Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

PROFESSIONAL INFORMATION FOR CABXEL 60 mg/1,5 ml INJ

SCHEDULING STATUS

S4

1. NAME OF THE MEDICINE

CABXEL 60 mg/1,5 ml INJ, Concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 60 mg cabazitaxel in 1,5 ml. After initial dilution with the entire solvent, each ml of solution

contains 10 mg cabazitaxel.

Excipient with known effect:

CABXEL 60 mg/1,5 ml INJ is sugar free.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion is a clear yellow to brownish yellow viscous solution and diluent (solvent)

is a clear colourless solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

CABXEL 60 mg/1,5 ml INJ in combination with prednisone or prednisolone is indicated for the treatment of

patients with hormone refractory metastatic prostate cancer previously treated with a docetaxel containing

regimen.

Each diluent (solvent) vial contains: Ethanol 96 % (573,3 mg), water for injection.

4.2 Posology and method of administration

Posology

General

Initial___K.B____

14 June 2023

Page 1 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

The use of CABXEL 60 mg/1,5 ml INJ should be confined to units specialised in the administration of

cytotoxics and it should be administered under the supervision of a medical practitioner qualified in the use

of anticancer chemotherapy.

Premedication:

Premedicate prior to each administration of CABXEL 60 mg/1,5 ml INJ with the following intravenous

medications to reduce the incidence and severity of a hypersensitivity reaction:

•

antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent),

corticosteroid (dexamethasone 8 mg or equivalent) and with

H2 antagonist (ranitidine or equivalent) (see section 4.4).

Antiemetics prophylaxis is recommended and can be given orally or intravenously as needed.

Dosage:

The recommended dose of CABXEL 60 mg/1,5 ml INJ is 25 mg/m²administered as a 1-hour intravenous

infusion every 3 weeks in combination with oral prednisone (or prednisolone) 10 mg administered daily

throughout CABXEL 60 mg/1,5 ml INJ treatment.

Dosage adjustments:

Dosage modifications should be made if patients experience the following adverse reactions.

Recommended Dosage Modifications for adverse reaction in patients treated with CABXEL 60 mg/1,5 ml

INJ

Adverse reactions

Prolonged grade ≥ 3 neutropenia Delay treatment until neutrophil count is > 1 500

(greater than

week) despite cells/mm³, then reduce dosage of CABXEL 60 mg/1,5 ml

Dosage Modification

1

appropriately medication including G- INJ from 25 mg/m²to 20 mg/m².

CSF

Febrile neutropenia

Delay treatment until improvement or resolution, and until

neutrophil count is > 1 500 cells/mm³, then reduce

Initial___K.B____

14 June 2023

Page 2 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

dosage of CABXEL 60 mg/1,5 ml INJ from 25 mg/m²to

20 mg/m².

Grade ≥ 3 diarrhoea or persisting Delay treatment until improvement or resolution, then

diarrhoea

despite

appropriate reduce dosage of CABXEL 60 mg/1,5 ml INJ from 25

medication, fluid and electrolytes mg/m²to 20 mg/m².

replacement

Discontinue CABXEL 60 mg/1,5 ml INJ treatment if a patient continues to experience any of these reactions

at 20 mg/m².

Special populations

The elderly ≥ 65 years:

No specific dose adjustment for the use of CABXEL 60 mg/1,5 ml INJ in senior adult patients is

recommended (see sections 4.4, 4.8 and 5)

Patients with hepatic impairment:

CABXEL 60 mg/1,5 ml INJ is extensively metabolised by the liver. No formal studies were conducted in

patients with severe hepatic impairment. As a precautionary measure, CABXEL 60 mg/1,5 ml INJ should

not be given to patients

with hepatic impairment [bilirubin ≥ 1 x Upper Limit of Normal (ULN), or AST/SGOT and/or ALT/SGPT ≥ 1,5

x ULN] (see sections 4.3, 4.4 and 5).

