuropathy

of Peripheral

Dose Modifications

2.6

Table 4 – Recommended Dose Modification for VELCADE related Neuropathic Pain

and/or Peripheral Sensory or Motor Neuropathy

Peripheral

Severity of

Sterility or

Neuropathy Signs and Symptoms*

Modification of Dose and Regimen

Grade 1 (asymptomatic ; loss of deep tendon

reflexes or paresthesia) without pain or loss

of function

No action

Grade 1 with pain or Grade 2 (moderate

symptoms; limiting Instrumental Activities of

Daily Living (ADL))**

Reduce VELCADE to 1 mg/m

Change VELCADE treatment schedule to

once per week

1.3 mg/m

Grade 2 with pain or Grade 3 (severe

symptoms; limiting self care ADL *** )

Withhold VELCADE therapy until toxicity

resolves. When toxicity resolves reinitiate

with a reduced dose of VELCADE at 0.7

once per week.

mg/m

Grade 4 (life threatening consequences;

Discontinue VELCADE

J-C Health Care Ltd.

Kibbutz Shefayim, 6099000

ISRAEL

Phone: 09-9591111 Fax: 09-9583636

urgent intervention indicated )

*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 medications, and not bedridden

ולעב םינמוסמ םייונישה

רוצמה

אכ ב שגדומה טסקטה רש לוחכ

קוחמה טסקטה וליאו ןולעל ףסוה

שגדומ .הצוח וק םע םודאב

אפורל ןולעה

םוסרפל חלשנ אולמב

ש תופורתה רגאמ .תואירבה דרשמ רתאב

,ןכ ומכ לבקל ןתינ

פדומ ןופלטל ונילא הינפב ס

09-9591111

,הכרבב

ןהכ רירפצ

נוממ חקור

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Prescribing Information

VELCADE® 3.5 mg (bortezomib) Powder for Solution for Injection

1

INDICATIONS AND USAGE

1.1

Multiple Myeloma

VELCADE

(bortezomib) for Injection is indicated for the treatment of patients with multiple

myeloma.

1.2

Mantle Cell Lymphoma

VELCADE

®

(bortezomib) for Injection is indicated for the treatment of patients with mantle cell

Lymphoma who have received at least one prior therapy.

VELCADE 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.

2

DOSAGE AND ADMINISTRATION

General Dosing Guidelines

The recommended starting dose of VELCADE is 1.3mg/m

. VELCADE may be administered

intravenously at a concentration of 1mg/mL, or subcutaneously at a concentration of 2.5 mg/mL

(see reconstitution /preparation for intravenous and subcutaneous administration section 2.10).

When administered intravenously, VELCADE is administered as a 3 to 5 second bolus

intravenous injection.

Because each route of administration has a different reconstituted concentration, caution

should be used when calculating the volume to be administered.

VELCADE IS FOR INTRAVENOUS OR SUBCUTANEOUS USE ONLY.

VELCADE

must not be administered by any other route. Intrathecal administration has resulted in death.

2.1 Dosage in Previously Untreated Multiple Myeloma

VELCADE (bortezomib) is administered in combination with oral melphalan and oral

prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, VELCADE is

administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, VELCADE is

administered once weekly (days 1, 8, 22 and 29).

At least 72 hours should elapse between consecutive doses of VELCADE

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43

Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Table 1 - Dose Regimen for Patients with Previously Untreated Multyple Myeloma

Twice Weekly VELCADE (Cycles 1-4)

Week

1

2

3

4

5

6

Velcade

(1.3 mg/m

rest

period

rest

period

Melphalan

(9 mg/m

Prednisone

(60 mg/m

rest

period

rest

period

Once Weekly VELCADE (Cycles 5-9 when used in combination with Melphalan and Prednisone)

Week

1

2

3

4

5

6

Velcade

(1.3 mg/m

rest

period

rest

period

Melphalan

(9 mg/m

Prednisone

(60 mg/m

rest

period

rest

period

2.2 Dose Modification Guidelines for Combination Therapy with VELCADE, Melphalan

and Prednisone

Prior to initiating any cycle of therapy with VELCADE in combination with melphalan and

prednisone:

Platelet count should be ≥70 x 10

/L and the absolute neutrophil count (ANC) should be ≥ 1.0 x

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

Table 2 – Dose Modifications During Cycles of combination VELCADE, Melphalan

and Prednisone therapy

Toxicity

Dose modification or delay

Hematological toxicity during a cycle:

If prolonged grade 4 neutropenia or

thrombocytopenia, or thrombocytopenia with

bleeding is observed in the previous cycle

Consider reduction of the Melphalan dose by

25% in the next cycle

If platelet count <30 x 10

/L or ANC< 0.75 x

/L on a VELCADE dosing day (other than

day 1)

Withhold Velcade dose

If several VELCADE doses in consecutive

Reduce VELCADE dose by 1 dose level (from

1.3 mg/m

to 1 mg/m

, or from 1 mg/m

to 0.7

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43

Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

cycles are withheld due to toxicity

mg/m

Grade > 3 non-hematological toxicities

Withhold VELCADE therapy until symptoms

of the toxicity have resolved to Grade 1 or

baseline. Then, VELCADE may be reinitiated

with one dose level reduction (from 1.3 mg/m

to 1 mg/m

, or from 1 mg/m

to 0.7 mg/m

For VELCADE-related neuropathic pain

and/or peripheral neuropathy, hold or modify

VELCADE as outlined in Table 5.

For information concerning melphalan and prednisone, see manufacturer’s prescribing

information.

For dose modifications guidelines for peripheral neuropathy see Management of peripheral neuropathy

section (2.6)

2.3

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

Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone

(VcR-CAP)

VELCADE 3.5mg powder for solution for injection is administered via intravenous injection at

the recommended dose of 1.3 mg/m

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 VELCADE cycles are recommended, although for patients with a response

first documented at cycle 6, two additional VELCADE cycles may be given.

At least 72 hours

should elapse between consecutive doses of VELCADE.

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

treatment cycle as intravenous infusions: rituximab at 375 mg/m

, cyclophosphamide at

750 mg/m

and doxorubicin at 50 mg/m

Prednisone is administered orally at 100 mg/m

on days 1, 2, 3, 4 and 5 of each VELCADE

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.

VELCADE treatment must be withheld at the onset of any ≥ Grade 3 VELCADE-related

non-haematological toxicities (excluding neuropathy) or ≥ Grade 3 haematological toxicities .

For dose adjustments, see Table 3 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.

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43

Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Table 3:

Dose adjustments during treatment for patients with previously untreated mantle cell

lymphoma

Toxicity

Posology modification or delay

Haematological toxicity

≥ Grade 3 neutropenia with fever,

Grade 4 neutropenia lasting more than

7 days, a platelet count < 10,000 cells/μL

VELCADE 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 VELCADE has been held, the

toxicity does not resolve, as defined

above, then VELCADE must be

discontinued.

If toxicity resolves i.e. patient has an

ANC ≥ 750 cells/μL and a platelet count

≥ 25,000 cells/μL, VELCADE may be

reinitiated at a dose reduced by one dose

level (from 1.3 mg/m

to 1 mg/m

, or

from 1 mg/m

to 0.7 mg/m

If platelet counts < 25,000 cells/μL. or

ANC < 750 cells/μL on a VELCADE

dosing day (other than Day 1 of each

cycle)

VELCADE therapy should be withheld

Grade ≥ 3 non-haematological toxicities

considered to be related to VELCADE

VELCADE therapy should be withheld until

symptoms of the toxicity have resolved to

Grade 2 or better. Then, VELCADE may be

reinitiated at a dose reduced by one dose

level (from 1.3 mg/m

to 1 mg/m

, or from

1 mg/m

to 0.7 mg/m

). For

VELCADE-related neuropathic pain and/or

peripheral neuropathy, hold and/or modify

VELCADE as outlined in Table 1.

In addition, when VELCADE 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.

2.4 Dosage in Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma

VELCADE (1.3 mg/m

/dose) is administered twice weekly for 2 weeks (Days 1, 4, 8, and 11)

followed by a 10-day rest period (Days 12-21).

For extended therapy of more than 8 cycles, VELCADE may be administered on the standard

schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for 4

weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35) [see Clinical

Studies section (13) for a description of dose administration during the trials]. At least 72 hours

should elapse between consecutive doses of VELCADE.

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

2.5 Dose Modification Guidelines for Relapsed Multiple Myeloma and Relapsed Mantle

Cell Lymphoma

VELCADE therapy should be withheld at the onset of any Grade 3 non-hematological or Grade

4 hematological toxicities excluding neuropathy as discussed below [

see Warnings and

Precautions (5)

]. Once the symptoms of the toxicity have resolved, VELCADE therapy may be

reinitiated at a 25% reduced dose (1.3 mg/m

/dose reduced to 1 mg/m

/dose; 1 mg/m

/dose

reduced to 0.7 mg/m

/dose).

For dose modifications guidelines for peripheral neuropathy see Management of peripheral

neuropathy section (2.6)

2.6 Dose Modifications of Peripheral Neuropathy

Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high

risk of peripheral neuropathy. Patients with pre-existing severe neuropathy should be treated

with VELCADE only after careful risk-benefit assessment.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may

require a decrease in the dose and/or a less dose-intense schedule.

For dose or schedule modification guidelines for patients who experience VELCADE-related

neuropathic pain and/or peripheral neuropathy see Table 4.

Table 4 – Recommended Dose Modification for VELCADE related Neuropathic Pain and/or

Peripheral Sensory or Motor Neuropathy

Severity of Peripheral Neuropathy Signs and

Symptoms*

Modification of Dose and Regimen

Grade 1 (asymptomatic ; loss of deep tendon

reflexes or paresthesia) without pain or loss of

function

No action

Grade 1 with pain or Grade 2 (moderate symptoms;

limiting Instrumental Activities of Daily Living

(ADL))**

Reduce VELCADE to 1 mg/m

Change VELCADE treatment schedule to

1.3 mg/m

once per week

Grade 2 with pain or Grade 3 (severe symptoms;

limiting self care ADL *** )

Withhold VELCADE therapy until toxicity

resolves. When toxicity resolves reinitiate with a

reduced dose of VELCADE at 0.7 mg/m

once per

week.

Grade 4 (life threatening consequences; urgent

intervention indicated )

Discontinue VELCADE

*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

medications, and not bedridden

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

2.7 Dosage in Patients with Hepatic Impairment

Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated

per the recommended VELCADE dose. Patients with moderate or severe hepatic impairment should

be started on VELCADE at a reduced dose of 0.7 mg/m

per injection during the first cycle, and a

subsequent dose escalation to 1.0 mg/m

or further dose reduction to 0.5 mg/m

may be considered

based on patient tolerance (see

Table 5)

[see Warnings and Precautions (5.10), Use in Specific

Populations (8.6) and Clinical Pharmacology (11.3)]

Table 5: Recommended Starting Dose Modification for VELCADE in Patients with Hepatic

Impairment

Bilirubin Level

SGOT (AST)

Levels

Modification of Starting dose

Mild

1.0x ULN

>

None

>

1.0x

1.5x ULN

None

Moderate

>

1.5x

3x ULN

Reduce VELCADE to 0.7 mg/m

the first cycle. Consider dose

escalation to 1.0 mg/m

or further

dose reduction to 0.5 mg/m

subsequent cycles based on patient

tolerability.

Severe

>

3x ULN

Abbreviations: SGOT = serum glutamic oxaloacetic transaminase;

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

2.8 Administration Precautions

The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution

should be used in calculating the dose to prevent overdose. (see reconstitution /preparation for

intravenous and subcutaneous administration section 2.9).

