Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
APPROVED PROFESSIONAL INFORMATION FOR BORTIV  
SCHEDULING STATUS  
S4  
PROPRIETARY NAME (AND DOSAGE FORM)  
BORTIV (powder for solution for injection)  
COMPOSITION  
Each 10 ml vial contains 3,5 mg bortezomib.  
BORTIV also contains the following excipients: mannitol (3,5 mg/ml), tertiary butyl alcohol, water for injection.  
BORTIV contains sugar (mannitol)  
PHARMACOLOGICAL CLASSIFICATION  
A 26 Cytostatic agents.  
PHARMACOLOGICAL ACTION:  
Pharmacodynamic properties:  
Bortezomib is a proteasome inhibitor. It specifically inhibits 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 orchestrating the turnover of specific proteins, thereby  
maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis and  
affects multiple signaling cascades within the cell, ultimately resulting in cell death.  
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Page 1 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Bortezomib is selective for the proteasome. At 10 μΜ concentration bortezomib does not inhibit any of a wide  
variety of receptors and proteases screened and is more than 1500-fold more selective for the proteasome than  
for its next preferable enzyme. The kinetics of proteasome inhibition were evaluated in vitro, and bortezomib was  
shown to dissociate from the proteasome with a t1/2 of 20 minutes, thus demonstrating that proteasome inhibition  
by bortezomib is reversible.  
Bortezomib mediated proteasome inhibition affects cells in a number of ways, including, but not limited to, altering  
regulatory protein, which control cell cycle progression and Nuclear Factor kappa B (NF-kB) activation. The  
inhibition of the proteasome results in cell cycle arrest and apoptosis. NF-kB is a transcription factor whose  
activation is required for many aspects of tumorigenesis, including cell growth and survival, angiogenesis, cell:cell  
interactions, and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone  
marrow microenvironment.  
Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types and that cancer  
cells are more sensitive to the proapoptotic effects of proteasome inhibition than normal cells.  
Bortezomib causes reduction of tumour growth in vivo in many preclinical tumour models, including multiple  
myeloma.  
Pharmacokinetic properties:  
Following intravenous bolus administration of a 1,0 mg/m2 and 1,3 mg/m2 dose to eleven patients with multiple  
myeloma, the mean maximum plasma concentrations of Bortezomib were 57 and 112 mg/mℓ respectively after  
the first dose. In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106  
ng/mℓ for the 1,0 mg/m2 dose and 89 to 120 ng/mℓ for the 1,3 mg/m2 dose.  
The mean elimination half-life of bortezomib upon multiple dosing ranged from 40-193 hours.  
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Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Mean total body  
clearances were 102 and 112 ℓ/h following the first dose for doses of 1,0 mg/m2 and 1,3 mg/m2, respectively, and  
ranged from 15 to 32 ℓ/h following subsequent doses for doses of 1,0 mg/m2 and 1,3 mg/m2, respectively.  
Distribution:  
The mean distribution volume of bortezomib was variable and ranged from 1 659 litres to  
3 294 litres following single- or repeat-dose administration of 1,0 mg/m2 or 1,3 mg/m2 to patients with multiple  
myeloma. This suggests that bortezomib distributes widely to peripheral tissues. The binding of bortezomib to  
human plasma averaged 83 % over the concentration range 100-1000 mg/ml.  
Metabolism:  
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate  
that bortezomib is primarily oxidatively metabolised via cytochrome P450 enzymes, 3A4, 2C19, and 1A2.  
Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation  
to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites.  
Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors. 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 characterised in humans.  
Special populations:  
The effects of age, gender, and race on pharmacokinetic of bortezomib have not been evaluated.  
Hepatic impairment:  
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Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in 51 cancer patients at  
bortezomib doses ranging from 0,5 to 1,3 mg/m2. When compared to patients with normal hepatic function, mild  
hepatic impairment did not alter dose-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 Table 2).  
Renal impairment:  
A pharmacokinetic study was conducted in patients with various degrees of renal  
impairment who were classified according to their creatinine clearance values (CrCL) into  
the following groups: Normal (CrCL ≥ 60 mℓ / min/1,73 m2, n=12), Mild (CrCL=40-59 mℓ /  
min/1,73 m2, n=10), Moderate (CrCL=20-39 mℓ / min/1,73 m2, n=9), and Severe (CrCL < 20 mℓ / min/1,73 m2,  
n=3). A group of dialysis patients who were dosed after dialysis was also included in the study (n=8). Patients  
were administered intravenous doses of 0,7 to 1,3 mg/m2 of bortezomib twice weekly. Exposure of bortezomib  
(dose-normalized AUC and Cmax) was comparable among all the groups (see DOSAGE AND DIRECTIONS FOR  
USE).  