Patients with renal impairment:

CABXEL 60 mg/1,5 ml INJ is minimally excreted through the kidney. No dose adjustment is necessary in

patients with mild renal impairment (creatinine clearance (CL_CR): 50 to 80 ml/min). Data in patients with

moderate (CL_CR: 30 to 50 ml/min) and severe renal impairment (CL_CR< 30 ml/min) is limited; therefore these

patients should be treated with caution and monitored carefully during treatment (see section 5).

Dose delay or reduction should be considered in the event of adverse effects.

Initial___K.B____

14 June 2023

Page 3 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

Paediatric population

The safety and the efficacy of CABXEL 60 mg/1,5 ml INJ in children have not been established.

Method of administration

Intravenous infusion.

Use an in-line filter of 0,22 micrometre nominal pore size during administration.

4.3 Contraindications

•

Known hypersensitivity to cabazitaxel or other medicines formulated with polysorbate 80 or to any

of the excipients of CABXEL 60 mg/1,5 ml INJ (see section 6.1).

Neutrophil counts ≤ 1 500/mm³.

•

Hepatic impairment (bilirubin ≥ 1 x ULN, or AST/SGOT and/or ALT/SGPT ≥ 1,5 x ULN).

Concomitant vaccination with yellow fever vaccine

4.4 Special warnings and precautions for use

Neutropenia

Neutropenia is the most common adverse reaction of CABXEL 60 mg/1,5 ml INJ (see section 4.8). The use

of G-CSF has been shown to limit the incidence and severity of neutropenia and its complications. Monitoring

of complete blood count is essential on a weekly basis during cycle 1 and before each treatment cycle

thereafter so that the dose can be adjusted, if needed (see section 4.2).

Reduce dose in case of febrile neutropenia, or prolonged neutropenia despite appropriate treatment (see

section 4.2).

Retreat only when neutrophils recover to a level > 1 500/mm³(see section 4.3).

Hypersensitivity reactions

All patients should be premedicated prior to the initiation of the infusion of CABXEL 60 mg/1,5 ml INJ (see

section 4.2).

Patients should be observed closely for hypersensitivity reactions. Hypersensitivity reactions may occur

within a few minutes following the initiation of the infusion of CABXEL 60 mg/1,5 ml INJ, thus facilities and

equipment for the treatment of hypotension and bronchospasm should be available. Severe reactions can

Initial___K.B____

14 June 2023

Page 4 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

occur and may include generalised rash/erythema, hypotension and bronchospasm. Severe hypersensitivity

reactions require immediate discontinuation of CABXEL 60 mg/1,5 ml INJ and appropriate therapy. Patients

who have a history of severe hypersensitivity reactions should not be rechallenged with CABXEL 60 mg/1,5

ml INJ (see section 4.3).

Gastrointestinal symptoms

If patients experience diarrhoea following administration of CABXEL 60 mg/1,5 ml INJ they may be treated

with commonly used anti-diarrhoeal medications. Appropriate measures should be taken to rehydrate the

patients. Treatment delay or dosage reduction may be necessary for grade ≥ 3 diarrhoea (see section 4.2).

If patients experience nausea or vomiting, they may be treated with commonly used anti-emetics.

Renal disorders

Renal disorders, have been reported in association with sepsis, severe dehydration due to diarrhoea,

vomiting and obstructive uropathy. Renal failure including cases with fatal outcome has been observed.

Appropriate measures should be taken to identify the cause and intensively treat the patients if this occurs.

Bone marrow suppression

Bone marrow suppression manifested as neutropenia, anaemia, thrombocytopenia or pancytopenia may

occur.

Peripheral neuropathy

Cases of peripheral neuropathy, peripheral sensory neuropathy (e.g., paraesthesias, dysaesthesias) and

peripheral motor neuropathy have been observed in patients receiving cabazitaxel. Patients under treatment

with cabazitaxel should be advised to inform their doctor prior to continuing treatment if symptoms of

neuropathy such as pain, burning, tingling, numbness, or weakness develop. Medical practitioners should

assess for the presence or worsening of neuropathy before each treatment. Treatment should be delayed

until improvement of symptoms. The dose of cabazitaxel should be reduced from 25 mg/m²to 20 mg/m²for

persistent grade ≥ 2 peripheral neuropathy (see section 4.2).