VELCADE is authorized for intravenous or subcutaneous use only. Intrathecal administration

has resulted in death.

When administered subcutaneously, sites for each injection (thigh or abdomen) should be

rotated. New injections should be given at least one inch from an old site and never into areas

where the site is tender, bruised, erythematous, or indurated.

If local injection site reactions occur following VELCADE administration subcutaneously, a less

concentrated VELCADE solution (1 mg/mL instead of 2.5 mg/mL ) may be administered

subcutaneously [see reconstitution /preparation for intravenous and subcutaneous administration

section 2.9) and follow reconstitution instructions for 1 mg/mL]. Alternatively, the intravenous

route of administration should be considered [see reconstitution /preparation for intravenous and

subcutaneous administration section 2.9].

VELCADE is an antineoplastic. Procedures for proper handling and disposal should be

considered.[ See

How Supplied/Storage and Handling (14)

2.9 Reconstitution/Preparation for Intravenous and Subcutaneous Administration

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Proper aseptic technique should be used. Reconstitute

only with 0.9% sodium chloride.

reconstituted product should be a clear and colorless solution.

Different volumes of 0.9% sodium chloride are used to reconstitute the product for the different

routes of administration. The reconstituted concentration of bortezomib for subcutaneous

administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for

intravenous administration (1 mg/mL).

Because each route of administration has a different

reconstituted concentration, caution should be used when calculating the volume to be

administered

(see Administration Precautions section 2.8).

For each 3.5 mg single-use vial of bortezomib reconstitute with the following volume of 0.9%

sodium chloride based on route of administration (Table 6):

Table 6: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous

Administration

Route of

administration

Bortezomib

(mg/vial)

Diluent

(0.9% Sodium

Chloride)

Final Bortezomib

concentration

(mg/mL)

Intravenous

3.5 mg

3.5 mL

1 mg/mL

Subcutaneous

3.5 mg

1.4 mL

2.5 mg/mL

Dose must be individualized to prevent overdose. After determining patient body surface area

(BSA) in square meters, use the following equations to calculate the total volume (

mL) of

reconstituted VELCADE to be administered:

Intravenous Administration [1 mg/mL concentration]

VELCADE dose (mg/m

) x patient BSA (m

_____________________________________ = Total VELCADE volume (mL) to be administered

1 mg/mL

Subcutaneous Administration [2.5 mg/mL concentration]

VELCADE dose (mg/m

) x patient BSA (m

_____________________________________ = Total VELCADE volume (mL) to be administered

2.5 mg/mL

Parenteral drug products should be inspected visually for particulate matter and discoloration

prior to administration whenever solution and container permit. If any discoloration or

particulate matter is observed, the reconstituted product should not be used.

Stability

: Unopened vials of VELCADE are stable until the date indicated on the package when

stored in the original package protected from light. Do not store above 30°C.

VELCADE contains no antimicrobial preservative.

The reconstituted solution should be used immediately after preparation. If the reconstituted

solution is not used immediately, in-use storage times and conditions prior to use are the

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

responsibility of the user. However, the chemical and physical in-use stability of the

reconstituted solution has been demonstrated for 8 hours at 25 °C stored in the original vial

and/or a syringe prior to administration.

The total storage time for the reconstituted medicinal product should not exceed 8 hours prior to

administration.

3 DOSAGE FORMS AND STRENGTHS

Each single use vial of VELCADE contains 3.5 mg of bortezomib as a sterile lyophilized white

to off-white powder.

4 CONTRAINDICATIONS

VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to

bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions [see adverse

events (6)].

VELCADE is contraindicated in acute diffuse infiltrative pulmonary and pericardial disease.

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

insert for additional contraindications.

VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with

intrathecal administration of VELCADE.

DO NOT ADMINISTER VELCDE

INTRATHECALLY.

5 WARNINGS AND PRECAUTIONS

VELCADE should be administered under the supervision of a physician experienced in the use

of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during

treatment with VELCADE.

There have been fatal cases of inadvertent itrathecal administration of VELCADE.

VELCADE is authorized for IV and subcutaneous use only.

DO NOT ADMINISTER

VELCADE INTRATHECALLY.

5.1 Peripheral Neuropathy

VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However,

cases of severe sensory and motor peripheral neuropathy have been reported. Patients with

preexisting symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of

peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3)

during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy,

such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic

pain or weakness. In the phase 3 relapsed multiple myeloma trial comparing VELCADE

subcutaneous versus intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was

24% for subcutaneous and 39% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6%

of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment

group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at

high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may

require a decrease in the dose and/or a less dose-intense schedule [see

Dosage and

Administration (2)

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

In the VELCADE versus dexamethasone phase 3 relapsed multiple myeloma study,

improvement in

or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral

neuropathy

following dose adjustment or interruption.

Improvement in or resolution of peripheral

neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who

had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies [see Adverse

Events (6)]. The long-term outcome of peripheral neuropathy has not been studied in mantle cell

lymphoma.

5.2 Hypotension

The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8 %. These

events are observed throughout therapy. Caution should be used when treating patients with a

history of syncope, patients receiving medications known to be associated with hypotension, and

patients who are dehydrated. Management of orthostatic/postural hypotension may include

adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids

and/or sympathomimetics

. [see Adverse Events

6)]

5.3 Cardiac Toxicity

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

ventricular ejection fraction have

occurred during VELCADE therapy

, including reports in

patients with no risk factors for decreased left ventricular ejection fraction. 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.

In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any

treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone

groups, respectively. The incidence of

adverse events suggestive of heart failure

(acute pulmonary

edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was

1% for each individual event in the VELCADE group. In the dexamethasone group the incidence

was ≤ 1% for cardiac failure and congestive cardiac failure; there were no reported events of acute

pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-

interval prolongation in clinical studies; causality has not been established.

5.4 Pulmonary Toxicity

There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology

such as pneumonitis, interstitial pneumonia, lung infiltration, lung and Acute Respiratory

Distress Syndrome (ARDS) in patients receiving VELCADE. 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 a clinical trial, the first two patients given high-dose cytarabine (2g/m

per day) by continuous

infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia 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/m

per day) by

continuous infusion over 24 hours is not recommended.

There have been reports of pulmonary hypertension associated with VELCADE administration

in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms,

consider interrupting VELCADE

until a prompt and comprehensive diagnostic evaluation is conducted.

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

5.5 Posterior Reversible encephalopathy Syndrome (PRES)

Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior

Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a

rare, reversible, neurological disorder which can present with seizure, hypertension, headache,

lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging,

preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients

developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients

previously experiencing PRES is not known.

5.6 Gastrointestinal Toxicity

VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting [

see Adverse

Events (6)]

sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration.

Interrupt VELCADE for severe symptoms.

5.7 Thrombocytopenia/Neutropenia

VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern

with nadirs occurring following the last dose of each cycle and typically recovering prior to

initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and

recovery remain consistent

in the studies of multiple myeloma and mantle cell lymphoma, with no

evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied.

Monitor complete blood counts (CBC) frequently during treatment with VELCADE. Measure

platelet counts prior to each dose of VELCADE. Adjust dose/schedule for thrombocytopenia [

see

Tables 2 and 3 and Dosage and Administration (2.5)

]. Gastrointestinal and intracerebral hemorrhage

has occurred during thrombocytopenia in association with VELCADE. Support with transfusions and

supportive care, according to published guidelines.

In the single-agent, relapsed multiple myeloma study of VELCADE versus dexamethasone, the mean

platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia

related to pretreatment platelet count is shown in Table 7. The incidence of bleeding (≥ Grade 3) was

2% on the VELCADE arm and was < 1% in the dexamethasone arm.

Table 7 Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the

Relapsed Multiple Myeloma Study

of VELCADE vs dexamethasone

Pretreatment

Platelet Count*

Number of

Patients (N=331)**

Number (%) of

Patients with Platelet

Count <10,000/μL

Number (%) of

Patients with Platelet

Count 10,000-

25,000/μL

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43

Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

≥75,000/μL

8 (3%)

36 (12%)

≥50,000/μL-

2 (14%)

11 (79%)

<75,000/μL

≥10,000/μL-

1 (14%)

5 (71%)

<50,000/μL

* A baseline platelet count of 50,000/μL was required for study eligibility.

**

Data were missing at baseline for 1 patient.

In the combination study of VELCADE with rituximab, cyclophosphamide, doxorubicin and

prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of

thrombocytopenia (≥ Grade 4) was 32% versus 1% for the rituximab, cyclophosphamide,

doxorubicin, vincristine, and prednisone (R-CHOP) arm as shown in Table 11. The incidence of

bleeding events (≥ Grade 3) was 1% in the VcR-CAP arm (3 patients) and was < 1% in the R-

CHOP arm (1 patient).

Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the

patients in the R-CHOP arm.

The incidence of neutropenia (≥ Grade 4) was 70% in the VcR-CAP arm and was 52% in the R-

CHOP arm. The incidence of febrile neutropenia (≥ Grade 4) was 5% in the VcR-CAP arm and

was 6% in the R-CHOP arm. Myeloid growth factor support was provided at a rate of 78% in

the VcR-CAP arm and 61% in the R-CHOP arm.

5.8 Tumor Lysis Syndrome

Because VELCADE is a cytotoxic agent and can rapidly kill malignant

plasma

cells and MCL

cells, the complications of tumor lysis syndrome may occur.

Tumor lysis syndrome has been

reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high

tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

5

9 Hepatic Toxicity

Cases of acute liver failure have been reported in patients receiving multiple concomitant

medications and with serious underlying medical conditions. Other reported hepatic events

include increases in liver enzymes, hyperbilirubinemia, and hepatitis.

Interrupt VELCADE

therapy to assess reversibility.

There is limited re-challenge information in these patients

5.10 Hepatic Impairment:

Bortezomib is metabolized by liver enzymes

.

Bortezomib exposure is increased in patients

with

moderate or severe

hepatic impairment

these patients should be

treated with VELCADE at

reduced starting doses and closely monitored for toxicities.

[

see Dosage and Administration (2.7),

Use in Specific Populations(8.6) and Clinical Pharmacology (11.3)]

5.11

Embryo-fetal Risk

Women of reproductive potential should avoid becoming pregnant while being treated with

VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

times the clinical dose of 1.3 mg/m

based on body surface area caused post-implantation loss and a

decreased number of live fetuses [

see Use in Specific Populations (8.1)

5.12 Herpes zoster virus reactivation

Antiviral prophylaxis should be considered in patients being treated with VELCADE.

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

VELCADE+Melphalan+Prednisone compared with Melphalan+Prednisone (14% versus 4%

respectively).

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

VcR-CAP arm and 1.2% in the R-CHOP arm.

5.13 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 VELCADE. Patients diagnosed with PML had

prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12

months of their first dose of VELCADE. 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 VELCADE if PML is diagnosed.

5.14 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

5.15 Renal impairment

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

should be monitored closely .

5.16 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 .

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

hypoglycemics .

5.17 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.

5.18 Hepatitis B Virus (HBV) reactivation and infection

When rituximab is used in combination with VELCADE, 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 VELCADE.

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

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

rituximab for more information.