INDICATIONS:  
BORTIV powder for solution for injection is indicated for:  
−
−
Primary treatment of multiple myeloma in combination with melphalan and prednisone.  
Monotherapy for the treatment of patients with multiple myeloma who have received at least one prior  
therapy and who have progressive disease.  
−
Treatment of relapsed or refractory mantle cell lymphoma for patients who have received at least 1 prior  
line of therapy, one of which should have included an anthracycline (or mitoxantrone) and/or rituximab  
as part of their chemotherapy regimen.  
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Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
CONTRAINDICATIONS:  
•
•
Hypersensitivity to any of the ingredients of BORTIV, boron, including the excipients.  
BORTIV is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal  
administration of BORTIV.  
•
•
Severe hepatic impairment.  
Pregnancy (see PREGNANCY AND LACTATION).  
WARNINGS AND SPECIAL PRECAUTIONS:  
Treatment must be initiated and administered under the supervision of a medical practitioner and experienced in  
the use of chemotherapeutic medicines.  
There have been fatal cases of inadvertent intrathecal administration of BORTIV.  
BORTIV is for IV use only.  
DO NOT ADMINISTER BORTIV INTRATHECALLY.  
Based on the integrated safety database from 256 patients with relapsed and/or refractory multiple myeloma, the  
following special precautions are suggested:  
Overall, the safety profile of patients treated with BORTIV in monotherapy was similar to that observed in patients  
treated with BORTIV in combination with melphalan and prednisone.  
Laboratory Tests:  
Complete blood counts (CBC) including platelet counts should be frequently monitored throughout treatment with  
BORTIV.  
Gastrointestinal toxicity:  
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Page 5 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Gastrointestinal toxicity, including diarrhoea, constipation, nausea and vomitinq are very common with BORTIV  
treatment (see SIDE EFFECTS). Reactions usually occur early in treatment (Cycles 1 and 2) and may persist for  
several cycles. Patients experiencing treatment emergent gastrointestinal toxicity may benefit from administration  
of anti-emetics and anti-diarrhoeals. Fluid and electrolyte replacement should be administered to prevent or treat  
dehydration. Cases of ileus have been reported, therefore patients who experience constipation should be closely  
monitored.  
Haematological toxicity:  
BORTIV treatment is very commonly associated with haematological toxicities (thrombocytopenia and  
neutropenia). However, febrile neutropenia is an uncommon undesirable effect. The most common haematologic  
toxicity is transient thrombocytopenia, which generally resolves between treatment cycles. Platelets were lowest  
at Day 11 of each cycle of BORTIV treatment and typically recovered to baseline by the next cycle. The cyclical  
pattern of platelet decrease and recovery remained consistent over the 8 cycles of twice weekly dosing and there  
was no evidence of cumulative thrombocytopenia including the Phase II extension study. The mean platelet count  
nadir measured was approximately 40 % of baseline. Severe bleeding, including CNS and gastrointestinal  
bleeding, associated with thrombocytopenia, has been reported. In patients with advanced myeloma, the severity  
of thrombocytopenia was related to pre-treatment platelet count (see Table 6). Platelet counts should be  
monitored prior to each dose of BORTIV. Therapy should be held when the platelet count is < 25,000/μℓ and re-  
initiated at a reduced dose after resolution (see SIDE EFFECTS). Potential benefit of the treatment should be  
carefully weighed against the risks. Platelet transfusions, red blood cell (RBC) transfusions and administration of  
growth factors may be utilised in the management of haematologic toxicities. Prophylactic platelet transfusions  
should be considered in thrombocytopenic patients at high risk of bleeding.  
Table 6: The severity of Thrombocytopenia Related to Pre-treatment Platelet Count in the Phase 3 Study  
Multiple Myeloma Study  
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Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Pretreatment  
Count  
Platelet Number  
Patients  
of Number  
Patients  
of Number  
of  
with  
with Patients  
(N=331)*  
Platelet Count < Platelet  
Count  
10 000/μℓ  
8 (3 %)  
10 000 – 20 000/μℓ  
36 (12 %)  
≥ 75 000/μℓ  
309  
> 50 000/μℓ - 75 000/μℓ  
14  
7
2 (14 %)  
1 (14 %)  
11 (79 %)  
≥ 10 000/μℓ - <50 000/μℓ  
5 (71 %)  
* Data for one patient was missing at baseline.  
Peripheral Neuropathy:  
BORTIV treatment causes a peripheral neuropathy 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 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 BORTIV. The incidence of peripheral neuropathy increases early in the treatment and has been observed  
to peak during cycle 5.  