Initial___K.B____

14 June 2023

Page 5 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

Anaemia

Anaemia has been observed in patients receiving cabazitaxel (see section 4.8). Haemoglobin and

haematocrit should be checked before treatment with cabazitaxel and if patients exhibit signs or symptoms

of anaemia or blood loss. Caution is recommended in patients with haemoglobin <10 g/dl and appropriate

measures should be taken as clinically indicated.

Respiratory disorders

Interstitial pneumonia/pneumonitis and interstitial lung disease have been reported and may be associated

with fatal outcome (see section 4.8).

If new or worsening pulmonary symptoms develop, patients should be closely monitored, promptly

investigated, and appropriately treated. Interruption of cabazitaxel therapy is recommended until diagnosis is

available. Early use of supportive care measures may help improve the condition. The benefit of resuming

cabazitaxel treatment must be carefully evaluated.

Risk of cardiac dysrhythmias

Cardiac dysrhythmias have been reported, most commonly tachycardia and atrial fibrillation (see section

4.8).

Interactions

Co-administration with strong CYP3A inhibitors should be avoided since they may increase the plasma

concentrations of cabazitaxel (see sections 4.2 and 4.5). If co-administration with a strong CYP3A inhibitor

cannot be avoided, close monitoring for toxicity and a cabazitaxel dose reduction should be considered (see

sections 4.2 and 4.5).

Co-administration with strong CYP3A inducers should be avoided since they may decrease plasma

concentrations of cabazitaxel (see sections 4.2 and 4.5).

Elderly patients ≥ 65 years

Senior adult patients (≥ 65 years of age) may be more likely to experience certain adverse reactions including

neutropenia (see section 4.8).

Initial___K.B____

14 June 2023

Page 6 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

Patients with liver impairment

Treatment with CABXEL 60 mg/1,5 ml INJ is contraindicated (see sections 4.2 and 4.3).

Excipients:

The solvent contains 573.3 mg ethanol 96% (15% v/v),

Harmful for those suffering from alcoholism.

To be taken into account in high-risk groups such as patients with liver disease, or epilepsy.

4.5 Interaction with other medicine and other forms of interaction

No formal clinical studies to assess the potential interaction between CABXEL 60 mg/1,5 ml INJ and other

medicines have been performed.

In vitro studies have shown that CABXEL 60 mg/1,5 ml INJ is mainly metabolised through CYP3A (80 % to

90 %) and inhibits CYP3A.

The metabolism of CABXEL 60 mg/1,5 ml INJ may be modified by the concomitant administration of

compounds which are known to be potent inhibitors (e.g., ketoconazole) or inducers (e.g., rifampicin,

carbamazepine, phenobarbital or phenytoin) of CYP3A.

Coadministration of CABXEL 60 mg/1,5 ml INJ with medicines that are known to be primarily metabolised

through CYP3A may increase the exposure of these medicines.

Therefore, caution should be exercised in patients concurrently taking medicines known to be either primarily

metabolised through CYP3A or to be potent inhibitors or inducers of this enzyme (see section 5.2).

Prednisone/prednisolone administered at 10 mg daily did not affect the pharmacokinetics of CABXEL 60

mg/1,5 ml INJ.

OATP1B1

In vitro, cabazitaxel has also been shown to inhibit the transport proteins of the Organic Anion Transport

Polypeptides OATP1B1. The risk of interaction with OATP1B1 substrates (e.g. statins, valsartan, repaglinide)

is possible, notably during the infusion duration (1 hour) and up to 20 minutes after the end of the infusion. A

time interval of 12 hours is recommended before the infusion and at least 3 hours after the end of infusion

before administering the OATP1B1 substrates.