6. ADVERSE EVENTS

The following adverse events are also discussed in other sections of the labeling:

Peripheral Neuropathy

[see Warnings and Precautions (5.1) ; Dosage and

Administration(2.6) (Table 4)]

Hypotension

[see Warnings and Precautions (5.2) ]

Cardiac Toxicity

[see Warnings and Precautions (5.3) ]

Pulmonary Toxicity

[see Warnings and Precautions (5.4) ]

Posterior Reversible Encephalopathy Syndrome (PRES)

[see Warnings and Precautions

(5.5) ]

Gastrointestinal Toxicity

[see Warnings and Precautions (5.6)]

Thrombocytopenia/Neutropenia

[see Warnings and Precautions (5.7)]

Tumor Lysis Syndrome

[see Warnings and Precautions (5.8)]

Hepatic Toxicity

[see Warnings and Precautions (5.9)]

6.1 Clinical Trials Safety Experience

Because clinical trials are conducted under widely varying conditions, adverse events rates

observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials

of another drug and may not reflect the rates observed in clinical practice.

Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma:

Table 8

describes safety data from 340 patients with previously untreated multiple myeloma who

received VELCADE (1.3 mg/m

) administered intravenously in combination with melphalan (9

mg/m

) and prednisone (60 mg/m

) in a prospective randomized study.

The safety profile of VELCADE in combination with melphalan/prednisone is consistent with

the known safety profiles of both VELCADE and melphalan/prednisone.

Table 8- Most Commonly Reported Adverse Events (

10% in VELCADE IV, Melphalan and

Prednisone arm) with Grades 3 and > 4 Intensity in the previously untreated

Multiple Myeloma Study

VELCADE, Melphalan and

Prednisone

Melphalan and Prednisone

(n=340)

(n=337)

System Organ Class

Total

Toxicity Grade, n (%)

Total

Toxicity Grade, n (%)

Preferred Term

n (%)

≥4

n (%)

≥4

Blood and Lymphatic System Disorders

Thrombocytopenia

164 ( 48) 60 ( 18)

57 ( 17)

140 ( 42) 48 ( 14)

39 ( 12)

Neutropenia

160 ( 47) 101 ( 30)

33 ( 10)

143 ( 42) 77 ( 23)

42 ( 12)

Anaemia

109 ( 32) 41 ( 12)

4 ( 1)

156 ( 46) 61 ( 18)

18 ( 5)

Leukopenia

108 ( 32) 64 ( 19)

8 ( 2)

93 ( 28) 53 ( 16)

11 ( 3)

Lymphopenia

78 ( 23) 46 ( 14)

17 ( 5)

51 ( 15) 26 ( 8)

7 ( 2)

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VELCADE, Melphalan and

Prednisone

Melphalan and Prednisone

(n=340)

(n=337)

System Organ Class

Total

Toxicity Grade, n (%)

Total

Toxicity Grade, n (%)

Preferred Term

n (%)

≥4

n (%)

≥4

Gastrointestinal Disorders

Nausea

134 ( 39) 10 ( 3)

70 ( 21) 1 ( <1)

Diarrhoea

119 ( 35) 19 ( 6)

2 ( 1)

20 ( 6) 1 ( <1)

Vomiting

87 ( 26) 13 ( 4)

41 ( 12) 2 ( 1)

Constipation

77 ( 23) 2 ( 1)

14 ( 4) 0

Abdominal Pain Upper

34 ( 10) 1 ( <1)

20 ( 6) 0

Nervous System Disorders

Peripheral Neuropathy

156 ( 46) 42 ( 12)

2 ( 1)

4 ( 1) 0

Neuralgia

117 ( 34) 27 ( 8)

2 ( 1)

<1)

Paraesthesia

42 ( 12) 6 ( 2)

4 ( 1) 0

General Disorders and Administration Site

Conditions

Fatigue

85 ( 25) 19 ( 6)

2 ( 1)

48 ( 14) 4 ( 1)

Asthenia

54 ( 16) 18 ( 5)

23 ( 7) 3 ( 1)

Pyrexia

53 ( 16) 4 ( 1)

19 ( 6) 1 ( <1)

1 ( <1)

Infections and Infestations

Herpes Zoster

39 ( 11) 11 ( 3)

9 ( 3) 4 ( 1)

Metabolism and Nutrition Disorders

Anorexia

64 ( 19) 6 ( 2)

19 ( 6) 0

Skin and Subcutaneous Tissue Disorders

Rash

38 ( 11) 2 ( 1)

7 ( 2) 0

Psychiatric Disorders

Insomnia

35 ( 10) 1 ( <1) 0

21 ( 6) 0

Represents High Level Term Peripheral Neuropathies NEC

Relapsed Multiple Myeloma Randomized Study of VELCADE vs. Dexamethasone

The safety data described below and in Table 10 reflect exposure to either VELCADE (n=331)

or dexamethasone (n=332) in a study of patients with multiple myeloma. VELCADE was

administered intravenously at doses of 1.3 mg/m

twice weekly for 2 out of 3 weeks (21 day

cycle). After eight 21-day cycles patients continued therapy for three 35-day cycles on a weekly

schedule. Duration of treatment was up to 11 cycles (9 months) with a median duration of 6

cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and 1

to 3 prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low

as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall

frequency of adverse events was similar in men and women, and in patients <65 and ≥65 years of

age. Most patients were Caucasian.

[see Clinical Studies (13.1)]

Among the 331 VELCADE treated patients, the most commonly reported (>20%) adverse events

overall were

nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies NEC (35%),

thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most

commonly reported (> 20%) adverse event reported among the 332 patients in the dexamethasone

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group was fatigue (25%). Eight percent (8%) of patients in the VELCADE-treated arm experienced a

Grade 4 adverse event; the most common events were thrombocytopenia (4%) and neutropenia (2%).

Nine percent (9%) of dexamethasonetreated patients experienced a Grade 4 adverse event. All

individual dexamethasone-related Grade 4 adverse events were less than 1%.

Serious Adverse Events (SAEs) and Events Leading to Treatment Discontinuation in the

Relapsed Multiple Myeloma Study of VELCADE vs. Dexamethasone

Serious adverse events are defined as any event that results in death, is life-threatening, requires

hospitalization or prolongs a current hospitalization, results in a significant disability, or is

deemed to be an important medical event.

A total of 80 (24%) patients from the VELCADE treatment arm experienced a serious adverse event

during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported

serious adverse events in the VELCADE treatment arm were diarrhea (3%), dehydration, herpes

zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone

treatment group, the most commonly reported serious adverse events were pneumonia (4%),

hyperglycemia (3%), pyrexia, and psychotic disorder (2% each).

A total of 145 patients, including 84 (25%) of 331 patients in the VELCADE treatment group

and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from

treatment due to adverse events.

Among the 331 VELCADE treated patients, the most commonly reported adverse event leading to

discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone

group, the most commonly reported adverse events leading to treatment discontinuation were

psychotic disorder and hyperglycemia (2% each).

Four deaths were considered to be VELCADE related in this relapsed multiple myeloma study: 1

case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac

arrest. Four deaths were considered dexamethasone-related: 2 cases of sepsis, 1 case of

bacterial meningitis, and 1 case of sudden death at home.

Most Commonly Reported Adverse Events in the Relapsed Multiple Myeloma Study of

VELCADE vs. Dexamethasone

The most common adverse events from the relapsed multiple myeloma study are shown in

Table 9. All adverse events with incidence

10% in the VELCADE arm are included.

Table 9: Most Commonly Reported Adverse Events (

10% in VELCADE arm),

with Grades 3 and 4 Intensity in Relapsed Multiple Myeloma Study of VELCADE vs.

Dexamethasone (N=663)

VELCADE

N=331

Dexamethasone

N=332

Preferred Term

Grade 3

Grade 4

Grade 3

Grade 4

Adverse events

324 (98)

193 (58)

28 (8)

297 (89)

110 (33)

29 (9)

Nausea

172 (52)

8 (2)

31 (9)

Diarrhea NOS

171 (52)

22 (7)

36 (11)

2 (< 1)

Fatigue

130 (39)

15 (5)

82 (25)

8 (2)

Peripheral neuropathies

115 (35)

23 (7)

2 (< 1)

14 (4)

1 (< 1)

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Thrombocytopenia

109 (33)

80 (24)

12 (4)

11 (3)

5 (2)

1 (< 1)

Constipation

99 (30)

6 (2)

27 (8)

1 (<1)

Vomiting NOS

96 (29)

8 (2)

10 (3)

1 (<1)

Anorexia

68 (21)

8(2)

8 (2)

1 (<1)

Pyrexia

66 (20)

2(<1)

21 (6)

3 (<1)

1 (<1)

Paresthesia

64 (19)

5(2)

24 (7)

Anemia NOS

63 (19)

20(6)

1 (<1)

21 (6)

8(2)

Headache NOS

62 (19)

3(<1)

23 (7)

1 (<1)

Neutropenia

58 (18)

37(11)

8 (2)

1 (<1)

1 (<1)

Rash NOS

43 (13)

3(<1)

7 (2)

Appetite decreased

36 (11)

12 (4)

Dyspnea NOS

35 (11)

11(3)

1 (<1)

37 (11)

7 (2)

1 (<1)

Abdominal pain NOS

35 (11)

5(2)

7 (2)

Weakness

34 (10)

10(3)

28 (8)

8 (2)

Based on High Level Term

Safety Experience from the Phase 2 Open-Label Extension Study in Relapsed Multiple

Myeloma

In the phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities

were observed with prolonged VELCADE treatment. These patients were treated for a total of

5.3 to 23 months, including time on VELCADE in the prior VELCADE study.

[see Clinical

Studies (13)]

Safety Experience from the Phase 3 Open-Label Study of VELCADE Subcutanous vs.

Intravenous in Relapsed MultipleMyeloma

The safety and efficacy of VELCADE administered subcutaneously were evaluated in one Phase 3

study at the recommended dose of 1.3 mg/m

. This was a randomized, comparative study of

VELCADE subcutaneous versus intravenous in 222 patients with relapsed multiple myeloma. The

safety data described below and in Table 10 reflect exposure to either VELCADE subcutaneous

(n=147) or VELCADE intravenous (n=74) [see Clinical Studies (13.1)].

Table 10: Most Commonly Reported Adverse Events (

10%), with Grade 3 and ≥ 4 Intensity

in the Relapsed Multiple Myeloma Study (N=221) of VELCADE Subcutaneous versus

Intravenous

Subcutaneous

Intravenous

(N=147)

(N=74)

System Organ Class

Total

Toxicity Grade, n (%)

Total

Toxicity Grade, n (%)

Preferred Term

n (%)

≥ 4

n (%)

≥ 4

Blood and lymphatic system disorders

Anemia

28 (19)

8 (5)

17 (23)

3 (4)

Leukopenia

26 (18)

8 (5)

15 (20)

4 (5)

1 (1)

Neutropenia

34 (23)

15 (10)

4 (3)

20 (27)

10 (14)

3 (4)

Thrombocytopenia

44 (30)

7 (5)

5 (3)

25 (34)

7 (9)

5 (7)

Gastrointestinal disorders

Diarrhea

28 (19)

1 (1)

21 (28)

3 (4)

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Nausea

24 (16)

10 (14)

Vomiting

13 (9)

3 (2)

8 (11)

General disorders and administration site

conditions

Asthenia

10 (7)

1 (1)

12 (16)

4 (5)

Fatigue

11 (7)

3 (2)

11 (15)

3 (4)

Pyrexia

18 (12)

6 (8)

Nervous system disorders

Neuralgia

34 (23)

5 (3)

17 (23)

7 (9)

Peripheral neuropathies NEC

55 (37)

8 (5)

1 (1)

37 (50)

10 (14)

1 (1)

Note: Safety population: 147 patients in the subcutaneous treatment group and 74 patients in the intravenous treatment group who

received at least 1 dose of study medication

Represents MedDRA High Level Term.

