DBL™ Bortezomib

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Bortezomib 2.5 mg (as a mannitol boronic ester)
Available from:
Pfizer New Zealand Limited
Dosage:
2.5 mg
Pharmaceutical form:
Powder for injection
Composition:
Active: Bortezomib 2.5 mg (as a mannitol boronic ester) Excipient: Mannitol
Prescription type:
Prescription
Therapeutic indications:
Bortezomib in combination with melphalan and prednisone, is indicated for the treatment of patients with previously untreated multiple myeloma, who are not suitable for high dose chemotherapy. Bortezomib as part of combination therapy, is indicated for induction therapy prior to high dose chemotherapy with autologous stem cell rescue for patients under 65 years of age with previously untreated multiple myeloma. Bortezomib is also indicated for the treatment of multiple myeloma patients who have received at least one prior therapy, and who have progressive disease.
Product summary:
Package - Contents - Shelf Life: Vial, glass, Clear type I with rubber stopper and aluminium seal in cardboard carton - 1 dose units - 12 months from date of manufacture stored at or below 25°C 8 hours reconstituted stored at or below 25°C
Authorization number:
TT50-10328
Authorization date:
2018-01-08

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NEW ZEALAND DATA SHEET

1. PRODUCT NAME

DBL™ Bortezomib 2.5mg, 3.0 mg, 3.5mg powder for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single dose vial contains:

2.5 mg of bortezomib as a sterile lyophilized powder or3.0 mg of bortezomib as a sterile

lyophilized powder or

3.5 mg of bortezomib as a sterile lyophilised powder or

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for Injection.

DBL™ Bortezomib Powder for Injection is supplied as white, to off white lyophilized powder.

The solubility of bortezomib, as the monomeric boronic acid, in water is: 3.3 – 3.8 mg/mL in a pH

range of 2 – 6.5

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

DBL™ Bortezomib powder for injection in combination with melphalan and prednisone, is

indicated for the treatment of patients with previously untreated multiple myeloma, who are not

suitable for high dose chemotherapy.

DBL™ Bortezomib powder for injection, as part of combination therapy, is indicated for induction

therapy prior to high dose chemotherapy with autologous stem cell rescue for patients under 65

years of age with previously untreated multiple myeloma

DBL™ Bortezomib powder for injection is also indicated for the treatment of multiple myeloma

patients who have received at least one prior therapy, and who have progressive disease.

4.2 Dose and method of administration

Recommended Dosage

DBL™

Bortezomib

POWDER

FOR

INJECTION

IS

FOR

INTRAVENOUS

OR

SUBCUTANEOUS USE ONLY. Intrathecal administration has resulted in death.

DBL™ Bortezomib Powder for Injection may be administered:

Intravenously (at a concentration of 1 mg/mL) as a 3-5 second bolus injection or

Subcutaneously (at a concentration of 2.5 mg/mL).

Because each route of administration has a different reconstituted concentration,

caution should be used when calculating the volume to be administered.

DBL™ Bortezomib powder for injection retreatment may be considered for multiple

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myeloma patients who had previously responded to treatment with bortezomib (see

section 5.1).

Previously Untreated Multiple Myeloma

Transplant Eligible

1. DBL™ Bortezomib powder for injection plus thalidomide-dexamethasone

During the induction stage, bortezomib is administered twice weekly in combination

with thalidomide-dexamethasone for three 3-week treatment cycles. Following stem cell

transplantation,

patients

receive

5-week

cycles

bortezomib

thalidomide-

dexamethasone. The treatment regimen is shown in Table 1.

Table 1: Recommended dosage regimen for Bortezomib when used in

combination with

thalidomide and dexamethasone

Induction Therapy: Twice weekly bortezomib (3 cycles)

Week

1

2

3

Bortezomib (1.3

mg/m

t (100 mg)-Cycle 1

Day 1-7

Day 8-14

t (200 mg)-Cycle 2-3

Day 1-7

Day 8-14

Day 15-21

d (40 mg)

Consolidation Therapy: Once Weekly bortezomib (2 cycles)

Week

1

2

3

4

5

Bortezomib (1.3

mg/m

t (100 mg)

8-14

15-21

22-28

29-35

d (40 mg)

Bortezomib ; t = thalidomide; d = dexamethasone

2. DBL™ Bortezomib

powder for injection

plus dexamethasone

Bortezomib is administered as an IV injection in combination with oral dexamethasone for

four 3-week treatment cycles as shown in Table 2.