It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burning sensation,  
hyperaesthesia, hypoaesthesia, paraesthesia, discomfort or neuropathic pain. Patients experiencing new or  
worsening peripheral neuropathy may require the dose and schedule of BORTIV to be modified (see DOSAGE  
AND DIRECTIONS FOR USE). Neuropathy has been managed with supportive care and other therapies.  
Peripheral neuropathy may not be reversible.  
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Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Improvement in, or resolution of, peripheral neuropathy was reported in 51 % of patients with ≥ Grade 2 peripheral  
neuropathy in single agent phase III multiple myeloma study and 71 % of patients with grade 3 or 4 peripheral  
neuropathy or peripheral neuropathy leading to discontinuation of treatment in phase II studies, respectively.  
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. The long term outcome of peripheral neuropathy has  
not been studied in Mantle Cell Lymphoma.  
Seizures:  
Seizures have been uncommonly reported in patients without previous history of seizures or epilepsy. Special  
care is required when treating patients with any risk factors for seizures.  
Hypotension:  
BORTIV treatment is commonly associated with orthostatic/postural hypotension.  
Most patients required treatment for their orthostatic hypotension. Patients with orthostatic hypotension  
experienced syncopal events. The mechanism of this event is unknown although a component may be due to  
autonomic neuropathy. Autonomic neuropathy may be related to BORTIV or BORTIV may aggravate an  
underlying condition such as diabetic neuropathy.  
Caution is advised when treating patients with a history of syncope receiving medicinal products known to be  
associated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting. Management of  
orthostatic/postural hypotension is symptomatic and may include adjustment of antihypertensive medicinal  
products, rehydration or administration of mineralocorticosteroids and/or sympathomimetics. Patients should be  
instructed to seek medical advice if they experience symptoms of dizziness, light-headedness or fainting spells.  
Cardiac disorders:  
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Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection  
fraction has been reported. Patients with risk factors for, or existing heart disease should be closely monitored.  
Fluid retention may be a predisposing factor for signs and symptoms of heart failure.  
There have been isolated cases of QT-interval prolongation in clinical trials, causality has not been established.  
Patients using angiotensin inhibitors, beta-blockers, antihypertensives, calcium channel blockers, angiotensin  
receptor blockers and diuretics may have a higher incidence of cardiac failure during BORTIV treatment.  
Pulmonary Disorders:  
There have been 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  
BORTIV. 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, the first two patients given high doses cytarabine (2 g/m2 per day) by continuous infusion in  
combination with daunorubicin and BORTIV for relapsed acute myelogenous leukaemia died of ARDS early in  
the course of therapy. The trial was discontinued subsequently.  
Renal Events:  
Renal complications are frequent in patients with multiple myeloma. Such patients should be monitored closely.  
Hepatic Events:  
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JAN 2023 (esub-vrr-0002)  
Page 9 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Cases of acute liver failure have been reported. Other reported hepatic events include asymptomatic increases  
in liver enzymes, hyperbilirubinemia and hepatitis. Such changes may be reversible upon discontinuation of  
BORTIV. There is limited re-challenge information in these patients.  
Hepatic Impairment:  
BORTIV is metabolised by liver enzymes.  
BORTIV exposure is increased in patients with moderate or severe hepatic impairment. These patients should  
be treated with BORTIV at reduced starting doses and closely monitored for toxicities. See (DOSAGE AND  
DIRECTIONS FOR USE and PHARMACOKINETICS).  
Tumour lysis syndrome:  
Because BORTIV is a cytotoxic substance and can rapidly kill malignant plasma 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 reactions monitored closely and appropriate precautions taken.  
Amyloidosis:  
The impact of proteasome inhibition by BORTIV on disorders associated with protein accumulation such as  
amyloidosis is unknown. Caution is advised in these patients.  
Potentially immunocomplex-mediated reactions:  
Potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis with rash  
and proliferative glomerulonephritis have been reported uncommonly. BORTIV should be discontinued if severe  
reactions occur.  
Reversible Posterior Leukoencephalopathy Syndrome (RPLS):  
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Page 10 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
There have been reports of RPLS in patients receiving BORTIV. RPLS 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 RPLS, discontinue BORTIV.  
The safety of reinitiating BORTIV therapy in patients previously experiencing RPLS is not known.  
Effects on ability to drive and use machines:  
BORTIV may have a moderate influence on the ability to drive and use machines.  
BORTIV may be associated with fatigue, dizziness, syncope, orthostatic/postural hypotension or blurred vision.  