In general, safety data were similar for the subcutaneous and intravenous treatment groups.

Differences were observed in the rates of some Grade ≥ 3 adverse events. Differences of ≥ 5% were

reported in neuralgia (3% subcutaneous versus 9% intravenous), peripheral neuropathies NEC (6%

subcutaneous versus 15% intravenous), neutropenia (13% subcutaneous versus 18% intravenous),

and thrombocytopenia (8% subcutaneous versus 16% intravenous).

A local event was reported in 6% of patients in the subcutaneous group, mostly redness. Only 2 (1%)

patients were reported as having severe events, 1 case of pruritus and 1 case of redness. Local events

led to reduction in injection concentration in one patient and drug discontinuation in one patient.

Local events resolved in a median of 6 days.

Dose reductions occurred due to adverse events in 31% of patients in the subcutaneous treatment

group compared with 43% of the intravenously-treated patients. The most common adverse events

leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous

treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the

subcutaneous treatment group compared with 19% in the intravenous treatment group).

Serious Adverse Events and Adverse Events Leading to Treatment Discontinuation in the

Relapsed Multiple Myeloma Study of VELCADE Subcutaneous versus Intravenous

The incidence of serious adverse events was similar for the subcutaneous treatment group (20%) and

the intravenous treatment group (19%). The most commonly reported serious adverse events in the

subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment

group, the most commonly reported serious adverse events were pneumonia, diarrhea, and peripheral

sensory neuropathy (3% each).

In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an

adverse event compared with 17 patients (23%) in the intravenous treatment group

.

Among the 147

subcutaneously-treated patients, the most commonly reported adverse events leading to

discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients

in the intravenous treatment group, the most commonly reported adverse events leading to treatment

discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%).

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Two patients (1%) in the subcutaneous treatment group and 1 (1%) patient in the intravenous

treatment group died due to an adverse event during treatment. In the subcutaneous group the causes

of death were one case of pneumonia and one case of sudden death. In the intravenous group the

cause of death was coronary artery insufficiency.

Safety Experience from the Clinical Trial in Patients with Previously Untreated Mantle Cell

Lymphoma

Table 11 describes safety data from 240 patients with previously untreated mantle cell

lymphoma who received VELCADE (1.3 mg/m

) administered intravenously in combination

with rituximab (375 mg/m

), cyclophosphamide (750 mg/m

), doxorubicin (50 mg/m

), and

prednisone (100 mg/m

) (VcR-CAP) in a prospective randomized study.

Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the

comparator (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP])

arm, including the predominant preferred term of pneumonia (VcR-CAP 8% versus R-CHOP

5%).

Table 11: Most Commonly Reported Adverse Reactions (≥ 5%)

with Grades 3 and ≥ 4 Intensity in the Previously Untreated Mantle Cell Lymphoma Study

VcR-CAP

n=240

R-CHOP

n=242

System Organ Class

Preferred Term

n (%)

Toxicity

Grade 3

n (%)

Toxicity

Grade ≥4

n (%)

n (%)

Toxicity

Grade 3

n (%)

Toxicity

Grade ≥4

n (%)

Blood and lymphatic system

disorders

Neutropenia

209 (87)

32 (13)

168 (70)

172 (71)

31 (13)

125 (52)

Leukopenia

116 (48)

34 (14)

69 (29)

87 (36)

39 (16)

27 (11)

Anemia

106 (44)

27 (11)

4 (2)

71 (29)

23 (10)

4 (2)

Thrombocytopenia

172 (72)

59 (25)

76 (32)

42 (17)

9 (4)

3 (1)

Febrile neutropenia

41 (17)

24 (10)

12 (5)

33 (14)

17 (7)

15 (6)

Lymphopenia

68 (28)

25 (10)

36 (15)

28 (12)

15 (6)

2 (1)

Nervous system disorders

Peripheral neuropathy

71 (30)

17 (7)

1 (< 1)

65 (27)

10 (4)

Hypoesthesia

14 (6)

3 (1)

13 (5)

Paresthesia

14 (6)

2 (1)

11 (5)

Neuralgia

25 (10)

9 (4)

1 (< 1)

General disorders and

administration site conditions

Fatigue

43 (18)

11 (5)

1 (< 1)

38 (16)

5 (2)

Pyrexia

48 (20)

7 (3)

23 (10)

5 (2)

Asthenia

29 (12)

4 (2)

1 (< 1)

18 (7)

1 (< 1)

Edema peripheral

16 (7)

1 (< 1)

13 (5)

Gastrointestinal disorders

Nausea

54 (23)

1 (< 1)

28 (12)

Constipation

42 (18)

1 (< 1)

22 (9)

2 (1)

Stomatitis

20 (8)

2 (1)

19 (8)

1 (< 1)

Diarrhea

59 (25)

11 (5)

11 (5)

3 (1)

1 (< 1)

Vomiting

24 (10)

1 (< 1)

8 (3)

Abdominal distension

13 (5)

4 (2)

Infections and infestations

Pneumonia

20 (8)

8 (3)

5 (2)

11 (5)

5 (2)

3 (1)

Skin and subcutaneous tissue

disorders

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

VcR-CAP

n=240

R-CHOP

n=242

System Organ Class

Preferred Term

n (%)

Toxicity

Grade 3

n (%)

Toxicity

Grade ≥4

n (%)

n (%)

Toxicity

Grade 3

n (%)

Toxicity

Grade ≥4

n (%)

Alopecia

31 (13)

1 (< 1)

1 (< 1)

33 (14)

4 (2)

Metabolism and nutrition

disorders

Hyperglycemia

10 (4)

1 (< 1)

17 (7)

10 (4)

Decreased appetite

36 (15)

2 (1)

15 (6)

1 (< 1)

Vascular disorders

Hypertension

15 (6)

1 (< 1)

3 (1)

Psychiatric disorders

Insomnia

16 (7)

1 (< 1)

8 (3)

Key: R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone;

VcR-CAP=VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone.

Represents High Level Term Peripheral Neuropathies NEC

The incidence of herpes zoster reactivation was 4.6% in the VcR-CAP arm and 0.8% in the R-

CHOP arm. Antiviral prophylaxis was mandated by protocol amendment.

The incidences of Grade ≥ 3 bleeding events were similar between the 2 arms (3 patients in the

VcR-CAP arm and 1 patient in the R-CHOP arm). All of the Grade ≥ 3 bleeding events resolved

without sequelae in the VcR-CAP arm.

Adverse reactions leading to discontinuation occurred in 8% of patients in VcR-CAP group and

6% of patients in R-CHOP group. In the VcR-CAP group, the most commonly reported adverse

reaction leading to discontinuation was peripheral sensory neuropathy (1%; 3 patients). The

most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was

febrile neutropenia (< 1%; 2 patients).

Integrated Summary of Safety (Multiple Myeloma and Mantle Cell Lymphoma)

Safety data from phase 2 and 3 studies of single agent VELCADE 1.3 mg/m

/dose twice weekly

for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple

myeloma (N=1008) and previously treated mantle cell lymphoma (N=155) were integrated and

tabulated. This analysis does not include data from phase 3 open label study of VELCADE

subcutaneous vs. intravenous in relapsed multiple myeloma. In the integrated studies, the safety

profile of VELCADE was similar in patients with multiple myeloma and mantle cell

lymphoma.

[see Clinical Studies (13)]

In the integrated analysis, the most commonly reported (> 20%) adverse events were nausea (49%),

diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral

neuropathies NEC (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and

pyrexia (21%). Eleven percent (11%) of patients experienced at least 1 episode of ≥ Grade 4 toxicity,

most commonly thrombocytopenia (4%) and neutropenia (2%).

In the Phase 2 relapsed multiple myeloma clinical trials of VELCADE administered intravenously,

local skin irritation was reported in 5% of patients, but extravasation of VELCADE was not

associated with tissue damage.

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Serious Adverse Events (SAEs) and Events Leading to Treatment Discontinuation in the

Integrated Summary of Safety

A total of 26% of patients experienced a serious adverse event during the studies. The most

commonly reported serious adverse events included diarrhea, vomiting and pyrexia (3% each),

nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral

neuropathies NEC, and herpes zoster (1% each).

Adverse events leading to discontinuation occurred in 22% of patients. The reasons for

discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea

(2% each).

In total, 2% of the patients died and the cause of death was considered by the investigator to be

possibly related to study drug: including reports of cardiac arrest, congestive heart failure,

respiratory failure, renal failure, pneumonia and sepsis.

Most Commonly Reported Adverse Events in the Integrated Summary of Safety

The most common adverse events are shown in Table 12. All adverse events occurring at

are included. In the absence of a randomized comparator arm, it is often not possible to

distinguish between adverse events that are drug-caused and those that reflect the patient’s

underlying disease. Please see the discussion of specific adverse events that follows.

Table 12: Most Commonly Reported (≥10% Overall) Adverse Events

in Integrated Analyses of Relapsed Multiple Myeloma and Mantle Cell Lymphoma Studies

using the 1.3 mg/m

2

Dose (N=1163)

All Patients

N=1163

Multiple Myeloma

N=1008

Mantle Cell Lymphoma

N=155

≥Grade 3

≥Grade 3

≥Grade 3

Preferred Term

Nausea

567 (49)

36 (3)

511 (51)

32 (3)

56 (36)

4 (3)

Diarrhea NOS

530 (46)

83 (7)

470 (47)

72 (7)

60 (39)

11 (7)

Fatigue

477 (41)

86 (7)

396 (39)

71 (7)

81 (52)

15 (10)

Peripheral

neuropathies NEC

443 (38)

129 (11)

359 (36)

110 (11)

84 (54)

19 (12)

Thrombocytopenia

369 (32)

295 (25)

344 (34)

283 (28)

25 (16)

12 (8)

Vomiting NOS

321 (28)

44 (4)

286 (28)

40 (4)

35 (23)

4 (3)

Constipation

296 (25)

17 (1)

244 (24)

14 (1)

52 (34)

3 (2)

Pyrexia

249 (21)

16 (1)

233 (23)

15 (1)

16 (10)

1 (< 1)

Anorexia

227 (20)

19 (2)

205 (20)

16 (2)

22 (14)

3 (2)

Anemia NOS

209 (18)

65 (6)

190 (19)

63 (6)

19 (12)

2 (1)

Headache NOS

175 (15)

8 (< 1)

160 (16)

8 (< 1)

15 (10)

Neutropenia

172 (15)

121 (10)

164 (16)

117 (12)

8 (5)

4 (3)

Rash NOS

156 (13)

8 (< 1)

120 (12)

4 (< 1)

36 (23)

4 (3)

Paresthesia

147 (13)

9 (< 1)

136 (13)

8 (< 1)

11 (7)

1 (< 1)

Dizziness (excl

vertigo)

129 (11)

13 (1)

101 (10)

9 (< 1)

28 (18)

4 (3)

Weakness

124 (11)

31 (3)

106 (11)

28 (3)

18 (12)

3 (2)

Based on High Level Term

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Description of Selected Adverse Events from the Phase 2 and 3 Relapsed Multiple Myeloma

and Phase 2 Mantle Cell Lymphoma Studies

Gastrointestinal Events

A total of 75% of patients experienced at least one GI disorder. The most common GI disorders

included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other GI disorders

included dyspepsia and dysgeusia. Grade 3 GI events occurred in 14% of patients; ≥Grade 4

events were rare (≤1%). GI events were considered serious in 7% of patients. Four percent

(4%) of patients discontinued due to a GI event. Nausea was reported more often in patients

with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%).