Initial___K.B____

14 June 2023

Page 7 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

Vaccinations

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic

medicines may result in serious or fatal infections. Vaccination with a live attenuated vaccine should be

avoided in patients receiving cabazitaxel. Killed or inactivated vaccines may be administered; however, the

response to such vaccines may be diminished.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential and female/male contraception

CABXEL 60 mg/1,5 ml INJ is not recommended for use in women of childbearing potential not using

contraception.

Due to potential exposure via seminal liquid, men with partners of childbearing potential should use reliable

contraception throughout treatment and are recommended to continue this for up to 3 months after the last

dose of CABXEL 60 mg/1,5 ml INJ.

Pregnancy

There are no data from the use of CABXEL 60 mg/1,5 ml INJ in pregnant women. Studies in animals have

shown reproductive toxicity and that CABXEL 60 mg/1,5 ml INJ crosses the placenta barrier. CABXEL 60

mg/1,5 ml INJ is not recommended for use during pregnancy.

Breastfeeding

Available pharmacokinetics data in animals have shown excretion of CABXEL 60 mg/1,5 ml INJ and its

metabolites in milk. CABXEL 60 mg/1,5 ml INJ should not be used during breastfeeding.

Fertility

The effect of CABXEL 60 mg/1,5 ml INJ on human fertility is unknown. Animal studies showed that CABXEL

60 mg/1,5 ml INJ affected the reproductive system in male rats and dogs.

Initial___K.B____

14 June 2023

Page 8 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, based on

the safety profile, CABXEL 60 mg/1,5 ml INJ may have moderate influence on the ability to drive and use

machines as it may cause fatigue and dizziness. Patients should be advised to not drive or use machines if

they experience these adverse reactions during treatment.

4.8 Undesirable effects

a) Summary of the safety profile

The safety of CABXEL 60 mg/1,5 ml INJ in combination with prednisone or prednisolone was evaluated in

371 patients with hormone refractory metastatic prostate cancer, in a randomised open label, controlled

phase III study. Patients received a median duration of 6 cycles of CABXEL 60 mg/1,5 ml INJ.

The most frequent Grade ≥ 3 adverse reactions in the cabazitaxel group were clinical neutropenia, febrile

neutropenia, diarrhoea, fatigue, and asthenia.

Discontinuation of treatment due to adverse drug reactions occurred in 68 patients in the CABXEL 60 mg/1,5

ml INJ group and 31 patients in the mitoxantrone group. The most frequent adverse reaction leading to

treatment discontinuation in the CABXEL 60 mg/1,5 ml INJ group was neutropenia.

b) Tabulated list of adverse reactions

CABXEL 60 mg/1,5 ml INJ in combination with prednisone or prednisolone

Infections and infestations

Frequent: Urinary tract infection, Septic shock, Sepsis, Cellulitis, Influenza, Cystitis, Upper respiratory tract

infection, Herpes zoster, Candidiasis

Blood and lymphatic system disorders

Frequent: Neutropenia, anaemia, leukopenia, thrombocytopenia, febrile neutropenia

Initial___K.B____

14 June 2023

Page 9 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

Immune system disorders

Frequent: Hypersensitivity

Metabolism and nutrition disorders

Frequent: Anorexia, dehydration, Hyperglycaemia, Hypokalemia

Psychiatric disorders

Frequent: Anxiety, Confusional state

Nervous system disorders

Frequent: Dysgeusia, neuropathy peripheral, dizziness, headache, peripheral sensory neuropathy,

Paraesthesia, Lethargy, Hypoaesthesia, Sciatica.

Eye disorders

Frequent: Conjunctivitis, Lacrimation increased.

Ear and labyrinth disorders

Frequent: Tinnitus, Vertigo.

Cardiac disorders

Frequent: Atrial fibrillation, Tachycardia.

Vascular disorders

Frequent: Hypotension, Deep vein thrombosis, Hypertension, Orthostatic hypotension, Hot flush, Flushing.

Respiratory, thoracic and mediastinal disorders

Frequent: Dyspnoea, cough, Oropharyngeal pain, Pneumonia.

