New Zealand - English - Medsafe (Medicines Safety Authority)
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
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
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
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
- Dr. Reddy’s when used in
combination with thalidomide and dexamethasone
Induction Therapy: Twice weekly Bortezomib (3 cycles)
t (100 mg) -
t (200 mg) -
d (40 mg)
Consolidation Therapy: Once Weekly Bortezomib (2 cycles)
Vc (1.3 mg/m
t (100 mg)
d (40 mg)
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
- Dr. Reddy’s when used in
combination with dexamethasone
Vc (1.3 mg/m
d (40 mg)-All Cycles
d (40 mg)-Cycle 1-2
Vc = bortezomib; d = dexamethasone
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
Table 3: Recommended Dosage Regimen for BORTEZOMIB - Dr. Reddy’s when used in
combination with melphalan and prednisone for Patients with Previously Untreated Multiple
Twice Weekly Bortezomib (Cycles 1-4)
Once Weekly Bortezomib (Cycles 5-9)
Vc (1.3 mg/m
m (9 mg/m
p (60 mg/m
Vc = bortezomib; m = melphalan, p=prednisone
Dose Management Guidelines
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
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
If platelet count ≤30 × 10
/L or ANC ≤0.75 x
/L on a bortezomib dosing day (other than
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
Bortezomib dose should be reduced by 1 dose level (from
to 1 mg/m
, or from 1 mg/m
to 0.7 mg/m
GRADE ≥ 3 NON-HAEMATOLOGICAL
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: 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
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
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)
* 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.
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
/dose reduced to 1.0 mg/m
/dose; 1.0 mg/m
/dose reduced to 0.7 mg/m
17 above contains the recommended dose modification for the management of patients who
Severe autonomic neuropathy resulting in treatment interruption or discontinuation has been
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
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
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
Modification of Starting Dose
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
in subsequent cycles based on patient tolerability
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.
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.
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:
Volume of diluent (0.9% Sodium Chloride) added to reconstitute
Final Concentration after reconstitution (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.
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.
Bortezomib is for IV or SC use only. DO NOT ADMINISTER BORTEZOMIB - Dr. Reddy’s
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
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
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
orthostatic hypotension prior to treatment with bortezomib. Most patients required treatment
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
sympathomimetics (see section 4.8).
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
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,
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 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.
Complete blood counts (CBC) should be frequently monitored throughout treatment with
BORTEZOMIB - Dr. Reddy’s.
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
Table 7: The Severity of Thrombocytopenia Related to Pre-treatment Platelet Count in the APEX
Number of Patients
Number (%) of
Patients with Platelet
Number (%) of Patients
with Platelet Count
10,000/µL – 25,000µL
> 50,000/µL - <75,000/µL
> 10,000/µL - <50,000/µL
*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
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.
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
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
nitrofurantoin, or statins), or with a decrease in blood pressure.
Effects on Laboratory Tests
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
Use in Pregnancy
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
organogenesis. These dosages are approximately half the clinical dose of 1.3 mg/m
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
(approximately 0.3 mg/m
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
Summary of Clinical Trials of bortezomib IV in patients with previously untreated
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.