Table 2: Recommended dosage regimen for Bortezomib when used in combination

with

dexamethasone

Week

1

2

3

Bortezomib (1.3

mg/m

d (40 mg)-All Cycles

d (40 mg)-Cycle 1-2

Day 1-4--

Day 9-12

Bortezomib = Bortezomib ; d = dexamethasone

Non-Transplant Eligible

Bortezomib for injection is administered in combination with oral melphalan and oral prednisone

for nine 6-week treatment cycles as shown in Table 3. In Cycles 1-4, bortezomib is administered

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

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

Table 3: Recommended Dosage Regimen for Bortezomib when used in combination with

melphalan and prednisone for Patients with Previously Untreated Multiple Myeloma

Twice Weekly Bortezomib (Cycles 1-4)

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Week

1

2

3

4

5

6

Bortezomib

(1.3

mg/m

rest

period

rest

period

m(9 mg/m

p(60 mg/m

rest

period

rest

period

Once Weekly Bortezomib (Cycles 5-9)

Week

1

2

3

4

5

6

Bortezomib

(1.3

mg/m

rest period

rest period

m (9 mg/m

p (60 mg/m

rest period

rest period

Bortezomib = bortezomib ; m = melphalan, p=prednisone

Dose Management Guidelines

Dose modification and re-initiation of therapy when bortezomib is administered in

combination with melphalan and prednisone.

Prior to initiating a new cycle of therapy:

Platelet count should be ≥70 x 10

/L and the ANC should be ≥ 1.0 x 10

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

Table 4: Dose Modifications During Subsequent Cycles

Toxicity

Dose modification or delay

Haematological toxicity during a cycle:

If prolonged Grade 4 neutropenia or

thrombocytopenia, or thrombocytopenia with bleeding is

observed in the previous cycle

Consider reduction of the melphalan dose by 25% in the

next

cycle.

If platelet count

/L or ANC

0.75 x 10

on a bortezomib dosing day (other than day 1)

Bortezomib dose should be withheld

If several bortezomib doses in a cycle are withheld

(≥ 3 doses during twice weekly administration or ≥ 2

doses during weekly administration)

bortezomib dose should be reduced by 1 dose level

(from 1.3 mg/m

to 1 mg/m

, or from 1 mg/m

to 0.7

mg/m

GRADE ≥ 3 NON-HAEMATOLOGICAL TOXICITIES

Bortezomib therapy should be withheld until symptoms of the

toxicity have resolved to Grade 1 or baseline. Then, bortezomib

may be reinitiated with one dose level reduction (from 1.3 mg/m

to 1 mg/m

, or from 1 mg/m

to 0.7 mg/m

). For bortezomib –

related

neuropathic

pain

and/or

peripheral

neuropathy,

hold

and/or modify bortezomib as outlined in Table 5.

For additional information concerning melphalan and prednisone, see manufacturer's

prescribing information.

Table 5: Recommended Dose Modification for Bortezomib -related Neuropathic Pain

and/or

Peripheral Sensory or Motor Neuropathy.

Severity of Peripheral Neuropathy

Signs and Symptoms*

Modification of Dose and Regimen

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Grade 1 (asymptomatic; loss of deep tendon reflexes

or paraesthesia) 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 bortezomib to 1.0 mg/m

Change bortezomib treatment

schedule to 1.3 mg/m

once per week

Grade 2 with pain or Grade 3 (severe symptoms;

limiting self care ADL)***)

Withhold bortezomib therapy until toxicity resolves.

When toxicity resolves reinitiate with a reduced dose of

bortezomib at 0.7 mg/m

once per week.

Grade 4

(life-threatening

consequences;

urgent

intervention indicated)

Discontinue bortezomib

* Grading based on NCI Common Toxicity Criteria

** 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.

Relapsed / Refractory Multiple Myeloma

The recommended dose of bortezomib is 1.3 mg/m

/dose administered twice weekly for

two weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). This 3-

week period is considered a treatment cycle. At least 72 hours should elapse between

consecutive doses of Bortezomib.

recommended

that

patients

with

confirmed

complete

response

receive

additional cycles of bortezomib

beyond a confirmation.

It is also recommended that

responding patients who do not achieve a complete remission receive a total of 8 cycles of

bortezomib therapy.

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

standard schedule or 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 section 5.1 for a

summary of dose administration during clinical trials).

