Bortezomib - Dr. Reddy's

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Bortezomib 3.5 mg (as a mannitol boronic ester)
Available from:
Dr Reddy's New Zealand Limited
Dosage:
3.5 mg
Pharmaceutical form:
Powder for injection
Composition:
Active: Bortezomib 3.5 mg (as a mannitol boronic ester) Excipient: Mannitol
Prescription type:
Prescription
Therapeutic indications:
Bortezomib - Dr. Reddy's, 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 - Dr. Reddy's 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 - Dr. Reddy's 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, USP type l, 10 mL, bromobutyl rubber stopper and aluminium flip-off seal in outer cardboard carton - 1 dose units - 24 months from date of manufacture stored at or below 25°C protect from light 8 hours reconstituted stored at 2° to 8°C (Refrigerate, do not freeze)
Authorization number:
TT50-9579
Authorization date:
2014-06-13

New Zealand Datasheet

1 PRODUCT NAME

BORTEZOMIB – Dr. Reddy’s 3.5 mg powder for injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Bortezomib 3.5.mg as a mannitol boronic ester.

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Each single dose vial contains 3.5mg of bortezomib as a sterile lyophilised powder for

injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

BORTEZOMIB – Dr. Reddy’s 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 - Dr. Reddy’s, 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 - Dr. Reddy’s 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

BORTEZOMIB - Dr. Reddy’s is for intravenous or subcutaneous use only. Intrathecal

administration has resulted in death.

BORTEZOMIB - Dr. Reddy’s 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.

BORTEZOMIB - Dr. Reddy’s retreatment may be considered for multiple myeloma patients

who had previously responded to treatment with bortezomib (see section 5.1 - Clinical Trials).

Previously Untreated Multiple Myeloma

Transplant Eligible

1. BORTEZOMIB - Dr. Reddy’s plus thalidomide-dexamethasone

During the induction stage, BORTEZOMIB - Dr. Reddy’s is administered twice weekly in

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

stem cell transplantation, patients receive two 5-week cycles of bortezomide-thalidomide-

dexamethasone. The treatment regimen is shown in Table 1.

Table 1: Recommended dosage regimen for

BORTEZOMIB

- Dr. Reddy’s when used in

combination with thalidomide and dexamethasone

Induction Therapy: Twice weekly Bortezomib (3 cycles)

Week

1

2

3

Vc (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

Vc (1.3 mg/m

15

t (100 mg)

8-14

15-21

22-28

29-35

d (40 mg)

8

9

16

22

Vc = bortezomib; t = thalidomide; d = dexamethasone

2. BORTEZOMIB - Dr. Reddy’s plus dexamethasone

BORTEZOMIB - Dr. Reddy’s 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

- Dr. Reddy’s when used in

combination with dexamethasone

Week

1

2

3

Vc (1.3 mg/m

d (40 mg)-All Cycles

d (40 mg)-Cycle 1-2

Day 1-4

Day 9-12

Vc = bortezomib; d = dexamethasone

Non-Transplant Eligible

BORTEZOMIB - Dr. Reddy’s 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 - Dr. Reddy’s is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and

32). In Cycles 5-9, BORTEZOMIB - Dr. Reddy’s is administered once weekly (days 1, 8, 22

and 29).

Table 3: Recommended Dosage Regimen for BORTEZOMIB - Dr. Reddy’s when used in

combination with melphalan and prednisone for Patients with Previously Untreated Multiple

Myeloma

Twice Weekly Bortezomib (Cycles 1-4)

Week

1

2

3

4

5

6

Vc (1.3

mg/m

rest

period

Day 32

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

Vc (1.3 mg/m

rest period

Day 22

Day 29

rest period

m (9 mg/m

p (60 mg/m

rest period

rest period

Vc = bortezomib; m = melphalan, p=prednisone

Dose Management Guidelines

Dose

modification

re-initiation

therapy

when

BORTEZOMIB

Reddy’s

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 ≤30 × 10

/L or ANC ≤0.75 x

/L 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.

additional

information

concerning

melphalan

prednisone,

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

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 - Dr. Reddy’s 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 - Dr. Reddy’s.

It is recommended that patients with a confirmed complete response receive 2 additional

cycles of BORTEZOMIB - Dr. Reddy’s 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 - Dr. Reddy’s therapy.

extended

therapy

more

than

cycles,

BORTEZOMIB

Reddy’s

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 - Clinical Trials for a summary of dose administration during clinical trials).

Dose Modification and Re-initiation of Therapy

BORTEZOMIB - Dr. Reddy’s therapy should be withheld at the onset of any Grade 3 non-

haematological or Grade 4 haematological toxicities excluding neuropathy as discussed below

(see section 4.4 - Warnings and Precautions). Once the symptoms of the toxicity have

resolved, BORTEZOMIB - Dr. Reddy’s 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

17 above contains the recommended dose modification for the management of patients who

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

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

Therefore, dosing adjustments of BORTEZOMIB - Dr. Reddy’s 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 - Pharmacokinetics).

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 - Dr. Reddy’s 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 6).