Thrombocytopenia

Across the studies, VELCADE associated thrombocytopenia was characterized by a decrease in

platelet count during the dosing period (days 1 to 11) and a return toward baseline during the 10-

day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32%

of patients. Thrombocytopenia was Grade 3 in 22%,

Grade 4 in 4%, and serious in 2% of

patients, and the event resulted in VELCADE discontinuation in 2% of patients [

see Warnings

and Precautions (5. 7)]

. Thrombocytopenia was reported more often in patients with multiple

myeloma (34% ) compared to patients with mantle cell lymphoma (16%). The incidence of

Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (28%) compared

to patients with mantle cell lymphoma (8%)

Peripheral Neuropathy

Overall, peripheral neuropathy NEC occurred in 38% of patients. Peripheral neuropathy was

Grade 3 for 11% of patients and ≥Grade 4 for <1% of patients. Eight percent (8%) of patients

discontinued VELCADE due to peripheral neuropathy. The incidence of peripheral neuropathy

was higher among patients with mantle cell lymphoma (54%) compared to patients with multiple

myeloma (36%).

In the VELCADE versus dexamethasone phase 3 relapsed multiple myeloma study, among the 62

VELCADE-treated patients who experienced ≥ Grade 2 peripheral neuropathy and had dose

adjustments, 48% had improved or resolved with a median of 3.8 months from first onset.

In the phase 2 relapsed multiple myeloma studies, among the 30 patients who experienced Grade 2

peripheral neuropathy resulting in discontinuation or who experienced ≥ Grade 3 peripheral

neuropathy, 73% reported improvement or resolution with a median time of 47 days to improvement

of one Grade or more from the last dose of VELCADE.

Hypotension

The incidence of hypotension (postural hypotension, orthostatic hypotension and hypotension

NOS) was 8% in patients treated with VELCADE. Hypotension was Grade 1 or 2 in the

majority of patients and Grade 3 in 2% and

Grade 4 in <1%. Two percent (2% ) of patients

had hypotension reported as an SAE, and 1% discontinued due to hypotension. The incidence of

hypotension was similar in patients with multiple myeloma (8% ) and those with mantle cell

lymphoma (9% ). In addition, <1% of patients experienced hypotension

associated with a

syncopal event.

Neutropenia

Neutrophil counts decreased during the VELCADE dosing period (days 1 to 11) and returned

toward baseline during the 10-day rest period during each treatment cycle. Overall, neutropenia

occurred in 15% of patients and was Grade 3 in 8% of patients and

Grade 4 in 2% .

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Neutropenia was reported as a serious event in <1% of patients and <1% of patients discontinued

due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma

(16% ) compared to patients with mantle cell lymphoma (5% ). The incidence of

Grade 3

neutropenia also was higher in patients with multiple myeloma (12% ) compared to patients

with mantle cell lymphoma (3% )

Asthenic conditions (Fatigue, Malaise, Weakness, Asthenia)

Asthenic conditions were reported in 54% of patients.

Fatigue was reported as Grade 3 in 7% and ≥ Grade 4 in < 1% of patients. Asthenia was reported

as Grade 3 in 2% and ≥ Grade 4 in < 1% of patients. Two percent (2%) of patients discontinued

treatment due to fatigue and < 1% due to weakness and asthenia. Asthenic conditions were

reported in 53% of patients with multiple myeloma and 59% of patients with mantle cell

lymphoma.

Pyrexia

Pyrexia (>38ºC) was reported as an adverse event for 21% of patients. The event was Grade 3

in 1% and

Grade 4 in <1%. Pyrexia was reported as a serious adverse event in 3% of patients

and led to VELCADE discontinuation in <1% of patients. The incidence of pyrexia was higher

among patients with multiple myeloma (23%) compared to patients with mantle cell lymphoma

(10%). The incidence of

Grade 3 pyrexia was 1% in patients with multiple myeloma and <1%

in patients with mantle cell lymphoma.

Herpes Virus Infection

Consider using antiviral prophylaxis in subjects being treated with VELCADE. In the

randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster

reactivation was more common in subjects treated with VELCADE (ranging between 6-11%)

than in the control groups (3-4%). Herpes simplex was seen in 1-3% in subjects treated with

VELCADE and 1-3% in the control groups. In the previously untreated multiple myeloma study,

herpes zoster virus reactivation in the VELCADE, melphalan and prednisone arm was less

common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did not

receive prophylactic antiviral therapy (17%).

Additional Serious Adverse Events from Clinical Studies

The following clinically important SAEs that are not described above have been reported in

clinical trials in patients treated with VELCADE administered as monotherapy or in combination

with other chemotherapeutics. These studies were conducted in patients with hematological

malignancies and in solid tumors.

Blood and lymphatic system disorders:

Anemia,

Disseminated intravascular coagulation, febrile

neutropenia , lymphopenia, leukopenia

Cardiac disorders:

Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus

arrest, cardiac amyloidosis, complete atrioventricular block, myocardial ischemia, myocardial

infarction, pericarditis, pericardial effusion, Torsades de pointes, ventricular tachycardia

Ear and labyrinth disorders

: Hearing impaired, vertigo

Eye disorders:

Diplopia and blurred vision, conjunctival infection, irritation

Gastrointestinal disorders

: Abdominal pain, Ascites, dysphagia, fecal impaction, gastroenteritis,

gastritis hemorrhagic, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

obstruction, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, large

intestinal perforation, stomatitis, melena, pancreatitis acute, oral mucosal petechiae,

gastroesophageal reflux

General disorders and administration site conditions:

Chills, edema, edema peripheral,

Injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitis

Hepatobiliary disorders:

Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein

thrombosis, hepatitis, liver failure.

Immune system disorders:

Anaphylactic reaction, drug hypersensitivity, immune complex

mediated hypersensitivity, angioedema, laryngeal edema

Infections and infestations:

Aspergillosis, bacteremia, bronchitis, urinary tract infection, herpes

viral infection, listeriosis, nasopharyngitis, pneumonia, respiratory tract infection, septic shock,

toxoplasmosis, oral candidiasis, sinusitis, catheter related infection

Injury, poisoning and procedural complications:

Catheter related complication, Skeletal

fracture, subdural hematoma

Investigations:

Weight decreased

Metabolism and nutrition disorders:

Dehydration, Hypocalcemia, hyperuricemia, hypokalemia,

hyperkalemia, hyponatremia, hypernatremia

Musculoskeletal and connective tissue disorders:

Arthralgia, back pain, bone pain, myalgia,

pain in extremity

Nervous system disorders:

Ataxia, coma, dizziness, dysarthria, dysesthesia, dysautonomia,

encephalopathy, cranial palsy, grand mal convulsion, headache, hemorrhagic stroke, motor

dysfunction, neuralgia, spinal cord compression, paralysis, postherpetic neuralgia,transient

ischemic attack

Psychiatric disorders:

Agitation, anxiety, confusion, insomnia, mental status change, psychotic

disorder, suicidal ideation

Renal and urinary disorders:

Calculus renal, bilateral hydronephrosis, bladder spasm,

hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure (acute and

chronic), glomerular nephritis proliferative

Respiratory, thoracic and mediastinal disorders:

Acute respiratory distress syndrome, aspiration

pneumonia, atelectasis, chronic obstructive airways disease exacerbated, cough, dysphagia,

dyspnea, dyspnea exertional, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion,

pneumonitis, respiratory distress, pulmonary hypertension

Skin and subcutaneous tissue disorders:

Urticaria, face edema, rash (which may be

pruritic),leukocytoclastic vasculitis, pruritus.

Vascular disorders:

Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis,

hypertension, peripheral embolism, pulmonary embolism, pulmonary hypertension

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

6.2 Postmarketing Experience

The following adverse drug events have been identified from the worldwide post-marketing

experience with VELCADE. Because these events are reported voluntarily from a population of

uncertain size, it is not always possible to reliably estimate their frequency or establish a causal

relationship to drug exposure: atrioventricular block complete, cardiac tamponade, ischemic

colitis, encephalopathy, dysautonomia, deafness bilateral, disseminated intravascular

coagulation, hepatitis, acute pancreatitis, progressive multifocal leukoencephalopathy (PML),

acute diffuse infiltrative pulmonary disease, PRES (formerly RPLS), toxic epidermal necrolysis,

acute febrile neutrophilic dermatosis (Sweet’s syndrome), herpes meningoencephalitis, optic

neuropathy, blindness and ophthalmic herpes, Stevens- Johnson Syndrome, septic shock,

Angioedema, Anaphylactic reaction, autonomic neuropathy,

Decubitus ulcer, Intestinal

obstruction

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.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@m

oh.gov.il

7. DRUG INTERACTIONS

Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2.

7.1 CYP3A4 inhibitors

Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of

bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider

a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4

inhibitors (e.g. ketoconazole, ritonavir).

7.2 CYP2C19 inhibitors

Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure

of bortezomib in 17 patients.

7.3 CYP3A4 inducers

Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure

of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to

exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur.

Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4

inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients

receiving VELCADE. (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital).

St. John’s Wort (

Hypericum perforatum

) may decrease bortezomib exposure unpredictably and

should be avoided.

7.4 Dexamethasone:

Co-administration of dexamethasone, a weak CYP3A4 inducer, had no

effect on the exposure of bortezomib in 7 patients.

7. 5 Melphalan-Prednisone:

Co-administration of melphalan-prednisone increased the exposure

of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

During clinical trials, hypoglycemia and hyperglycemia were uncommonly and commonly

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

receiving VELCADE treatment may require close monitoring of their blood glucose levels and

adjustment of the dose of their antidiabetics.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D

[see Warnings and Precautions (5.11)]

Risk Summary

VELCADE may cause fetal harm when administered to a pregnant woman. There are no

adequate and well-controlled studies in pregnant women. If VELCADE is used during

pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be

apprised of the potential hazard to the fetus. Bortezomib caused embryo-fetal lethality in rabbits

at doses lower than the clinical dose.

Animal Data

Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits

at the highest dose tested (0.075 mg/kg; 0.5 mg/m

in the rat and 0.05 mg/kg; 0.6 mg/m

in the

rabbit) when administered during organogenesis. These dosages are approximately half the

clinical dose of 1.3 mg/m

based on body surface area.

Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05mg/kg (0.6 mg/m

experienced significant post-implantation loss and decreased number of live fetuses. Live

fetuses from these litters also showed significant decreases in fetal weight. The dose is

approximately 0.5 times the clinical dose of 1.3 mg/m

based on body surface area.

8.2 Nursing Mothers

It is not known whether bortezomib is excreted in human milk. Because many drugs are

excreted in human milk and because of the potential for serious adverse events in nursing infants

from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the

drug, taking into account the importance of the drug to the mother .

8.3 Pediatric Use

The effectiveness of VELCADE in pediatric patients with relapsed pre-B acute lymphoblastic

leukemia (ALL) has not been established.

The activity and safety of VELCADE in combination with intensive reinduction chemotherapy was

evaluated in pediatric and young adult patients with lymphoid malignancies (pre-B cell ALL 77%,

16% with T-cell ALL, and 7% T-cell lymphoblastic lymphoma (LL)), all of whom relapsed within

36 months of initial diagnosis in a single-arm multicenter, non-randomized cooperative group trial.