Therefore, patients must be cautious when operating machinery, or when driving.  
Any special precaution necessary relating to excipients:  
BORTIV contains mannitol. At doses that exceeds 10 g of mannitol per maximum recommended daily dose  
BORTIV may have a laxative effect.  
INTERACTIONS:  
In vitro studies indicate that BORTIV is a weak inhibitor of the cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19,  
2D6 and 3A4. Based on the limited contribution (7 %) of CYP2D6 to the metabolism of BORTIV the CYP2D6  
poor metaboliser phenotype is not expected to affect the overall disposition of BORTIV.  
An interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of  
BORTIV, showed a bortezomib AUC mean increase of 35 %, based on data from 12 patients. Therefore, patients  
should be monitored closely when given BORTIV in combination with potent CYP3A4-inhibitors (e.g.  
ketoconazole, ritonavir).  
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Page 11 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
In an interaction study assessing the effect of omeprazole, a potent inhibitor of CYP2C19, on the  
pharmacokinetics of BORTIV there was no significant effect on the pharmacokinetics of bortezomib, based on  
data from 17 patients.  
An interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of  
BORTIV showed a mean bortezomib AUC reduction of 45 % based on data from 6 patients. The concomitant  
use of BORTIV with strong CYP3A4 inducers is therefore not recommended, as efficacy may be reduced.  
Examples of CYP3A4 inducers are rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's Wort. In  
the same 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.  
Concomitant exposure to narcotics may increase the incidence of constipation, nausea and vomiting.  
An interaction study assessing the effect of melphalan-prednisone on BORTIV 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 medicines receiving BORTIV treatment may require close monitoring of their blood  
glucose levels and adjustment of the dose of their antidiabetic medication. Normal liver function should be  
confirmed and caution should be exercised in patients receiving oral hypoglycaemic.  
PREGNANCY AND LACTATION:  
Safety in pregnancy and lactation has not been established.  
Pregnancy:  
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Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
BORTIV should be avoided during pregnancy and women are advised to avoid falling pregnant while on treatment  
with BORTIV.  
Males and females of childbearing capacity should use effective contraceptive measures during treatment and  
for 3 months following BORTIV therapy. If BORTIV is used during pregnancy, or if the patient becomes pregnant  
while receiving BORTIV, the patient needs to be informed of potential for hazards to the foetus.  
Lactation:  
It is not known whether BORTIV is excreted in human milk. Because of the potential for serious undesirable  
effects in breast-fed infants from BORTIV, women should breastfeeding their infants while receiving BORTIV.  
DOSAGE AND DIRECTIONS FOR USE:  
Administration Precautions  
BORTIV IS FOR INTRAVENOUS USE ONLY.  
Intrathecal administration has resulted in death.  
Monotherapy  
Recommended dosage:  
The recommended starting dose of BORTIV is 1,3 mg/m2 body surface area 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 lapse between consecutive doses of BORTIV.  
It is recommended that patients with a confirmed complete response receive 2 additional cycles of BORTIV  
beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission  
receive a total of 8 cycles of BORTIV therapy.  
There are limited data concerning re-treatment with BORTIV.  
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Page 13 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Recommended dosage adjustments during treatment and re-initiation of treatment:  
BORTIV treatment must be withheld at the onset of any grade 3 non-haematological or any grade 4  
haematological toxicities, excluding neuropathy as discussed below (see also WARNINGS AND SPECIAL  
PRECAUTIONS). Once the symptoms of the toxicity have resolved, BORTIV treatment may be re-initiated at a  
25 % reduced dose (1,3 mg/m2 reduced to 1,0 mg/m2; 1,0 mg/m2 reduced to 0,7mg/m2) . If toxicity is not resolved  
or if it recurs at the lowest dose, discontinuation of BORTIV must be considered.  
Patients who experience BORTIV related neuropathic pain and/or peripheral neuropathy are to be managed as  
presented in table 1. Patients with pre-existing severe neuropathy may be treated with BORTIV only after careful  
risk/benefit assessment.  
Table 1: Recommended* dose modifications for BORTIV related Neuropathic Pain and /or Peripheral  
Sensory Neuropathy  
Severity of peripheral neuropathy  
Modification  
regimen  
of  
dose  
and  
Grade 1 (paraesthesia, weakness and/or loss of No action  
reflex) with no pain or loss of function  
Grade 1 with pain or grade 2 (interfering with Reduce to 1,0 mg/m2  
function but not activities of daily living)  
Grade 2 with pain or Grade 3 (interfering with Withhold BORTIV treatment until  
activities of daily living)  
symptoms  
of  
toxicity  
have  
resolved. When toxicity resolves  
re-initiate BORTIV treatment and  
reduce dose to 0,7 mg/m2 and  
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Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
change treatment schedule to  
once per week.  