Dose Modification and Reinitiation of Therapy

Bortezomib therapy should be withheld at the onset of any Grade 3 non-haematological

Grade

haematological

toxicities

excluding

neuropathy

discussed

below

(see

section 4.4). Once the symptoms of the toxicity have resolved, bortezomib therapy may be

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

/dose reduced to 1.0 mg/m

/dose; 1.0

mg/m

/dose reduced to 0.7 mg/m

/dose). Table 5 above contains the recommended dose

modification

management

patients

experience

bortezomib

-related

neuropathic pain and/or peripheral sensory neuropathy. Severe autonomic neuropathy

resulting in treatment interruption or discontinuation has been reported. Patients with pre-

existing severe neuropathy should be treated with bortezomib only after careful risk/benefit

assessment.

Retreatment for Multiple Myeloma

Patients who have previously responded to treatment with bortezomib (either alone or

in combination) and who have relapsed should be started on retreatment at the last

tolerated dose.

Patients with Renal Impairment

pharmacokinetics

bortezomib

influenced

degree

renal

impairment. Therefore, dosing adjustments of bortezomib are not necessary for patients

with renal insufficiency. Since dialysis may reduce bortezomib concentrations, the drug

should be administered after the dialysis procedure (see section 5.2).

Patients with Hepatic Impairment

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

be treated per the recommended bortezomib dose. Patients with moderate or severe

hepatic impairment should be started on bortezomib at a reduced dose of 0.7 mg/m

injection during

first

cycle,

subsequent

dose

escalation

mg/m

further dose reduction to 0.5 mg/m

may be considered based on patient tolerance (see

Table 6).

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Table 6: Recommended Starting Dose Modification for Bortezomib in Patients with

Hepatic

Impairments

Bilirubin Level

SGOT (AST)

Levels

Modification of Starting Dose

Mild

≤1.0x ULN

>ULN

None

>1.0x – 1.5x ULN

None

Moderate

>1.5x – 3x ULN

Reduce bortezomib to 0.7 mg/m

first cycle. Consider dose

escalation to

1.0 mg/m

or further reduction to 0.5

mg/m

in subsequent cycles based on

patient tolerability

Severe

>3x ULN

SGOT = serum glutamic oxaloacetic transaminase;

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

Administration

For instructions on reconstitution of

DBL™ Bortezomib

powder for injection before administration,

Reconstitution/Preparation for Administration table in

section 6.6.

Intravenous injection (IV)

Bortezomib is administered as a 3-5 second bolus intravenous injection through a

peripheral or central

intravenous

catheter

followed

flush

with

0.9%

sodium

chloride solution for injection.

Subcutaneous injection (SC)

The reconstituted solution is injected into the thighs (right or left) or abdomen (right or

left). Injection sites should be rotated for successive injections.

If local injection site reactions occur following bortezomib injection subcutaneously, a

less concentrated

bortezomib solution

mg/mL

instead

mg/mL)

administered subcutaneously or change to IV injection.

4.3 Contraindications

Bortezomib is contraindicated in patients with hypersensitivity to bortezomib, boron or

mannitol.

4.4 Special warnings and precautions for use

Overall treatment with bortezomib must be done under the supervision of a physician,

however administration of the drug product may be done by a healthcare professional

experienced in the administration of oncology medications.

There have been fatal cases of inadvertent intrathecal administration of bortezomib is for

IV or SC use only

. DO NOT ADMINISTER DBL™ Bortezomib POWDER FOR INJECTION

INTRATHECALLY.

Overall, the safety profile of patients treated with bortezomib in monotherapy was similar

to that observed in patients treated with bortezomib in combination with melphalan and

prednisone.

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Peripheral Neuropathy

Bortezomib

treatment

causes

peripheral

neuropathy

(PN)

that

predominantly

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

neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or

burning

feeling

feet

hands)

and/or

signs

peripheral

neuropathy

experience worsening (including

Grade 3) during treatment with bortezomib. Patients

should

monitored

symptoms

neuropathy,

such

burning

sensation,

hyperaesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness.

In the Phase 3 study

comparing

bortezomib IV vs. SC the incidence of

Grade ≥ 2

peripheral neuropathy events was 24% for SC and 41% for IV (p=0.0124). Grade ≥ 3

peripheral neuropathy occurred in 6% of subjects in the SC treatment group, compared with

16% in the IV treatment group (p=0.0264). Therefore, patients with pre-existing PN or at

high risk of peripheral neuropathy may benefit from starting bortezomib subcutaneously.