Initial___K.B____

14 June 2023

Page 10 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

Gastrointestinal disorders

Frequent: Diarrhoea, nausea, vomiting, constipation, abdominal pain, dyspepsia, upper abdominal pain,

haemorrhoids, gastro-oesophageal reflux disease, Rectal haemorrhage, Dry mouth, Abdominal distension.

Skin and subcutaneous tissue disorders

Frequent: Alopecia, Dry skin, Erythema.

Musculoskeletal and connective tissue disorders

Frequent: Back pain, arthralgia, muscle spasms, Pain in extremity, Myalgia, Musculoskeletal chest pain,

Flank pain.

Renal and urinary disorders

Frequent: Haematuria, dysuria, urinary incontinence, acute renal failure, Renal failure, Renal colic,

Pollakiuria, Hydronephrosis, Urinary retention, Urinary incontinence, Ureteric obstruction.

Reproductive system and breast disorders

Frequent: Pelvic pain.

General disorders and administration site conditions

Frequent: Fatigue, asthenia, pyrexia, peripheral oedema, mucosal inflammation, Pain, Chest pain, Oedema,

Chills, Malaise.

Investigations

Frequent: Weight decreased, Aspartate aminotransferase increased, Transaminases

Increased

Reporting of suspected adverse reactions

Initial___K.B____

14 June 2023

Page 11 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued

monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any

suspected adverse reactions via the “6.04 Adverse Drug Reactions Reporting Form”, found online under

SAHPRA’s publications: https://www.sahpra.org.za or to the Holder of certificate of registration through the

mail: pvg.cdma@heterogroups.com

4.9 Overdose

The anticipated complications of overdose would be exacerbation of adverse reactions as bone marrow

suppression and gastrointestinal disorders.

There is no known antidote to CABXEL 60 mg/1,5 ml INJ. In case of overdose, the patient should be kept in

a specialised unit and closely monitored. Patients should receive therapeutic G-CSF as soon as possible

after discovery of overdose. Other appropriate symptomatic measures should be taken.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Category and Class: A 26 Cytostatic Agents

Pharmacotherapeutic group: Antineoplastic agents, taxanes, ATC code: L01CD04.

Cabazitaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells. Cabazitaxel

binds to tubulin and promotes the assembly of tubulin into microtubules while simultaneously inhibiting their

disassembly. This leads to the stabilisation of microtubules, which results in the inhibition of mitotic and

interphase cellular functions.

5.2 Pharmacokinetic properties

Absorption:

After a 1-hour IV administration dose of cabazitaxel at 25 mg/m², in patients with metastatic prostate cancer

the mean C_maxwas 226 ng/ml (coefficient of variation, CV 107 %) and was reached at the end of the 1-hour

infusion (T_max). The mean AUC was 991 ng.h/ml (CV: 34 %).

Initial___K.B____

14 June 2023

Page 12 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

No major deviation to the dose proportionality was observed from 10 to 30 mg/m²in patients with advanced

solid tumours.

Distribution

The volume of distribution (Vss) was 4 870 l (2 640 l/m²for a patient with a median BSA of 1,84 m²) at steady

state.

In vitro, the binding of cabazitaxel to human serum proteins was 89 to 92 % and was not saturable up to 50

000 ng/ml, which covers the maximum concentration observed in clinical studies. Cabazitaxel is mainly bound

to human serum albumin (82,1 %) and lipoproteins (87,9 % for HDL, 69,8 % for LDL, and 55,8 % for VLDL).

The in vitro blood-to-plasma concentration ratios in human blood ranged from 0,90 to 0,99 indicating that

cabazitaxel was equally distributed between blood and plasma.

Biotransformation

Cabazitaxel is extensively metabolised in the liver (≥ 95 %), mainly by the CYP3A4 isoenzyme (80 to 90 %).

Cabazitaxel is the main circulating compound in human plasma. Seven metabolites were detected in plasma

(including 3 active metabolites issued from O-demethylation), with the main one accounting for 5 % of parent

exposure. Around 20 metabolites of cabazitaxel are excreted into human urine and faeces.