Grade 4 (sensory neuropathy which is disabling or Discontinue BORTIV  
motor neuropathy that is life threatening or leads to  
paralysis)  
* based on dose modification in phase II and Ill multiple myeloma studies  
Paediatric patients:  
BORTIV has not been studied in children and adolescents. Therefore, it should not be used in the paediatric age  
group until further data become available.  
Elderly patients:  
There is no evidence to suggest that dose adjustments are necessary in the elderly (see SIDE EFFECTS).  
Patients with renal impairment:  
The pharmacokinetics of BORTIV are not influenced by the degree of renal impairment. Therefore, dosing  
adjustments of BORTIV are not necessary for patients with renal insufficiency. Since dialysis may reduce  
BORTIV  
concentrations,  
BORTIV  
should  
be  
administered  
after  
the  
dialysis  
procedure  
(see  
PHARMACOKINETIC PROPERTIES).  
Patients with Hepatic Impairment:  
Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the  
recommended BORTIV dose. Patients with moderate or severe hepatic impairment should be started on BORTIV  
at a reduced dose of 0,7 mg/m2 per injection during the first cycle, and a subsequent dose escalation to 1,0 mg/m2  
or further dose reduction to 0,5 mg/m2 may be considered based on patient tolerance (see Table 2).  
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Page 15 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Table 2: Recommended Starting Dose Modification for BORTIV in Patients with Hepatic Impairment  
Bilirubin Level  
SGOT (AST) Levels  
Modification of Starting  
Dose  
Mild  
≤ 1,0 Χ ULN  
> ULN  
Any  
None  
> 1,0 Χ -1,5 Χ ULN  
> 1,5 Χ -3 Χ ULN  
> 3 Χ ULN  
None  
Moderate  
Severe  
Any  
Reduce BORTIV to 0,7  
mg/m2 in the first cycle.  
Consider dose escalation  
to 1,0 mg/m2 or further  
dose reduction to 0,5  
Any  
mg/m2  
in  
subsequent  
cycles based on patient  
tolerability.  
Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN =  
upper limit of the normal range.  
Administration:  
Administration Precautions:  
There have been fatal cases of inadvertent intrathecal administration of BORTIV.  
BORTIV is for IV use only.  
DO NOT ADMINISTER BORTIV INTRATHECALLY.  
The reconstitution solution 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.  
Combination therapy  
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JAN 2023 (esub-vrr-0002)  
Page 16 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Recommended dosage:  
BORTIV (bortezomib) is administered as a 3-5 second bolus IV injection in combination with oral melphalan and  
oral prednisone for nine 6-week treatment cycles as shown in Table 3.  
In cycles 1-4 BORTIV is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32).  
In cycles 5-9, BORTIV is administered once weekly (days 1, 8, 22 and 29).  
Table 3: Recommended dosage regimen for BORTIV when used in combination with melphalan and  
prednisone for patients with previously untreated multiple myeloma:  
Twice weekly BORTIV (cycles 1-4)  
Week  
Vc  
1
2
3
4
5
6
Day  
1
Day  
4
Day Day  
Rest  
period  
Day Day  
Day  
29  
Day Rest  
(1,3  
8
11  
22  
--  
25  
32  
Perio  
d
mg/m2)  
m(9  
Day  
1
Day  
2
--  
--  
Rest  
--  
--  
--  
Rest  
perio  
d
mg/m2)  
p(60  
period  
Day  
3
Day  
4
mg/m2)  
Once weekly BORTIV (cycles 5-9)  
Week  
Vc  
1
2
3
4
5
Day 29  
6
Day - - -  
1
Day  
8
Rest  
period  
Day 22  
Rest  
Perio  
d
(1,3  
mg/m2)  
m(9  
Day  
1
Day  
--  
Rest  
--  
--  
Rest  
perio  
d
mg/m2)  
2
period  
Day  
Day  
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JAN 2023 (esub-vrr-0002)  
Page 17 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
p(60  
3
4
mg/m2)  
Vc = BORTIV; m = melphalan; p = prednisone  
Dose Management Guidelines for Combination Therapy:  
Dose modification and re-initiation of therapy when BORTIV is administered in combination with melphalan and  
prednisone prior to initiating a new cycle of therapy:  
−
−
Platelet count should be ≥ 70 x 109/ℓ and the ANC should be ≥ 1,0 x109/ℓ  
Non-haematological 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 Consider reduction of the melphalan dose  
thrombocytopenia  
with  
bleeding  
is by 25 % in the next cycle.  