Patients experiencing new or worsening peripheral neuropathy may require a change in

dose, schedule or route of administration to SC (see section 4.2).

Following

dose

adjustments,

improvement

resolution

peripheral

neuropathy

was reported in 51% of patients with

Grade 2 peripheral neuropathy in the phase III

multiple myeloma (APEX) study of bortezomib IV vs. dexamethasone. 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

II studies (see section 4.8

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

some

adverse

reactions

such

postural

hypotension

severe constipation

with ileus.

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

Hypotension

Patients

developing

orthostatic

hypotension

bortezomib

have

evidence

orthostatic

hypotension

prior

treatment

with

bortezomib.

Most

patients

required

treatment

their

orthostatic

hypotension.

minority

patients

with

orthostatic

hypotension experienced syncopal events. Orthostatic/postural hypotension was not acutely

related to bolus infusion of bortezomib.

phase

studies

APEX

study,

incidence

hypotension

(postural,

orthostatic and hypotension not otherwise specified) was 11% to 12%. These events are

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

of syncope receiving medications known to be

associated

with hypotension and

with

patients

dehydrated.

Management

orthostatic/postural

hypotension

include

adjustment

antihypertensive

medications,

hydration,

administration

mineralocorticoids and/or sympathomimetics (see section 4.8).

Cardiac Disorders

Acute

development

exacerbation

congestive

heart

failure,

and/or

onset

decreased left ventricular ejection fraction has been reported, including reports in patients

with

few or no risk factors for decreased left ventricular ejection fraction. Patients with risk

factors for, or an existing heart disease should be closely monitored. In the phase III (APEX)

study of bortezomib

dexamethasone, the incidence of

any treatment-emergent

cardiac disorder was 15% and 13%, respectively. The incidence of heart failure events

(acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock,

pulmonary edema) was similar in the bortezomib and dexamethasone groups, 5% and 4%,

respectively.

There

have

been

isolated

cases

QT-interval

prolongation

clinical

studies; causality has not been established.

Pulmonary Disorders

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

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

Distress Syndrome (ARDS) in patients receiving bortezomib. Some of these events have

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been fatal. A higher proportion of these events have been reported in Japan. In the event of

worsening

pulmonary

symptoms,

prompt

diagnostic

evaluation

should

performed and patients treated appropriately.

In a clinical trial, two patients given high-dose cytarabine (2g/m

per day) by continuous

infusion with daunorubicin and bortezomib for relapsed acute myelogenous leukaemia died

of ARDS early in the course of therapy.

Posterior Reversible Encephalopathy Syndrome (PRES)

There have been reports of PRES in patients receiving bortezomib. PRES is a rare, reversible,

neurological

disorder

which

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

bortezomib. The

safety

reinitiating

bortezomib therapy

patients

previously experiencing PRES is not known.

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.

Laboratory Tests

Complete blood counts (CBC) should be frequently monitored throughout treatment with

bortezomib.

Thrombocytopenia:

Bortezomib

treatment

associated

with

thrombocytopenia

(see

section 4.8). Platelet counts were lowest at Day 11 of each cycle of bortezomib treatment

and typically recovered to baseline by the next cycle. On average, the pattern of platelet

count decrease and recovery remained consistent over the 8 cycles of twice weekly dosing,

and there was no evidence of cumulative thrombocytopenia. The mean platelet count nadir

measured was approximately 40% of baseline. The severity of thrombocytopenia related

to pre-treatment platelet count is shown in Table 7 for the APEX study. In the phase III

(APEX) study of bortezomib IV vs. dexamethasone, the incidence of significant bleeding

events (

Grade 3) was similar on both the bortezomib (4%) and dexamethasone (5%)

arms. Platelet counts should be monitored prior to each dose of bortezomib. Bortezomib

therapy should be held when the platelet count is <25,000/

L and reinitiated at a reduced

dose after resolution (see section 4.2

and section 4.8).

Transfusions may be used at the discretion of the physician. There have been reports of

gastrointestinal and intracerebral haemorrhage in association with bortezomib.

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Table 7: The Severity of Thrombocytopenia Related to Pre-treatment Platelet Count in the

APEX study

Pre-treatment Platelet

Count*

Number of Patients (N=

331)**

Number (%) of

Patients with Platelet

Count < 10,000/

L

Number (%) of

Patients with Platelet

Count 10,000/

L –

25,000

L

> 75,000/

8 (3%)

36 (12%)

> 50,000/

L - <75,000/

2 (14%)

11 (79%)

> 10,000/

L - <50,000/

1(14%)

5 (71%)

*A baseline platelet count of 50,000/

L was required for study eligibility.