Based on in vitro data, the potential risk of inhibition by cabazitaxel at clinically relevant concentrations is

possible for medicines that are mainly substrate of CYP3A. However, there is no potential risk of inhibition of

medicines that are substrates of other CYP enzymes (1A2, 2B6, 2C9, 2C8, 2C19, 2E1, and 2D6) as well as

no potential risk of induction by cabazitaxel on medicines that are substrates of CYP1A, CYP2C9, and

CYP3A.

Elimination

After a 1-hour IV infusion [¹⁴C]-cabazitaxel at 25 mg/m²in patients, approximately 80 % of the administered

dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the faeces as numerous metabolites

(76 % of the dose); while renal excretion of cabazitaxel and metabolites account for less than 4 % of the dose

(2,3 % as unchanged medicine in urine).

Initial___K.B____

14 June 2023

Page 13 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

Cabazitaxel had a high plasma clearance of 48,5 l/h (26,4 l/h/m²for a patient with a median BSA of 1,84 m²)

and a long terminal half-life of 95 hours.

Characteristics in specific groups of patients

The elderly ≥ 65 years:

In the population pharmacokinetic analysis in 70 patients of 65 years and older (57 from 65 to 75 and 13

patients above 75), no age effect on the pharmacokinetics of cabazitaxel was observed.

Hepatic impairment:

No formal studies in patients with hepatic impairment have been conducted.

Renal impairment:

Cabazitaxel is minimally excreted via the kidney (2,3 % of the dose). No formal pharmacokinetic studies were

conducted with cabazitaxel in patients with renal impairment. However, the population pharmacokinetic

analysis carried out in 170 patients that included 14 patients with moderate renal impairment (creatinine

clearance in the range of 30 to 50 ml/min) and 59 patients with mild renal impairment (creatinine clearance

in the range of 50 to 80 ml/min) showed that mild to moderate renal impairment did not have meaningful

effects on the pharmacokinetics of cabazitaxel.

Paediatric patients:

Safety and effectiveness of cabazitaxel have not been established in children.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Concentrate for solution for infusion:

•

Nitrogen

Polysorbate 80

Diluent (solvent):

Ethanol

Initial___K.B____

•

14 June 2023

Page 14 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

•

Nitrogen

Water for injection

6.2 Incompatibilities

This medicine must not be mixed with other medicines except those mentioned in section 6.6.

Do not use PVC infusion containers and polyurethane infusion sets for the preparation and administration of

CABXEL 60 mg/1,5 ml INJ.

6.3 Shelf life

24 months.

After opening:

Concentrate and solvent vials must be used immediately. If not used immediately, in-use storage times and

conditions are the responsibility of the user.

After initial dilution:

Chemical and physical in-use stability for the resulting concentrate-solvent mixture has been demonstrated

for one hour at ambient temperature. From a microbiological point of view, the concentrate-solvent mixture

should be used immediately.

After final dilution:

Chemical and physical stability of the infusion solution has been demonstrated for 8 hours at ambient

temperature (including the 1-hour infusion time) and for 48 hours under refrigerated conditions. From a

microbiological point of view, the infusion solution should be used immediately. If not used immediately, in-

use storage times and conditions are the responsibility of the user and would normally not be longer than 24

hours at 2 °C to 8 °C unless dilution has taken place in controlled and validated aseptic conditions.

As the infusion solution is supersaturated, it may crystallise over time. In this case, the solution must not be

used and should be discarded.

Initial___K.B____

14 June 2023

Page 15 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

6.4 Special precautions for storage

•

Store at or below 25 °C.

Do not refrigerate.

Keep the vials in the outer carton until required for use.

6.5 Nature and contents of container

Concentrate for solution for infusion: 1,5 ml (deliverable volume) of CABXEL 60 mg/1,5 ml INJ

concentrate for solution for infusion in a 15 ml type-I, round clear tubular glass vial with 20 mm serum rubber

GCB stopper with flurotec coating and 20 mm purple colour flip off aluminium seal.