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

Reduce bortezomib to 0.7 mg/m

in the 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

Method of Administration

Intravenous injection (IV)

BORTEZOMIB - Dr. Reddy’s is administered as a 3-5 second bolus intravenous injection

through a peripheral or central intravenous catheter followed by a 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.

local

injection

site

reactions

occur

following

BORTEZOMIB

Reddy’s

injection

subcutaneously, a less concentrated bortezomib solution (1 mg/mL instead of 2.5 mg/mL) may

be administered subcutaneously or change to IV injection.

Precautions to be taken before handling or administering this medicine.

Administration Precautions: BORTEZOMIB - Dr. Reddy’s is an antineoplastic. Caution should

be used during handling and preparation. Proper aseptic technique should be used. Use of

gloves and other protective clothing to prevent skin contact is recommended. In clinical trials,

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

associated with tissue damage.

When administered subcutaneously, alternate sites for each injection (thigh or abdomen). New

injections should be given at least one inch from an old site and never into areas where the

site is tender, bruised, red, or hard.

There

have

been

fatal

cases

inadvertent

intrathecal

administration

bortezomib.

BORTEZOMIB - Dr. Reddy’s

is for IV and subcutaneous use only. DO NOT ADMINISTER

BORTEZOMIB - Dr. Reddy’s INTRATHECALLY.

Reconstitution/Preparation Administration: Prior to use, the contents of each vial must be

reconstituted only with normal (0.9%) saline, Sodium Chloride for Injection according to the

following instructions based on route of administration:

IV

SC

(3.5 mg

bortezomib)

(3.5 mg

bortezomib)

Volume of diluent (0.9% Sodium Chloride) added to reconstitute

one vial

3.5 mL

1.4 mL

Final Concentration after reconstitution (mg/mL)

1.0 mg/mL

2.5 mg/mL

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

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

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

For instructions on reconstitution of the medicine before administration, see section 6.6.

Procedure for proper disposal: Any unused product or waste material should be disposed of

in accordance with local requirements.

4.3 Contraindications

BORTEZOMIB - Dr. Reddy’s is contraindicated in patients with hypersensitivity to bortezomib,

boron or mannitol.

4.4 Special warnings and precautions for use

Overall treatment with BORTEZOMIB - Dr. Reddy’s 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

inadvertent

intrathecal

administration

bortezomib.

Bortezomib is for IV or SC use only. DO NOT ADMINISTER BORTEZOMIB - Dr. Reddy’s

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.

Peripheral Neuropathy

Bortezomib treatment causes a peripheral neuropathy (PN) that is 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

in the feet or hands) and/or signs of peripheral neuropathy may experience worsening

(including ≥ Grade 3) during treatment with bortezomib. Patients should be monitored for

symptoms of neuropathy, such as a 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 in or resolution of 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 as postural hypotension and 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 to 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.

In phase II studies and the APEX study, the incidence of 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 who are

dehydrated. Management of orthostatic/postural hypotension may include adjustment of

antihypertensive

medications,

hydration,

administration

mineralocorticoids

and/or

sympathomimetics (see section 4.8).

Cardiac Disorders

Acute development or exacerbation of congestive heart failure, and/or new onset of 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 IV vs. 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 of QT-interval prolongation in clinical studies; causality has not been

established.

Pulmonary Disorders

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

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

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

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

worsening pulmonary symptoms, a prompt diagnostic evaluation should be performed and

patients treated appropriately.

In a clinical trial, two patients given high-dose cytarabine (2 g/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 can present with seizure, hypertension, headache, lethargy,

confusion,

blindness,

other

visual

neurological

disturbances.

Brain

imaging,

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

developing PRES, discontinue bortezomib. The safety of reinitiating bortezomib therapy in

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 - Dr. Reddy’s.

Thrombocytopenia:

Bortezomib

treatment

associated

with

thrombocytopenia

(see

Adverse Effects). 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/µL and reinitiated at a reduced dose after resolution

(see sections 4.2 and 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.

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/µL

Number (%) of Patients

with Platelet Count

10,000/µL – 25,000µL

> 75,000/µL

8 (3%)

36 (12%)

> 50,000/µL - <75,000/µL

2 (14%)

11 (79%)

> 10,000/µL - <50,000/µL

1(14%)

5 (71%)

*A baseline platelet count of 50,000/µL 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 - Adverse Effects) sometimes requiring use of antiemetics and antidiarrhoeals. Fluid and

electrolyte replacement should be administered to 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 - Dr. Reddy’s 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 - Dr. Reddy’s. There is limited re-challenge

information in these patients.

Patients with Hepatic Impairment

Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in 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 - Dr.

Reddy’s and closely monitored for toxicities (see sections 4.2 and 5.2).

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 the pharmacokinetics of IV bortezomib, showed a bortezomib AUC mean increase of 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.

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.

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

Effects on Laboratory Tests

None known.

4.6 Fertility, pregnancy and lactation

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.

Use in Pregnancy

Category C

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

BORTEZOMIB - Dr. Reddy’s. 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 was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits

highest

dose

tested

(approximately

mg/m

/day)

when

administered

during

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

based

on body surface area and calculated on a single-dose basis. Increased post-implantation loss

and reduced foetal weights were seen in rabbits at the highest dose tested, which was 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 - Dr. Reddy’s 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.

Use in 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 in breast-fed infants from bortezomib, women should be advised against

breast-feeding while being treated with BORTEZOMIB - Dr. Reddy’s.

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.

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.

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