observed in the previous cycle  
If platelet count ≤ 30 x 109/ℓ or ANC ≤ 0,75 BORTIV dose should be withheld.  
x 109/ℓ on a BORTIV dosing day (other than  
day 1)  
If several BORTIV doses in a cycle are BORTIV dose should be reduced by 1  
withheld (≥ 3 doses during twice weekly dose level (from 1,3 mg/m2 to 1 mg/m2 or  
administration or ≥ 2 doses during weekly from 1 mg/m2 to 0,7 mg/m2)  
administration  
Grade ≥ 3 non haematological toxicities  
BORTIV therapy should be withheld until  
symptoms of the toxicity have resolved to  
Grade 1 or baseline. Then, BORTIV may  
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Page 18 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
be reinitiated with one dose level reduction  
(from 1,3 mg/m2 to 1 mg/m2 or from 1  
mg/m2 to 0,7 mg/m2). For BORTIV–  
related neuropathic pain and/or peripheral  
neuropathy, hold and/or modify BORTIV  
as outlined in Table 1.  
For additional information concerning melphalan and prednisone, see the respective package inserts.  
Instructions for use and handling and disposal:  
For single use only.  
BORTIV is a cytotoxic medicine. Therefore, caution should be used during handling and preparation. Use of  
gloves and other protective clothing to prevent skin contact is recommended.  
Administration Precautions  
There have been fatal cases of inadvertent intrathecal administration of BORTIV.  
BORTIV is for IV use only.  
DO NOT ADMINISTER BORTIV INTRATHECALLY.  
ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF BORTIV SINCE  
NO PRESERVATIVE IS PRESENT:  
BORTIV is provided as a lyophilised powder in the form of a mannitol boronic ester. When reconstituted, the  
mannitol ester is in equilibrium with its hydrolysis product, the monomeric boronic acid.  
The contents of each 10 ml vial must be constituted with 3,5 mℓ of normal (0,9 %) saline. Dissolution is completed  
in less than 2 minutes. The reconstituted solution is clear and colourless, with a final pH of 4 to 7.  
Initial………KB……  
JAN 2023 (esub-vrr-0002)  
Page 19 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
The reconstituted solution must be inspected visually for particulate matter and discolouration prior to  
administration. If any discolouration or particulate matter is observed, the reconstituted product must be  
discarded.  
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, with a maximum of 8 hours in the syringe.  
Any unused product or waste material should be disposed of appropriately.  
SIDE EFFECTS:  
The following undesirable effects included are considered to have at least a possible or probable causal  
relationship to BORTIV.  
Infections and infestations:  
Frequent: herpes zoster (including disseminated), pneumonia, bronchitis, sinusitis, nasopharyngitis, herpes  
simplex.  
Less frequent: sepsis, bacteraemia, pneumonia pneumococcal, bronchopneumonia, upper and lower respiratory  
tract infection, catheter related infection, pleural infection, haemophilus infection, cytomegalovirus infection,  
influenza, infectious, mononucleosis, varicella, urinary tract infection, gastroenteritis, candidal infection, fungal  
infection, post herpetic neuralgia oral candidiasis, blepharitis, infection.  
Neoplasms benign, malignant and unspecified (including cysts and polyps):  
Less frequent: tumour lysis syndrome (see WARNINGS AND SPECIAL PRECAUTIONS).  
Initial………KB……  
JAN 2023 (esub-vrr-0002)  
Page 20 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Blood and the lymphatic system disorders (see WARNINGS AND SPECIAL PRECAUTIONS):  
Frequent: thrombocytopenia, neutropenia, anaemia, leukopenia, lymphopenia.  
Less frequent: pancytopenia, febrile neutropenia, haemolytic anaemia, thrombocytopenic purpura, and  
lymphadenopathy.  
Immune system disorders:  
Less frequent: hypersensitivity, immunocomplex mediated hypersensitivity, potentially immuneocomplex-  
mediated reactions, such as serum-sickness-type reaction, polyarthritis with rash and proliferative  
glomerulonephritis (see WARNINGS AND SPECIAL PRECAUTIONS).  
Endocrine disorders:  
Less frequent: inappropriate antidiuretic hormone (ADH) secretion.  
Metabolism and nutrition disorders:  
Frequent: appetite decreased, dehydration, hypokalaemia, hyperglycaemia.  
Less frequent: hyperkalaemia, cachexia, hypercalcaemia, hypocalcaemia, hypernatremia, hyponatraemia,  
hypoglycaemia,  
hyperuricaemia,  
vitamin  
B12  
deficiency,  
appetite  
increased,  
hypomagnesaemia,  
hypophosphataemia.  