An effective reinduction multiagent chemotherapy regimen was administered in 3 blocks. Block 1

included vincristine, prednisone, doxorubicin and pegaspargase; block 2 included cyclophosphamide,

etoposide and methotrexate; block 3 included high dose cytosine arabinoside and asparaginase.

VELCADE was administered at a dose of 1.3 mg/m

as a bolus intravenous injection on days 1, 4, 8,

and 11 of block 1 and days 1, 4, and 8 of block 2. There were 140 patients with ALL or LL enrolled

and evaluated for safety. The median age was 10 years (range 1 to 26), 57% were male, 70% were

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

white, 14% were black, 4% were Asian, 2% were American Indian/ Alaska Native, 1% were Pacific

Islander.

The activity was evaluated in a pre-specified subset of the first 60 evaluable patients enrolled on the

study with pre-B ALL ≤ 21 years and relapsed < 36 months from diagnosis. The complete remission

(CR) rate at day 36 was compared to that in a historical control set of patients who had received the

identical backbone therapy without VELCADE. There was no evidence that the addition of

VELCADE had any impact on the CR rate.

No new safety concerns were observed when VELCADE was added to a chemotherapy backbone

regimen as compared with a historical control group in which the backbone regimen was given

without VELCADE.

The BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in

adults.

8.4 Geriatric Use

Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of

age or older: 125 (38%) on the VELCADE arm and 120 (36%) on the dexamethasone arm.

Median time to progression and median duration of response for patients ≥65 were longer on

VELCADE compared to dexamethasone [5.5 mo versus 4.3 mo, and 8.0 mo versus 4.9 mo,

respectively]. On the VELCADE arm, 40% (n=46) of evaluable patients aged ≥65 experienced

response (CR+PR) versus 18% (n=21) on the dexamethasone arm. The incidence of Grade 3 and

4 events was 64%, 78% and 75% for VELCADE patients ≤50, 51-64 and ≥65 years old,

respectively.

[see Adverse Events (6.1); Clinical Studies (13)]

No overall differences in safety or effectiveness were observed between patients ≥ age 65 and

younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot

be ruled out.

8.5 Patients with Renal Impairment

The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment.

Therefore, dosing adjustments of VELCADE are not necessary for patients with renal

insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be

administered after the dialysis procedure. [see Clinical Pharmacology (12.3)]

8.6 Patients with Hepatic Impairment

The exposure of bortezomib is increased in patients with moderate

(bilirubin ≥ 1.5 – 3x ULN)

severe

(bilirubin > 3 x ULN)

hepatic impairment. Starting dose should be reduced in those

patients. [see

Dosage and administration

(2.7), Warnings and Precautions (5.10), and

Pharmacokinetics (12.3)]

8.7 Patients with Diabetes

During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients

receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE

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

of their antidiabetic medication.

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

9. OVERDOSAGE

There is no known specific antidote for VELCADE overdosage. In humans, fatal outcomes

following the administration of more than twice the recommended therapeutic dose have been

reported, which were associated with the acute onset of symptomatic hypotension (5.2) and

thrombocytopenia (5.7). In the event of an overdosage, 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.

Studies in monkeys and dogs showed that intravenous bortezomib as low as 2 times the

recommended clinical dose on a mg/m

basis were associated with increases in heart rate,

decreases in contractility, hypotension, and death. In dog studies, a slight increase in the

corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m

and greater (approximately twice the recommended clinical dose) resulted in hypotension

starting at 1 hour post-administration, with progression to death in 12 to 14 hours following drug

administration.

10. DESCRIPTION

VELCADE

®

(bortezomib) for Injection is an antineoplastic agent

Bortezomib is a modified dipeptidyl boronic acid.

The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1-

oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid.

Bortezomib has the following chemical structure:

The molecular weight is 384.24. The molecular formula is C

The solubility of

bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to

6.5.

VELCADE is available for intravenous injection or subcutaneous use. Each single use vial

contains 3.5 mg of bortezomib as a sterile lyophilized powder. It also contains the inactive

ingredient: 35 mg mannitol, USP. The product is provided as a mannitol boronic ester which, in

reconstituted form, consists of the mannitol ester in equilibrium with its hydrolysis product, the

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a trimeric

boroxine.

11 CLINICAL PHARMACOLOGY

11.1 Mechanism of Action

Bortezomib is a reversible inhibitor of 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 intracellular

concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of

the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling

cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell

death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell

types

in vitro

. Bortezomib causes a delay in tumor growth

in vivo

in nonclinical tumor models,

including multiple myeloma.

11.2 Pharmacodynamics

Following twice weekly administration of 1 mg/m

and 1.3 mg/m

bortezomib doses (n=12 per

each dose level), the maximum inhibition of 20S proteasome activity (relative to baseline) in

whole blood was observed 5 minutes after drug administration. Comparable maximum

inhibition of 20S proteasome activity was observed between 1 and 1.3 mg/m

doses. Maximal

inhibition ranged from 70% to 84% and from 73% to 83% for the 1 mg/m

and 1.3 mg/m

dose

regimens, respectively.

11.3 Pharmacokinetics

Following intravenous administration of 1 mg/m

and 1.3 mg/m

doses to 24 patients with

multiple myeloma (n=12, per each dose level), the mean maximum plasma concentrations of

bortezomib (C

) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. In

subsequent doses, when administered twice weekly, the mean maximum observed plasma

concentrations ranged from 67 to 106 ng/mL for the 1 mg/m

dose and 89 to 120 ng/mL for the

1.3 mg/m

dose. The mean elimination half-life of bortezomib upon multiple dosing ranged

from 40 to 193 hours after the 1 mg/m

dose and 76 to 108 hours after the 1.3mg/m

dose. The

mean total body clearances was 102 and 112 L/h following the first dose for doses of 1 mg/m

and 1.3 mg/m

, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses

of 1 and 1.3 mg/m

, respectively.

Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m

dose to patients (n = 14

for intravenous, n = 17 for subcutaneous) with multiple myeloma, the total systemic exposure

after repeat dose administration (AUC

last

) was equivalent for subcutaneous and intravenous

administration. The C

after subcutaneous administration (20.4 ng/mL) was lower than

intravenous (223 ng/mL). The AUC

last

geometric mean ratio was 0.99 and 90% confidence

intervals were 80.18% - 122.80%.

Distribution

: The mean distribution volume of bortezomib ranged from 1659 liters to 3294 liters

(498 to 1884 L/m

) following single- or repeat-dose IV administration of 1.0 mg/m

or 1.3mg/m

to patients with multiple myeloma. This suggests bortezomib distributes widely to peripheral

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

tissues. The binding of bortezomib to human plasma proteins averaged 83% over the

concentration range of 100 to 1000 ng/mL.

Metabolism

In vitro

studies with human liver microsomes and human cDNA-expressed

cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via

cytochrome P450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9

enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated

metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated

bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8

patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low

compared to the parent drug.

Elimination:

The pathways of elimination of bortezomib have not been characterized in humans.

Age:

Analyses of data after the first dose of Cycle 1 (Day 1) in 39 multiple myeloma patients

who had received intravenous doses of 1 mg/m

and 1.3 mg/m

showed that both dose-

normalized AUC and C

tend to be less in younger patients. Patients < 65 years of age (n=26)

had about 25% lower mean dose-normalized AUC and C

than those ≥ 65 years of age (n=13).

Gender:

Mean dose-normalized AUC and C

values were comparable between male (n=22)

and female (n=17) patients after the first dose of Cycle 1 for the 1 and 1.3 mg/m

doses.

Race:

The effect of race on exposure to bortezomib could not be assessed as most of the patients

were Caucasian.

Hepatic Impairment:

The effect of hepatic impairment (see Table 5 for definition of hepatic impairment)on the

pharmacokinetics of IV bortezomib was assessed in 60 patients with cancer at bortezomib doses

ranging from 0.5 to 1.3 mg/m

. When compared to patients with normal hepatic function, mild

hepatic impairment did not alter dose-normalized bortezomib AUC. However, the dose-

normalized 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 monitored closely [

see

Dosage and

Administration ( 2.7), Warnings and Precautions(5.10) and Use in Specific Populations (8.6)]

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 m

, N=12), Mild (CrCl=40-59

mL/min/1.73 m

, N=10), Moderate (CrCl=20-39 mL/min/1.73 m

, N=9), and Severe (CrCl < 20

mL/min/1.73 m

, 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/ m

of bortezomib twice weekly. Exposure of bortezomib (dose-normalized AUC and C

) was

comparable among all the groups.

[See Use in Specific Populations (8.5)]

Pediatric

See use in specific population 8.3

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Cytochrome P450:

Bortezomib is a poor inhibitor of human liver microsome cytochrome P450

1A2, 2C9, 2D6, and 3A4, with IC

values of >30μM (>11.5μg/mL). Bortezomib may inhibit

2C19 activity (IC

= 18 μM, 6.9 μg/mL) and increase exposure to drugs that are substrates for

this enzyme. Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in

primary cultured human hepatocytes.

12 NONCLINICAL TOXICOLOGY

12.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with bortezomib.

Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro

chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not

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

assay in mice.

Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has

been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative

effects in the ovary were observed at doses ≥0.3 mg/ m

(one-fourth of the recommended clinical

dose), and degenerative changes in the testes occurred at 1.2 mg/ m

. VELCADE could have a

potential effect on either male or female fertility.

12.2 Animal Toxicology and/or Pharmacology

Cardiovascular Toxicity

: Studies in monkeys showed that administration of dosages

approximately twice the recommended clinical dose resulted in heart rate elevations, followed by

profound progressive hypotension, bradycardia, and death 12 to 14 hours post dose. Doses

≥1.2 mg/ m

induced dose-proportional changes in cardiac parameters. Bortezomib has been

shown to distribute to most tissues in the body, including the myocardium. In a repeated dosing

toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also

observed.

Chronic Administration:

In animal studies at a dose and schedule similar to that recommended

for patients (twice weekly dosing for 2 weeks followed by 1-week rest), toxicities observed

included severe anemia and thrombocytopenia, and gastrointestinal, neurological and lymphoid

system toxicities. Neurotoxic effects of bortezomib in animal studies included axonal swelling

and degeneration in peripheral nerves, dorsal spinal roots, and tracts of the spinal cord.

Additionally, multifocal hemorrhage and necrosis in the brain, eye, and heart were observed.

13 CLINICAL STUDIES

13.1 Multiple Myeloma

Randomized, Open-Label Clinical Study in Patients with Previously Untreated Multiple

Myeloma:

A prospective Phase 3, international, randomized (1:1), open-label clinical study of 682 patients

was conducted to determine whether VELCADE

administered intravenously

(1.3 mg/m

) in

combination with melphalan (9 mg/m

) and prednisone (60 mg/m

) resulted in improvement in

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

time to progression (TTP) when compared to melphalan (9 mg/m

) and prednisone (60 mg/m

) 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.

Antiviral prophylaxis was recommended for patients on the VELCADE study arm.

The median age of the patients in the study was 71 years (48;91), 50% were male, 88% were

Caucasian and the median Karnofsky performance status score for the patients was 80 (60;100).

Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of

105 g/L (64;165), and a median platelet count of 221,500 /microliter (33,000;587,000).