**Data for one patient was missing at baseline

Thrombocytopenia was reported in 43% of patients in the phase II studies.

Gastrointestinal Adverse Events

Bortezomib treatment can cause nausea, diarrhoea, constipation and vomiting (see section

4.8)

sometimes

requiring

antiemetics

antidiarrhoeals.

Fluid

electrolyte

replacement

should

administered

prevent

dehydration.

Since

patients

receiving

bortezomib therapy may experience vomiting and/or diarrhoea, patients should be advised

regarding appropriate measures to avoid dehydration. Patients should be instructed to seek

medical advice if they experience symptoms of dizziness, light headedness or fainting spells.

Tumour Lysis Syndrome

Because bortezomib is a cytotoxic agent and can rapidly kill malignant cells the complications

of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndrome are those

with high tumour burden prior to treatment. These patients should be monitored closely

and appropriate precautions taken.

Hepatic Events

Rare 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. Such changes may be

reversible upon discontinuation of bortezomib. There is limited re-challenge information in

these patients.

Patients with Hepatic Impairment

Bortezomib

metabolized

liver

enzymes.

Bortezomib

exposure

increased

patients with moderate or severe hepatic impairment. Patients with moderate and severe

hepatic impairment should be treated with caution at reduced starting doses of bortezomib

and closely monitored for toxicities (see section 4.2 and 5.2).

Effects on Laboratory Tests

None known.

4.5 Interaction with other medicines and other forms of interaction

In vitro and animal ex vivo studies indicate that bortezomib is a weak inhibitor of cytochrome

P450 (CYP) isoenzymes, 1A2, 2C9. 2C19, 2D6, and 3A4. Based on the limited contribution

(7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metabolizer phenotype is

not expected to affect the overall disposition of bortezomib.

A drug-drug interaction study assessing the effect of ketoconazole (a potent CYP3A inhibitor) on

pharmacokinetics

bortezomib,

showed

bortezomib

mean

increase

35%, based on data from 12 patients. Therefore, patients should be closely monitored when

given bortezomib in combination with potent CYP3A4-inhibitors (e.g., ketoconazole, ritonavir).

In a drug-drug interaction study assessing the effect of omeprazole (a potent inhibitor of

CYP2C19) on the pharmacokinetics of IV bortezomib, there was no significant effect on

the pharmacokinetics of bortezomib, based on data from 17 patients.

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

the pharmacokinetics of bortezomib showed a mean bortezomib AUC reduction of 45%

based on data from 6 patients. The concomitant use of bortezomib with strong CYP3A4

inducers is not recommended, as efficacy may be reduced. Examples of CYP-3A4 inducers

are rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s Wort. IN the same

drug- drug interaction study, the effect of dexamethasone, a weaker CYP3A4 inducer was

assessed. There was no significant effect on bortezomib pharmacokinetics based on data

from 7 patients.

drug-drug

interaction

study

assessing

effect

melphalan-prednisone

bortezomib showed a 17% increase in mean bortezomib AUC based on data from 21

patients. This is not considered clinically relevant.

During clinical trials, hypoglycaemia and hyperglycaemia were reported in diabetic patients

receiving oral hypoglycaemics. Patients on oral antidiabetic agents receiving bortezomib

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

dose of their antidiabetic medication.

Patients should

cautioned about

the use of

concomitant

medications that

may be

associated

with

peripheral

neuropathy

(such

amiodarone,

anti-virals,

isoniazid,

nitrofurantoin, or statins), or with a decrease in blood pressure.

4.6 Fertility, pregnancy and lactation

Pregnancy

Category C

Women of child bearing potential should avoid becoming pregnant while being treated with

bortezomib.

The placental transfer of bortezomib is unknown, but any occurrence may

disrupt cycling in the developing foetus, although teratogenicity was not observed in rats and

rabbits at maximum tolerated doses.

Bortezomib w a s

teratogenic

nonclinical

developmental

toxicity

studies

rats

and rabbits at the highest dose tested (approximately 0.5 mg/m

/day) when administered

during organogenesis. These dosages are approximately half the clinical dose of 1.3 mg/m

based

body

surface

area

calculated

single-dose

basis.