Psychiatric disorders:  
Frequent: confusion, depression, insomnia, anxiety.  
Less frequent: agitation, delirium, hallucinations, restlessness, mood swings, mental status changes, sleep  
disorder, irritability, abnormal dreams.  
Nervous system disorders:  
Initial………KB……  
JAN 2023 (esub-vrr-0002)  
Page 21 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Frequent: peripheral neuropathy, peripheral sensory neuropathy, paraesthesia, headache, polyneuropathy,  
peripheral neuropathy aggravated, dizziness (excluding vertigo), dysgeusia, dysaesthesia, hypoesthesia, tremor.  
Less frequent: paraplegia, intracranial haemorrhage, subarachnoid haemorrhage convulsions, peripheral motor  
neuropathy, syncope, paresis, disturbance in attention, increased activity, ageusia, somnolence, migraine,  
cognitive disorder, jerky movements, dizziness postural, sciatica, mononeuropathy, speech disorder, restless leg  
syndrome.  
Eye disorders:  
Frequent: vision blurred, eye pain.  
Less frequent: eye haemorrhage, vision abnormal, keratitis sicca, conjunctivitis, eye discharge, photophobia, eye  
irritation, lacrimation increased, conjunctival hyperaemia, eye swelling.  
Ear and labyrinth disorders:  
Frequent: vertigo.  
Less frequent: deafness, tinnitus, hypoacusis, hearing impaired.  
Cardiac disorders:  
Less frequent: cardiac arrest, cardiogenic shock, myocardial infarction, angina pectoris, angina unstable,  
development or exacerbation of congestive heart failure (see WARNINGS AND SPECIAL PRECAUTIONS),  
cardiac failure, ventricular hypokinesia, pulmonary oedema and acute pulmonary oedema, sinus arrest,  
atrioventricular block complete, tachycardia, sinus tachycardia, supraventricular tachycardia, arrhythmia, atrial  
fibrillation, palpitations, new onset of decreased left ventricular ejection fraction (see WARNINGS AND SPECIAL  
PRECAUTIONS).  
Vascular disorders:  
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JAN 2023 (esub-vrr-0002)  
Page 22 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Frequent: hypotension, orthostatic and postural hypotension (see WARNINGS AND SPECIAL PRECAUTIONS),  
phlebitis, haematoma, hypertension.  
Less frequent: cerebral haemorrhage, vasculitis, cerebrovascular accident, pulmonary hypertension, petechiae,  
ecchymosis, purpura, vein discolouration, vein distended, wound haemorrhage, flushing, hot flushes.  
Respiratory, thoracic and mediastinal disorders  
Frequent: dyspnoea, dyspnoea exertional, epistaxis, cough, rhinorrhoea.  
Less frequent: respiratory arrest, hypoxia, pulmonary congestion, pleural effusion, asthma, respiratory alkalosis,  
tachypnoea, wheezing, nasal congestion, hoarseness, rhinitis, hyperventilation, orthopnoea, chest wall pain,  
sinus pain, throat tightness, productive cough.  
Gastrointestinal disorders:  
Frequent: vomiting, diarrhoea, nausea, constipation, abdominal pain, stomatitis, dyspepsia, loose stools,  
abdominal pain upper, flatulence, abdominal distension, hiccups, mouth ulceration, pharyngolaryngeal pain, dry  
mouth.  
Less frequent: acute pancreatitis, ileus paralytic, antibiotic associated colitis, colitis, haematemesis, diarrhoea  
haemorrhagic, gastrointestinal haemorrhage, rectal haemorrhage, enteritis, dysphagia, abdominal discomfort,  
eructation, gastrointestinal motility disorder, oral pain, retching, change in bowel habit, spleen pain, oesophagitis,  
gastritis, gastro-oesophageal reflux disease, gastrointestinal pain, gingival bleeding, gingival pain, hiatus hernia,  
irritable bowel syndrome, oral mucosal petechiae, salivary hypersecretion, tongue coated, tongue discolouration,  
faecal impaction.  
Hepatobiliary disorder (see WARNINGS AND SPECIAL PRECAUTIONS):  
Less frequent: hepatitis, hepatic haemorrhage, hypoproteinaemia, hyperbilirubinaemia.  
Skin and subcutaneous tissue disorders:  
Initial………KB……  
JAN 2023 (esub-vrr-0002)  
Page 23 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Frequent: rash, periorbital oedema, urticaria, rash pruritic, pruritus, erythema, sweating increased, dry skin,  
eczema.  