Efficacy results for the trial are presented in Table 13. At a pre-specified interim analysis (with

median follow-up of 16.3 months), the combination of VELCADE, melphalan and prednisone

therapy resulted in significantly superior results for time to progression, progression-free survival,

overall survival and response rate. Further enrollment was halted, and patients receiving melphalan

and prednisone were offered VELCADE in addition. A later, pre-specified analysis of overall

survival (with median follow-up of 36.7 months with a hazard ratio of 0.65, 95% CI: 0.51, 0.84)

resulted in a statistically significant survival benefit for the VELCADE, melphalan and prednisone

treatment arm despite subsequent therapies including VELCADE based regimens. In an updated

analysis of overall survival based on 387 deaths (median follow-up 60.1 months), the median overall

survival for the VELCADE, melphalan and prednisone treatment arm was 56.4 months and for the

melphalan and prednisone treatment arm was 43.1 months, with a hazard ratio of 0.695 (95% CI:

0.57, 0.85).

Table 13: Summary of Efficacy Analyses in the previously Untreated Multiple Myeloma

Study

Efficacy Endpoint

VELCADE,

Melphalan and

Prednisone

n=344

Melphalan and

Prednisone

n=338

Time to Progression

Events n (%)

101 (29)

152 (45)

Median

(months)

(95% CI)

20.7

(17.6, 24.7)

15.0

(14.1, 17.9)

Hazard ratio

(95% CI)

0.54

(0.42, 0.70)

p-value

0.000002

Progression-free Survival

Events n (%)

135 (39)

190 (56)

Median

(months)

(95% CI)

18.3

(16.6, 21.7)

14.0

(11.1, 15.0)

Hazard ratio

(95% CI)

0.61

(0.49, 0.76)

p-value

0.00001

Response Rate

n(%)

102 (30)

12 (4)

n (%)

136 (40)

103 (30)

nCR n (%)

5 (1)

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

CR + PR

n (%)

238 (69)

115 (34)

p-value

<10

Overall Survival at median follow up of 36.7 months

Events (deaths) n (%)

109 (32)

148 (44)

Median

(months)

(95% CI)

Not Reached

(46.2, NR)

43.1

(34.8, NR)

Hazard ratio

(95% CI)

0.65

(0.51, 0.84)

p-value

0.00084

Note: All results are based on the analysis performed at a median follow-up duration of 16.3 months except for the

overall survival analysis that was performed at a median follow-up duration of 60.1months.

Kaplan-Meier estimate.

Hazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors: beta2-

microglobulin, albumin, and region. A hazard ratio less than 1 indicates an advantage for VELCADE, melphalan

and prednisone

c

p-value based on the stratified log-rank test adjusted for stratification factors: beta2-microglobulin, albumin, and

region

EBMT criteria

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

stratification factors

NE: Not estimable

TTP was statistically significantly longer on the VELCADE, Melphalan and prednisone arm (see

figure 1

(median follow up 16.3 months)

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Overall survival was statistically significantly longer on the VELCADE, Melphalan and

Prednisone arm (see Figure 2). (median follow up 60.1months)

Randomized, Clinical Study in Relapsed Multiple Myeloma

of VELCADE vs. Dexamethasone

A prospective phase 3, international, randomized (1:1), stratified, open-label clinical study

enrolling 669 patients was designed to determine whether VELCADE resulted in improvement

in time to progression (TTP) compared to high-dose dexamethasone in patients with progressive

multiple myeloma following 1 to 3 prior therapies. Patients considered to be refractory to prior

high-dose dexamethasone were excluded as were those with baseline grade ≥ 2 peripheral

neuropathy or platelet counts <50,000/µL. A total of 627 patients were evaluable for response.

Stratification factors were based on the number of lines of prior therapy the patient had

previously received (1 previous line versus more than 1 line of therapy), time of progression

relative to prior treatment (progression during or within 6 months of stopping their most recent

therapy versus relapse > 6 months after receiving their most recent therapy), and screening

-microglobulin levels (≤2.5 mg/L versus >2.5 mg/L).

Baseline patient and disease characteristics are summarized in Table 14.

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Table 14: Summary of Baseline Patient and Disease Characteristics

in the Relapsed Multiple Myeloma Study

Patient Characteristics

VELCADE

N=333

Dexamethasone

N=336

Median age in years (range)

62.0 (33, 84)

61.0 (27, 86)

Gender: male/female

56% / 44%

60% / 40%

Race: Caucasian/black/other

90% / 6% / 4%

88% / 7% / 5%

Karnofsky performance status score ≤70

Hemoglobin <100 g/L

Platelet count <75 x 10

Disease Characteristics

Type of myeloma (%): IgG/IgA/Light chain

60% / 23% / 12%

59% / 24% / 13%

Median

-microglobulin (mg/L)

Median albumin (g/L)

39.0

39.0

Creatinine clearance

30 mL/min [n (%)]

17 (5%)

11 (3%)

Median Duration of Multiple Myeloma Since

Diagnosis (Years)

Number of Prior Therapeutic Lines of Treatment

Median

1 prior line

> 1 prior line

Previous Therapy

Any prior steroids, e.g., dexamethasone, VAD

Any prior anthracyclines, e.g., VAD, mitoxantrone

Any prior alkylating agents, e.g., MP, VBMCP

Any prior thalidomide therapy

Vinca alkaloids

Prior stem cell transplant/other high-dose therapy

Prior experimental or other types of therapy

Patients in the VELCADE treatment group were to receive eight 3-week treatment cycles

followed by three 5-week treatment cycles of VELCADE. Patients achieving a CR were treated

for 4 cycles beyond first evidence of CR. Within each 3-week treatment cycle, VELCADE 1.3

mg/m

/dose alone was administered by IV bolus twice weekly for 2 weeks on Days 1, 4, 8, and

11 followed by a 10-day rest period (Days 12 to 21). Within each 5-week treatment cycle,

VELCADE 1.3 mg/m

/dose alone was administered by IV bolus once weekly for 4 weeks on

Days 1, 8, 15, and 22 followed by a 13-day rest period (Days 23 to 35)

[see Dosage and

Administration(2.1)]

Patients in the dexamethasone treatment group were to receive four 5-week treatment cycles

followed by five 4-week treatment cycles. Within each 5-week treatment cycle, dexamethasone

40 mg/day PO was administered once daily on Days 1 to 4, 9 to 12, and 17 to 20 followed by a

15-day rest period (Days 21-35). Within each 4-week treatment cycle, dexamethasone 40

mg/day PO was administered once daily on Days 1 to 4 followed by a 24-day rest period (Days 5

to 28). Patients with documented progressive disease on dexamethasone were offered

VELCADE at a standard dose and schedule on a companion study. Following a preplanned

interim analysis of time to progression, the dexamethasone arm was halted and all patients

randomized to dexamethasone were offered VELCADE, regardless of disease status.

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

In the VELCADE arm, 34% of patients received at least one VELCADE dose in all 8 of the 3-

week cycles of therapy, and 13% received at least one dose in all 11 cycles. The average number

of VELCADE doses during the study was 22, with a range of 1 to 44. In the dexamethasone

arm, 40% of patients received at least one dose in all 4 of the 5-week treatment cycles of therapy,

and 6% received at least one dose in all 9 cycles

The time to event analyses and response rates from the relapsed multiple myeloma study are

presented in

Table 15.

Response and progression were assessed using the European Group for

Blood and Marrow Transplantation (EBMT) criteria. Complete response (CR) required < 5%

plasma cells in the marrow, 100% reduction in M-protein, and a negative immunofixation test

). Partial Response (PR) requires

50% reduction in serum myeloma protein and

reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks

along with stable bone disease and normal calcium. Near complete response (nCR) was defined

as meeting all the criteria for complete response including 100% reduction in M-protein by

protein electrophoresis, however M-protein was still detectable by immunofixation (IF

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Table 15: Summary of Efficacy Analyses in the Relapsed Multiple Myeloma study

Kaplan-Meier estimate.

Hazard ratio is based on Cox proportional-hazard model with the treatment as single

independent variable. A hazard ratio less than 1 indicates an advantage for VELCADE.

Kaplan-Meier estimate

Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable.

A hazard ratio less than 1 indicates an advantage for VELCADE

p-value based on the stratified log-rank test including randomization stratification factors.

Precise p-value cannot be rendered

Response population includes patients who had measurable disease at baseline and received

at least 1 dose of study drug.

EBMT criteria

; nCR meets all EBMT criteria for CR but has positive IF. Under EBMT criteria

nCR is in the PR category.

In 2 patients, the IF was unknown.

p-value for Response Rate (CR + PR) from the Cochran-Mantel-Haenszel chi-square test

adjusted for the stratification factors;

TTP was statistically significantly longer on the VELCADE arm (see Fig.

3).

All Patients

1 Prior Line of Therapy

> 1 Prior Line of

Therapy

VELCADE

Dex

VELCADE

Dex

VELCADE

Dex

Efficacy Endpoint

n=333

n=336

n=132

n=119

n=200

n=217

Time to Progression

Events n (%)

147(44)

196(58)

55(42)

64(54)

92(46)

132(61)

Median

(95% CI)

6.2 mo

(4.9, 6.9)

3.5 mo

(2.9,

4.2)

7.0 mo

(6.2, 8.8)

5.6 mo

(3.4, 6.3)

4.9 mo

(4.2, 6.3)

2.9 mo

(2.8,

3.5)

Hazard ratio

(95% CI)

0.55

(0.44, 0.69)

0.55

(0.38, 0.81)

0.54

(0.41, 0.72)

p-value

< 0.0001

0.0019

<0.0001

Overall Survival

Events (deaths) n

51(15)

84(25)

12(9)

24(20)

39(20)

60(28)

Hazard ratio

(95% CI)

0.57

(0.40, 0.81)

0.39

(0.19, 0.81)

0.65

(0.43, 0.97)

p-value

<0.05

<0.05

<0.05

Response Rate

population

n = 627

n=315

n=312

n=128

n=110

n=187

n=202

n (%)

20(6)

2(<1)

8(6)

2(2)

12(6)

0(0)

n(%)

101(32)

54(17)

49(38)

27(25)

52(28)

27(13)

n(%)

21(7)

3(<1)

8(6)

2(2)

13(7)

1(<1)

CR + PR

n (%)

121 (38)

56 (18)

57(45)

29(26)

64(34)

27(13)

p-value

<0.0001

0.0035

<0.0001

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Fig. 3: Time to Progression

Bortezomib vs. Dexamethasone (relapsed multiple meyeloma study)

As shown in Figure

4,

VELCADE had a significant survival advantage relative to

dexamethasone (p<0.05). The median follow-up was 8.3 months.

Fig. 4: Overall Survival

Bortezomib vs. Dexamethasone (relapsed multiple meyeloma study)

For the 121 patients achieving a response (CR or PR) on the VELCADE arm, the median

duration was 8.0 months (95% CI: 6.9, 11.5 months) compared to 5.6 months (95% CI:

4.8, 9.2 months) for the 56 responders on the dexamethasone arm.

Bortezomib (n*)

Dexamethasone (n*)

Proportion of Patients

* Patients remaining after the indicated timepoint

p-value from log-rank test

p <0.05

Bortezomib

Dexamethasone

* Patients remaining after the indicated timepoint

p-value from log-rank test

p <0.0001

Bortezomib

Dexamethasone

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

The response rate was significantly higher on the VELCADE arm regardless of

microglobulin levels at baseline.