Increased

post-

implantation loss and reduced foetal weights were seen in rabbits at the highest dose

tested,

which

a maternally

toxic

dose.

Litter

values

were

unaffected

non-

maternotoxic dose (approximately 0.3 mg/m

/day).

No placental transfer studies have been conducted with bortezomib. There are no adequate

and well-controlled studies in pregnant women. If bortezomib is used during pregnancy, or if

the patient becomes pregnant while receiving this drug, the patient should be informed of the

potential hazard to the foetus.

Patients should be advised to use effective contraceptive measures to prevent pregnancy.

Lactation

It is not known whether bortezomib or its metabolites are excreted in animal or human milk.

Because many drugs are excreted in human milk and because of the potential for serious

adverse

reactions

breast-fed

infants

from

bortezomib,

women

should

advised

against breast-feeding while being treated with bortezomib.

Fertility

Fertility studies with bortezomib were not performed but degenerative changes seen in the

testes and ovary in a rat general toxicity study suggest that bortezomib may affect male and

female fertility.

4.7 Effects on ability to drive and use machines

Bortezomib may cause tiredness, dizziness, fainting or blurred vision. Patients should be

advised not to drive or operate machinery if they experience these symptoms.

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4.8 Undesirable effects

Adverse events

Summary of Clinical Trials of bortezomib IV in patients with previously untreated

multiple myeloma:

Results from the GIMEMA and IFM2005 studies

The following table describes the safety data from the GIMEMA and IFM2005 studies in

patients with previously untreated multiple myeloma who were eligible for autologous stem cell

transplantation, and received bortezomib (1.3 mg/m

) in combination with thalidomide (100

mg, then 200 mg) and dexamethasone (40 mg) in the GIMEMA study, or dexamethasone (40

mg) in the IFM2005 study.

Table 8: Adverse events (Grade III/IV) following induction in randomised, controlled

studies GIMEMA and IFM2005

Adverse event, n (%)

GIMEMA

IFM2005

Bortezomib-TD

n=236

n=238

Bortezomib-D

n=239

n=239

Any adverse event

231 (96.7)*

219 (91.6)*

Any serious adverse event

31 (13.1)

30 (12.6)

65 (27.2)

81 (33.9)

Any grade 3 or 4 adverse event

132 (55.9)

79 (33.1)

112 (46.9)

110 (46.0)

Any grade 3 or 4 non-haematologic adverse

event

120 (50.8)

73 (30.6)

Skin rash

24 (10.1)

4 (1.6)

Peripheral neuropathy

23 (9.7)

5 (2.1)

17 (7.1)

5 (2.1)

Deep vein thrombosis

8 (3.3)

12 (5.0)

Constipation

10 (4.2)

7 (2.9)

Infections

21 (8.8)

29 (12.1)

Infections excluding herpes zoster

7 (2.9)

11 (4.6)

Herpes zoster (all grades)

22 (9.2)

5 (2.1)

Gastrointestinal events (excluding constipation

5 (2.1)

1 (0.4)

where individually reported)

Cardiac toxicity

5 (2.1)

5 (2.1)

Liver toxicity

4 (1.6)

7 (2.9)

Fatigue (all grades)

68 (28.5)

50 (20.9)

Oedema (all grades)

25 (11)

13 (5)

Any grade 3 or 4 haematologic adverse event

Anaemia

10 (4.2)*

21 (8.8)*

Neutropaenia

12 (5.0)*

24 (10.0)*

Thrombocytopenia

7 (2.9)

3 (1.3)

Thrombosis

4 (1.7)*

13 (5.4)*

Discontinued during or after induction therapy

13 (5.5)

26 (10.9)

44 (18.4)

32 (13.4)

Adverse event leading to death

1 (0.4)

0 (0)

0 (0)*

7 (2.9)*

* p < 0.05 for comparison of AE rate between Bortezomib-D and VAD Bortezomib-TD:

bortezomib-thalidomide-

dexamethasone; TD: thalidomide-dexamethasone; Bortezomib-D: bortezomib-dexamethasone; VAD: vincristine-

doxorubicine-dexamethasone.

During consolidation therapy of the GIMEMA study, grade 3-4 adverse events were similar to

those reported during induction, although rates were much lower. Notably, the rate of grade 3- 4

peripheral neuropathy was 1.2% with Bortezomib TD consolidation.

Results from the VISTA study

The following table describes safety data from the VISTA study in 340 patients with

previously untreated

multiple

myeloma

received

bortezomib

(1.3

mg/m

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