Less frequent: vasculitis rash (including leukocytoclastic vasculitis), rash erythematous, photosensitivity reaction,  
contusion, pruritus generalised, rash macular, rash popular, psoriasis, rash generalized, eyelid oedema, face  
oedema, dermatitis, alopecia, nail disorder, skin discolouration, dermatitis, atopic, hair texture abnormal, heat  
rash, night sweats, pressure sore, ichthyosis, skin nodule.  
Musculoskeletal tissue disorders:  
Frequent: myalgia, muscle weakness, musculoskeletal pain, pain in limb, muscle cramps, arthralgia, bone pain,  
back pain, peripheral swelling.  
Less frequent: muscle spasms, muscle twitching or sensation of heaviness, muscle stiffness, joint swelling, joint  
stiffness, buttock pain, swelling, pain in jaw.  
Renal and urinary disorders:  
Frequent: renal impairment, dysuria, renal failure acute, renal failure oliguria, renal colic, haematuria, proteinuria,  
urinary retention, urinary frequency, difficulty in micturition, loin pain, urinary incontinence, micturition urgency.  
Reproductive system and breast disorders:  
Less frequent: testicular pain, erectile dysfunction.  
General disorders and administration site disorders:  
Frequent: fatigue, pyrexia, asthenia, weakness, lethargy, rigors, malaise, influenza like illness, oedema  
peripheral, chest pain, pain, oedema.  
Less frequent: fall, mucosal haemorrhage, mucosal inflammation, neuralgia, injection site phlebitis, extravasation  
inflammation tenderness, injection site erythema, feeling cold, chest pressure sensation, chest discomfort, groin  
pain, chest tightness.  
Initial………KB……  
JAN 2023 (esub-vrr-0002)  
Page 24 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
Investigations:  
Frequent: weight decreased, blood lactate dehydrogenase increased.  
Less frequent: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin  
increased, blood alkaline phosphate increased, blood creatinine increased, blood urea increased, gamma-  
glutamyltransferase increased, blood amylase increased, liver function tests abnormal, red blood cell count  
decreased, white blood cell count decreased, blood bicarbonate decreased, heart rate irregular, C-reactive  
protein decreased, blood phosphate decreased, weight increased.  
Injury, poisoning and procedural complications:  
Less frequent: catheter related complications, post procedural pain, post procedural haemorrhage, burns.  
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS  
TREATMENT:  
Overdosage is associated with acute onset of the symptomatic hypotension and patient subsequently died.  
Treatment: It is recommended that in the events of overdosage, patients should undergo careful haemodynamic  
monitoring and hypotension should be treated aggressively with intravenous hydration and other clinically  
appropriate measures.  
IDENTIFICATION:  
Lyophilised powder for solution for injection. White to off-white cake or powder.  
PRESENTATION:  
BORTIV is supplied as a single use 10 ml clear, colourless glass vial with a grey bromo-butyl rubber stopper and  
a rust coloured flip off seal cap. The 10 ml vial contains white to off white cake or powder containing 3,5 mg of  
bortezomib. Each vial placed into an outer carton together with a package insert.  
Initial………KB……  
JAN 2023 (esub-vrr-0002)  
Page 25 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
STORAGE INSTRUCTIONS:  
Store at or below 25 °C, in a dry place, well closed in original container, protected from light and moisture.  
KEEP OUT OF REACH OF CHILDREN.  
Reconstituted solution:  
From a microbiological point of few, the product should be used immediately. If not used immediately, in-use  
storage times and conditions prior to use are the responsibility of the user and would normally not be longer than  
24 hours at 2 to 8°C unless reconstitution, dilution (etc.) has taken place in controlled and validated aseptic  
conditions. Chemical and physical in use stability after reconstituted has been demonstrated for 8 hours at 25 °C  
and for up to 30 days at 2 to 8 °C protected from light in the original vial and / or in a syringe, prior to administration,  
with a maximum of 8 hours in the syringe.  
Discard unused portion after dosing.  
REGISTRATION NUMBER:  
51/26/0054  
NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall corporate campus,  
Building no. 2, first floor,  
74 waterfall drive,  
Midrand 2066.  
DATE OF PUBLICATION OF THIS PACKAGE INSERT:  
Initial………KB……  
JAN 2023 (esub-vrr-0002)  
Page 26 of 27  
Applicant/PHRC: Hetero Drugs SA  
Product proprietary name: BORTIV  
Dosage form and strength: Lyophilized powder for solution for injection.  
Each 10 ml glass vial contains 3,5 mg of bortezomib as a sterile lyophilised powder.  
06 May 2022  
Initial………KB……  
JAN 2023 (esub-vrr-0002)  
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