Randomized, Open-Label Clinical Study of VELCADE Subcutaneous versus

Intravenous in Relapsed Multiple Myeloma

An open-label, randomized, phase 3 non-inferiority study compared the efficacy and

safety of the subcutaneous administration of VELCADE versus the intravenous

administration. This study included 222 bortezomib naïve patients with relapsed multiple

myeloma, who were randomized in a 2:1 ratio to receive 1.3 mg/m

of VELCADE by

either the subcutaneous (n=148) or intravenous (n=74) route for 8 cycles. Patients who

did not obtain an optimal response (less than Complete Response (CR)) to therapy with

VELCADE alone after 4 cycles were allowed to receive oral dexamethasone 20 mg daily

on the day of and after VELCADE administration (82 patients in subcutaneous treatment

group and 39 patients in the intravenous treatment group). Patients with baseline Grade ≥

2 peripheral neuropathy or neuropathic pain, or platelet counts < 50,000/μL were

excluded. A total of 218 patients were evaluable for response.

Stratification factors were based on the number of lines of prior therapy the patient had

received (1 previous line versus more than 1 line of therapy), and international staging

system (ISS) stage (incorporating beta

-microglobulin and albumin levels; Stages I, II, or

III).

The baseline demographic and others characteristics of the two treatment groups are

summarized as follows: the median age of the patient population was approximately 64

years of age (range 38-88 years), primarily male (subcutaneous: 50%, intravenous: 64%);

the primary type of myeloma is IgG (subcutaneous: 65% IgG, 26% IgA, 8% light chain;

intravenous: 72% IgG, 19% IgA, 8% light chain), ISS staging I/II/III (%) was 27, 41, 32

for both subcutaneous and intravenous, Karnofsky performance status score was ≤ 70%

in 22% of subcutaneous and 16% of intravenous, creatinine clearance was 67.5 mL/min

in subcutaneous and 73 mL/min in intravenous, the median years from diagnosis was

2.68 and 2.93 in subcutaneous and intravenous respectively and the proportion of patients

with more than one prior line of therapy was 38% in subcutaneous and 35% in

intravenous.

This study met its primary (non-inferiority) objective that single agent subcutaneous

VELCADE retains at least 60% of the overall response rate after 4 cycles relative to

single agent intravenous VELCADE. The results are provided in Table 16.

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Table 16: Summary of Efficacy Analyses in the Relapsed Multiple Myeloma Study of

VELCADE Subcutaneous vs. Intravenous

Subcutaneous

VELCADE

Intravenous

VELCADE

Intent to Treat Population

n=148

n=74

Primary Endpoint

Response Rate at 4 cycles

ORR (CR + PR) n(%)

63 (43)

31 (42)

Ratio of Response Rates (95% CI)

1.01 (0.73, 1.40)

CR n(%)

11 (7)

6 (8)

PR n(%)

52 (35)

25 (34)

nCR n(%)

9 (6)

4 (5)

Secondary Endpoints

Response Rate at 8 cycles

ORR (CR + PR)

78 (53)

38 (51)

CR n(%)

17 (11)

9 (12)

PR n(%)

61 (41)

29 (39)

nCR n(%)

14 (9)

7 (9)

Median Time to Progression, months

10.4

Median Progression Free Survival, months

10.2

1-year Overall Surviaval (%)

a

72.6

76.7

Median duration of follow up is 11.8 months

A Randomized Phase 2 Dose-Response Study in Relapsed Multiple Myeloma

An open-label, multicenter study randomized 54 patients with multiple myeloma who had

progressed or relapsed on or after front-line therapy to receive VELCADE 1.0 mg/m

1.3 mg/m

IV bolus twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-

day rest period (Days 12 to 21). The median duration of time between diagnosis of

multiple myeloma and first dose of VELCADE on this trial was 2.0 years, and patients

had received a median of 1 prior line of treatment (median of 3 prior therapies). A single

complete response was seen at each dose. The overall response rates (CR + PR) were

30% (8/27) at 1.0 mg/m

and 38% (10/26) at 1.3 mg/m

A Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma

Patients from the two phase 2 studies who in the investigators’ opinion would experience

additional clinical benefit continued to receive VELCADE beyond 8 cycles on an

extension study. Sixty-three (63) patients from the phase 2 multiple myeloma studies

were enrolled and received a median of 7 additional cycles of VELCADE therapy for a

total median of 14 cycles (range 7 to 32). The overall median dosing intensity was the

same in both the parent protocol and extension study. Sixty-seven percent (67%) of

patients initiated the extension study at the same or higher dose intensity at which they

completed the parent protocol, and 89% of patients maintained the standard 3-week

dosing schedule during the extension study. No new cumulative or new long-term

toxicities were observed with prolonged VELCADE treatment

[see Adverse Events (6.1)]

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13.2 Mantle Cell Lymphoma

A Randomized, Open-Label Clinical Study in Patients with Previously Untreated

Mantle Cell Lymphoma

A randomized, open-label, Phase 3 study was conducted in 487 adult patients with

previously untreated mantle cell lymphoma (Stage II, III or IV) who were ineligible or

not considered for bone marrow transplantation to determine whether VELCADE

administered in combination with rituximab, cyclophosphamide, doxorubicin, and

prednisone (VcR-CAP) resulted in improvement in progression free survival (PFS) when

compared to the combination of rituximab, cyclophosphamide, doxorubicin, vincristine,

and prednisone (R-CHOP). This clinical study utilized independent pathology

confirmation and independent radiologic response assessment.

Patients in the VcR-CAP treatment arm received VELCADE (1.3 mg/m

) administered

intravenously on days 1, 4, 8, and 11 (rest period days 12-21); rituximab (375 mg/m

) on

Day 1; cyclophosphamide (750 mg/m

) on Day 1; doxorubicin (50 mg/m

) on Day 1; and

prednisone (100 mg/m

) on Day 1 through Day 5 of the the 21-day treatment cycle. For

patients with a response first documented at cycle 6, two additional treatment cycles were

allowed.

Median patient age was 66 years, 74% were male, 66% were Caucasian and 32% were

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 (high-intermediate) or higher and 76% had Stage IV disease.

The majority of the patients in both groups received 6 or more cycles of treatment, 84%

in the VcR-CAP group and 83% in the R-CHOP group. Median number of cycles

received by patients in both treatment arms was 6 with 17% of patients in the R-CHOP

group and 14% of subjects in the VcR-CAP group receiving up to 2 additional cycles.

The efficacy results of the study with a median follow-up of 40 months are presented in

Table 18. The response criteria used to assess efficacy were based on the International

Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphoma (IWRC).

The combination of VcR-CAP resulted in statistically significant prolongation of PFS

compared with R-CHOP (see Table 17 and Figure 5).

Table 17:

Summary of Efficacy Analyses in the Previously Untreated Mantle

Cell Lymphoma Study

Efficacy endpoint

n: Intent to Treat patients

VcR-CAP

n=243

R-CHOP

n=244

Progression-free Survival (by independent radiographic assessment)

Events n (%)

133 (55)

165 (68)

Median

(months)

(95% CI)

(20, 32)

(12, 17)

Hazard ratio

(95% CI)

0.63

(0.50, 0.79)

p-value

<0.001

Complete Response Rate

(CR)

n (%)

(95% CI)

108 (44)

(38, 51)

82 (34)

(28, 40)

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Efficacy endpoint

n: Intent to Treat patients

VcR-CAP

n=243

R-CHOP

n=244

Overall Response Rate (CR+CRu+PR)

e

n (%)

214 (88)

208 (85)

(95% CI)

(83, 92)

(80, 89)

Based on Kaplan-Meier product limit estimates.

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.

Based on Log rank test stratified with IPI risk and stage of disease.

Includes CR by independent radiographic assessment, bone marrow, and LDH using ITT population.

Includes CR+ CRu+PR by independent radiographic assessment, regardless of the verification by bone

marrow and LDH, using ITT population.

CI=Confidence Interval; IPI= International Prognostic Index; LDH=Lactate dehydrogenase

Figure 5:

Progression Free Survival

VcR-CAP versus R-CHOP (previously untreated mantle cell lymphoma study)

Key: R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone;

VcR-CAP=VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone.

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

A Phase 2 Single-arm Clinical Study in Relapsed Mantle Cell Lymphoma After Prior

Therapy

The safety and efficacy of VELCADE in relapsed or refractory mantle cell lymphoma

were evaluated in an open-label, single-arm, multicenter study of 155 patients with

progressive disease who had received at least 1 prior therapy. The median age of the

patients was 65 years (42, 89), 81% were male, and 92% were caucasian. Of the total,

75% had one or more extra-nodal sites of disease, and 77% were stage 4. In 91% of the

patients, prior therapy included all of the following: an anthracycline or mitoxantrone,

cyclophosphamide, and rituximab. A total of thirty seven percent (37%) of patients were

refractory to their last prior therapy. An IV bolus injection of VELCADE

1.3 mg/m

/dose was administered twice weekly for 2 weeks on Days 1, 4, 8, and 11

followed by a 10-day rest period (Days 12 to 21) for a maximum of 17 treatment cycles.

Patients achieving a CR or Cru were treated for 4 cycles beyond first evidence of CR or

CRu. The study employed dose modifications for toxicity

[see Dosage and

Administration (2)]

Responses to VELCADE are shown in Table 18. Response rates to VELCADE were

determined according to the International Workshop Criteria (IWRC) based on

independent radiologic review of CT scans. The median number of cycles administered

across all patients was 4; in responding patients the median number of cycles was 8. The

median time to response was 40 days (range 31 to 204 days). The median duration of

follow-up was more than 13 months.

Table 18: Response Outcomes in a Phase 2 Mantle Cell Lymphoma Study

Response Analyses (N = 155)

N (%)

95% CI

Overall Response Rate (IWRC) (CR + CRu + PR)

48 (31)

(24, 39)

Complete Response (CR + CRu)

12 (8)

(4, 13)

10 (6)

(3, 12)

2 (1)

(0, 5)

Partial Response (PR)

36 (23)

(17, 31)

Duration of Response

Median

95% CI

CR + CRu + PR (N = 48)

9.3 months

(5.4, 13.8)

CR + CRu (N = 12)

15.4 months

(13.4, 15.4)

PR (N=36)

6.1 months

(4.2, 9.3)

14 HOW SUPPLIED/STORAGE AND HANDLING

VELCADE® (bortezomib) for Injection is supplied as individually cartoned 10 mL vials

containing 3.5 mg of bortezomib as a white to off-white cake or powder.

Velcade 3.5 mg is available in cartons containing 1 single-use vial.

There have been fatal cases of inadvertent intrathecal administration of VELCADE.

VELCADE is authorized for IV or subcutaneous

use only.

DO NOT ADMINISTER VELCADE INTRATHECALLY

Unopened vials: Do not store above 30°C. Keep container in the outer carton.

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Velcade 3.5mg_SPC_July_18_sub (USPI SEP 15)

Consider handling and disposal of VELCADE according to guidelines issued for

cytotoxic drugs, including the use of gloves and other protective clothing to prevent skin

contact.

The reconstituted solution should be used immediately after preparation. If the

reconstituted solution is not used immediately, in-use storage times and conditions prior

to use are the responsibility of the user. However, the chemical and physical in-use

stability of the reconstituted solution has been demonstrated for 8 hours at 25 °C stored in

the original vial and/or a syringe prior to administration. The total storage time for the

reconstituted medicinal product should not exceed 8 hours prior to administration.

MANUFACTURER

Janssen Pharmaceutica N.V., Beerse, Belgium

LICENSE HOLDER

J-C Healthcare Ltd.

Kibbutz Shefayim, Shefayim Mall 6099000

Registration Number: 131-60-31039-01/02/03

The content of this leaflet was approved by the ministry of health in Aug2016 and

updated according to the guidelines of the Ministry of Health in July2018.