Diluent (solvent): 4,5 ml (deliverable volume) of solvent in a 15 ml type-I, round clear tubular glass vial with

20 mm serum rubber GCB stopper with flurotec coating and 20 mm white colour flip off aluminium seal.

Pack size: 1 vial of concentrate for solution for infusion and 1 vial of diluent (solvent) together are packed in

an outer carton.

6.6 Special precautions for disposal and other handling

Caution should be exercised when handling and preparing CABXEL 60 mg/1,5 ml INJ solutions. The use of

gloves is recommended.

If CABXEL 60 mg/1,5 ml INJ, at any step of its handling, should come into contact with the skin, wash

immediately and thoroughly with soap and water. If it should come into contact with mucous membranes,

wash immediately and thoroughly with water.

CABXEL 60 mg/1,5 ml INJ should only be prepared and administered by personnel trained in handling

cytotoxic agents. Pregnant staff should not handle it.

Any unused product or waste material should be disposed of in accordance with local requirements.

The following 2-step dilution process must be carried out in an aseptic manner for preparing the solution for

infusion:

Step 1: Initial dilution of CABXEL 60 mg/1,5 ml INJ 60 mg/1,5 ml concentrate for solution for infusion

with the supplied solvent.

•

Set aside the CABXEL 60 mg/1,5 ml INJ 60 mg/1,5 ml concentrate vial and the supplied solvent.

The concentrate solution should be clear if appropriately stored (see section 6.4).

Initial___K.B____

14 June 2023

Page 16 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

•

Withdraw the entire content of the supplied solvent using a syringe, by partially inverting the vial,

and inject it into the corresponding vial of CABXEL 60 mg/1,5 ml INJ 60 mg/1,5 ml concentrate. To

limit as much as possible foaming when injecting the solvent, direct the needle onto the inside wall

of the vial of concentrate solution and inject slowly.

•

Remove the syringe and needle and mix manually and gently by repeated inversions until obtaining

clear and homogeneous solution. It could take approximately 45 seconds.

Let stand this solution for few minutes (approximately 5 minutes) and check then that the solution is

homogeneous and clear. It is normal for foam to persist after this time period.

This resulting concentrate-solvent mixture contains 10 mg/ml of cabazitaxel (at least 6 ml deliverable volume).

It should be immediately diluted as detailed in step 2.

Step 2: Preparation of the infusion solution.

•

Withdraw the required amount of initial diluted CABXEL 60 mg/1,5 ml INJ solution (10 mg/ml of

cabazitaxel), with a graduated syringe and inject in a sterile PVC-free container of either 5 % glucose

solution or 0,9 % sodium chloride solution for infusion. The concentration of the infusion solution

should be between 0,10 mg/ml and 0,26 mg/ml.

As an example, a dose of 45 mg CABXEL 60 mg/1,5 ml INJ would require 4,5 ml of the concentrate-solvent

mixture prepared following step 1. More than one vial of the initial diluted solution may be necessary to

administer the prescribed dose.

•

Since foam may persist on the wall of the vial of this solution, following its preparation described in

step 1, it is preferable to place the needle of the syringe in the middle when extracting.

Remove the syringe and mix the content of the infusion bag or bottle manually using a rocking

motion.

As with all parenteral products, the resulting infusion solution should be visually inspected prior to

use. Solution containing a precipitate should be discarded.

The CABXEL 60 mg/1,5 ml INJ infusion solution should be used immediately.

7 HOLDER OF CERTIFICATE OF REGISTRATION

Initial___K.B____

14 June 2023

Page 17 of 18

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: CABXEL 60 mg/1,5 ml INJ

Dosage form and strength: Concentrate for Solution for infusion and 60 mg/1,5 ml

Hetero Drugs South Africa (Pty) Ltd

Waterfall Corporate Campus

Building No. 2, First floor

74 Waterfall Drive

Midrand

2066

8 REGISTRATION NUMBER(S)

56/26/0827

9 DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

27 June 2023

10 DATE OF REVISION OF THE TEXT

27 June 2023

Initial___K.B____

14 June 2023

Page 18 of 18